Vol. 65 ■ Suppl.

1 ■ May 2024

JNM
The Journal of Nuclear Medicine

Advancing Global Nuclear Medicine: The Role and Future Contributions of China
Guest Editors: Wolfgang Weber, MD, PhD, Ken Herrmann, MD, MBA, Haojun Chen, MD, PhD, Kuangyu Shi, PhD, and Weibo Cai, PhD
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Volume 65 ! Supplement 1 ! May 2024
1S Advancing Global Nuclear Medicine: The Role and
Future Contributions of China
Haojun Chen, Kuangyu Shi, Weibo Cai, Sijin Li, and Jing Wang
Chen and colleagues introduce this JNM supplement, a
timely overview of the current status of nuclear medicine in
China, highlighting significant advances in research and
development, as well as clinical translation of novel
radiopharmaceuticals.
4S Fibroblast Activation Protein Inhibitor Tracers and
Their Preclinical, Translational, and Clinical Status in
China
Liang Zhao, Fei Kang, Yizhen Pang, Jianyang Fang, Long Sun,
Hua Wu, XiaoLi Lan, Jing Wang, and Haojun Chen
Zhao and colleagues offer an in-depth review of the evolution and
use of FAP tracers in China, from preclinical to clinical research,
including the expanding potential of FAP-targeted radionuclide
therapy.
12S Translational PET Imaging of Nectin-4 Expression in
Multiple Different Cancers with 68Ga-N188
Jianhua Zhang, Xiaojiang Duan, Xueqi Chen,
Zhuochen Zhang, Hongwei Sun, Jiayin Shou, Guangyu Zhao,
Jianxin Wang, Yongsu Ma, Yinmo Yang, et al.
Zhang and colleagues report on the feasibility of nectin-4–targeted
PET imaging as a noninvasive method to quantify membranous
nectin-4 expression in various tumor types—an approach with
promise for patient stratification and treatment selection.
19S Melanin-Targeting Radiotracers and Their
Preclinical, Translational, and Clinical Status: From
Past to Future
Xiao Zhang, Zhaoguo Lin, Yuan Feng, Fei Kang,
Jing Wang, and Xiaoli Lan
Zhang and colleagues describe the features of melanin-targeted
radiolabeled molecules as detailed in preclinical studies, clinical
trials, and patient practice, with additional discussion of novel
applications.
29S Landscape of Nuclear Medicine in China and Its
Progress on Theranostics
Weidong Yang, Fei Kang, Yue Chen, Zhaohui Zhu, Feng Wang,
Chunxia Qin, Jin Du, Xiaoli Lan, and Jing Wang
Yang and colleagues review historic milestones and current status
of nuclear medicine in China, including radioisotope production,
radiopharmaceutical development, advanced instrumentation, and
theranostic research.
38S Recent Advances in Radiotracers Targeting Novel
Cancer-Specific Biomarkers in China: A Brief
Overview
Jingming Zhang, Fei Kang, Xiao Wang, Xuejiao Chen,
Xing Yang, Zhi Yang, and Jing Wang
Zhang and colleagues review the exploration of novel imaging
targets, preclinical evaluation of targeting ligands, and associated
translational research in China from 2020 to 2023.
46S The Role of Total-Body PET in Drug Development
and Evaluation: Status and Outlook
Xiangxi Meng, Xiangxing Kong, Lei Xia, Runze Wu, Hua Zhu,
and Zhi Yang
Meng and colleagues look at advances in total-body PET imaging
and the impact of its introduction on drug development, novel
tracers, and new clinical opportunities.
54S Advantages and Challenges of Total-Body PET/CT at
a Tertiary Cancer Center: Insights from Sun Yat-sen
University Cancer Center
Wanqi Chen, Yinghe Li, Zhijian Li, Yongluo Jiang, Yingpu Cui,
Jiling Zeng, Yiwen Mo, Si Tang, Shatong Li, Lei Liu, et al.
Chen and colleagues document clinical experience with total-body
PET at their institution, including diseases treated, patient selection,
workflow, scanning protocols, and enhanced applications.
64S Clinical Implementation of Total-Body PET in China
Yaping Wu, Tao Sun, Yee Ling Ng, Jianjun Liu, Xiaohua Zhu,
Zhaoping Cheng, Baixuan Xu, Nan Meng, Yun Zhou,
and Meiyun Wang
Wu and colleagues assess the use of total-body PET in China for
both oncologic and nononcologic indications, highlighting recent
technologic innovations and challenges to widespread clinical
integration.
72S Pathway to Approval of Innovative
Radiopharmaceuticals in China
Shuxian An, Lu Wang, Fang Xie, Dawei Jiang, Gang Huang,
Jianjun Liu, Xiaowei Ma, Weijun Wei
An and colleagues provide an overview of the approval process for
novel radiopharmaceuticals by China’s National Medical Products
Administration and the status of radiolabeled agents in research
and development.
GUEST EDITORS
Wolfgang Weber, MD, PhD
Technical University of Munich
Munich, Germany
Ken Herrmann, MD, MBA
Universit€atsklinikum Essen
Essen, Germany
Haojun Chen, MD, PhD
The First Affiliated Hospital of Xiamen University
Xiamen, China
Kuangyu Shi, PhD
University of Bern
Bern, Switzerland
Weibo Cai, PhD
University of Wisconsin
Madison, Wisconsin
Editor-in-Chief
Johannes Czernin, MD
David Geffen School of Medicine at UCLA
Los Angeles, California
Opinions expressed in the contributions to this supplement are solely
those of the authors and do not necessarily reflect those of The Journal
of Nuclear Medicine or the Society of Nuclear Medicine and Molecular
Imaging. The journal, however, invites and welcomes different opinions
in order to initiate and stimulate discussion.
Publications Committee
Todd E. Peterson, PhD, FSNMMI
Chair
Carolyn J. Anderson, PhD, FSMMMI
Paige B. Bennett, MD
Joyita Dutta, PhD
Michael M. Graham, MD, PhD, FACR,
FSNMMI
Hossein Jadvar, MD, PhD, MPH, MBA,
MSL, FACNM, FSNMMI
Steven M. Larson, MD, FACNM
Ashwin Singh Parihar, MBBS, MD
Heinrich R. Schelbert, MD, PhD, FSNMMI
Heiko Schöder, MD, MBA, FSNMMI
David M. Schuster, MD
Ex officio
Johannes Czernin, MD, FSNMMI
Arnold M. Strashun, MD, FSNMMI
Associate Director of Communications
Susan Alexander
Senior Copyeditor
Susan Nath
Senior Publications & Marketing Service
Manager
Steven Klein
Editorial Production Manager
Amy Turner
Editorial Project Manager
Mark Sumimoto
Director of Communications
Rebecca Maxey
CEO
Virginia Pappas
MISSION STATEMENT: The Journal of Nuclear Medicine advances the knowledge and
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Advancing Global Nuclear Medicine: The Role and Future
Contributions of China
Haojun Chen1, Kuangyu Shi2, Weibo Cai3, Sijin Li4, and Jing Wang5
1
Department of Nuclear Medicine and Minnan PET Center, Xiamen Key Laboratory of Radiopharmaceuticals, First Affiliated Hospital
of Xiamen University, School of Medicine, Xiamen University, Xiamen, China; 2Department of Nuclear Medicine, University of Bern,
Bern, Switzerland; 3Departments of Radiology and Medical Physics, University of Wisconsin–Madison, Madison, Wisconsin;
4
Department of Nuclear Medicine, First Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, China; and
5
Department of Nuclear Medicine, Xijing Hospital, Fourth Military Medical University, Xi’an, China
N uclear medicine in China has experienced a significant evo-
lution in both research and clinical applications (1). The field was
inaugurated in 1956 with the first isotope use training course in
Xi’an, Shaanxi Province, marking the advent of nuclear medicine
in the country, and since then, nuclear medicine has begun its inte-
gration into clinical practice, serving patients across the nation.
However, the subsequent two decades presented challenges due to
several devastating events, impacting both researchers and the
general population, until the 1980s brought a pivotal shift in
China’s reform and opening-up policies. During this period, the
Chinese Society of Nuclear Medicine, a branch of the Chinese
Medical Association, was established in 1980, and the Chinese
Journal of Nuclear Medicine was launched in 1981 (2). These
developments signified the resurgence of nuclear medicine in
China, setting it on a path of slow yet steady progress.
The advancement of nuclear medicine and molecular imaging
in China has been characterized by significant technologic mile-
stones and strategic initiatives (2). The installation of the first
SPECT system in 1983 marked the beginning of this era. This was
followed by the introduction of the first PET system and medical
cyclotron in 1995, the first small-animal PET system in 2000, and
the first PET/CT system in 2002. The period from 2000 to 2010
was characterized by learning, accumulation, and significant
investment, laying the groundwork for rapid expansion in the sub-
sequent decade. This fast-track phase was highlighted by the
installation of the first PET/MRI system in 2012, the launch of the
“one nuclear medicine department per county” initiative in 2016,
which aimed at improving access to nuclear medicine services
nationwide, and the introduction of the first total-body PET/CT
system in 2019 (3).
As of now, the National Medical Products Administration in
China has approved over 40 radiopharmaceuticals for commercial
use (4), which include 18F, 99mTc, 131I, 125I, 153Sm, and 32P.
Among these, 23 are 99mTc-labeled radiopharmaceuticals along
with their associated kits, one is 18F-FDG, and 9 are therapeutic
radiopharmaceuticals such as [131I]NaI oral solution (or capsules),
Received Apr. 9, 2024; accepted Apr. 9, 2024.
For correspondence or reprints, contact Sijin Li (lisjnm123@163.com) or
Jing Wang (13909245902@163.com).
COPYRIGHT ! 2024 by the Society of Nuclear Medicine and Molecular Imaging.
DOI: 10.2967/jnumed.124.267918
89
SrCl2 injection, and 125I brachytherapy sources (in contrast to
other countries, 125I brachytherapy sources are categorized as
radiopharmaceuticals by regulatory standards in China). In a sig-
nificant effort to move the field forward, in June 2021, 8 state
departments, including the China Atomic Energy Authority, the
Ministry of Science and Technology, and the National Medical
Products Administration, jointly issued a mid- and long-term
development plan (2021–2035) for medical isotopes (5). This stra-
tegic plan outlines key tasks for the development of medical iso-
tope–related industries, particularly radiopharmaceuticals. It aims
to advance the research and development of novel radiopharma-
ceuticals, enhance self-reliance in the production and supply of
medical isotopes, and promote their clinical applications. The plan
stands as a cornerstone, offering a strategic road map to propel the
radiopharmaceutical industry’s advancement in China.
In the last 10 years, remarkable advancements in nuclear medicine
have been made in China. The Chinese Society of Nuclear Medicine
plays a pivotal role in charting this progress through a biennial
national survey (6). However, the 2022 iteration was unfortunately
not conducted because of the coronavirus disease 2019 pandemic, a
decision reflecting the challenges faced globally during this period.
The most recent data, meticulously presented by Yang et al. in this
supplement issue to The Journal of Nuclear Medicine (JNM) (7),
shows there are over 1,000 departments of nuclear medicine, over 400
PET/CT systems, more than 20 PET/MRI systems, more than 300
SPECT systems, approximately 500 SPECT/CT systems, 16 total-
body PET systems, and over 120 cyclotrons in China. This infrastruc-
ture supports nearly 1 million annual PET/CT scans, over 14,000
annual PET/MRI scans, and more than 2.5 million annual SPECT
scans, engaging a workforce of 12,000 nuclear medicine profes-
sionals (Fig. 1 of Yang et al. (7)). With such a vast workforce, state-
of-the-art preclinical and clinical equipment, and increased funding
from various sources for nuclear medicine and molecular imaging
research, we are witnessing the golden era of nuclear medicine and
molecular imaging. It is occurring not only in China but also around
the world. We eagerly anticipate the exciting developments yet to
come in this dynamic field, confident that the future will be bright.
The JNM—self-published by the Society of Nuclear Medicine
and Molecular Imaging—is the top journal for the nuclear medi-
cine and molecular imaging community. JNM offers readers
around the globe clinical and basic science investigations, continu-
ing education articles, state-of-the-art reviews, and updates on
INTRODUCTION ! Chen et al. 1S

FIGURE 1. Number of publications in JNM, number of JNM publications
with Chinese affiliation, and percentage over last 20 years. Data are from
on PubMed search on March 31, 2024. Steady increase is seen in JNM
publications with Chinese affiliations over time, especially during last
5 years.
rapidly changing issues in practice and research. On March 31,
2024, we conducted a PubMed search of “J Nucl Med” [jour]
AND “China” [affiliation], and the results over the last 20 years
are shown in Figure 1. In the first decade of the 21st century, the
number of publications with Chinese affiliations was quite low,
typically ranging from 5 to 7 per year. The first 6 years of the sec-
ond decade witnessed a significant increase in the number of pub-
lications in JNM, reaching 5.6% in 2016 (23/408 publications).
Starting in 2018, the numbers have increased steadily each year,
reaching 6.8% in 2022 (27 of a total of 397 JNM publications).
The past 5 years have represented a rare opportunity for the
development of this JNM special issue—a time during which pub-
lications with Chinese affiliations have increased significantly.
Invited by JNM Editor-in-Chief Johannes Czernin, along with Ken
Herrmann and Wolfgang Weber, senior authors from China’s lead-
ing institutes and hospitals actively contributed manuscripts, all of
which underwent a thorough peer-review process involving at
least 2–3 reviewers per submission. Ten articles are featured in
this supplement issue, comprising 8 review articles, 1 editorial,
and 1 research article.
Beyond the original goal of highlighting the current status of
nuclear medicine in China and its implications for the field’s
future development, this special issue also seeks to capture the
diversity of nuclear medicine and molecular imaging research
within the country. This field intersects various scientific and tech-
nologic disciplines, ensuring a rich representation of current hot
topics, including total-body PET (8–10), fibroblast activation pro-
tein inhibitors (11), nectin-4 (12), melanin-targeting radiotracers
(13), and other innovative radiotracers (14), along with discussions
on their approval pathways in China (15).
Radiopharmaceuticals play a critical role in nuclear medicine,
providing novel tools for specifically delivering radioisotopes for
the diagnosis and treatment of various cancers. As the starting
point for development of radiopharmaceuticals, cancer-specific
biomarkers are important and receive worldwide attention. This
field in China is currently experiencing a rapid expansion; multiple
radiotracers targeting novel targets are being developed and trans-
lated into clinical studies. In this supplement, Zhang et al. (14)
provides a brief overview of the exploration of novel imaging
targets, preclinical evaluation of their targeting ligands, and
translational research in China from 2020 to 2023 for detecting
2S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65 ! No. 5 (Suppl. 1)
cancer, guiding targeted therapy, and visualizing the immune
microenvironment.
Among the novel imaging agents, radiolabeled fibroblast activa-
tion protein inhibitors and melanin-targeting radiotracers have
recently emerged as a focal point in global nuclear medicine,
underscored by their promising applications in cancer theranostics.
In this supplement, Zhao et al. (11) and Zhang et al. (13) offer
an in-depth summary of the existing literature on the evolution
and use of fibroblast activation protein inhibitors and melanin-
targeting tracers in China, tracing their preclinical, translational,
and clinical status and presenting perspectives for broadening their
applications. Some promising findings for fibroblast activation
protein inhibitor radioligand therapy in China have also been
reported in this supplement (Fig. 4 from Zhao et al. (11)). Overall,
Chinese nuclear medicine experts are poised to collaborate with
international peers, ushering in a groundbreaking phase in the
convergence of radionuclide-based cancer diagnosis and therapy.
We expect that through unremitting and collaborative efforts,
these novel radiopharmaceuticals will play a crucial role in
improving and enhancing the quality of human life and health care
worldwide.
Nectin cell adhesion molecule 4 (nectin-4) is another key
molecular target that is overexpressed on a variety of cancers and
plays an important role in oncogenic and metastatic processes.
The nectin-4–targeted antibody–drug conjugate enfortumab vedo-
tin has been approved for treating locally advanced or metastatic
urothelial cancer. Zhang et al. evaluated the feasibility of nectin-
4–targeted PET imaging with 68Ga-N188 as a noninvasive method
to quantify membranous nectin-4 expression in multiple tumor
types (12), which provided an approach that may provide insight
for patient stratification and treatment selection.
Although preclinical development and clinical translation of
radiopharmaceuticals are undergoing rapid evolution in China, the
radiopharmaceutical industry in China is still in a developing
stage, with gaps remaining in several aspects compared with
developed countries. In this issue, An et al. provide an overview
of the process for acquiring National Medical Products Adminis-
tration approval for an innovative radiopharmaceutical in China
and discuss the current status of research and development of
radiopharmaceuticals in China (15). We believe the development
and use of radiopharmaceuticals in China will contribute to the
growth of nuclear medicine worldwide and improve the manage-
ment of human diseases in the era of precision medicine.
In addition to the development of novel radiopharmaceuticals,
another paradigm shift in PET imaging in China is the develop-
ment of total-body PET technologies. The introduction of total-
body PET/CT technology, particularly the 2-m-long uEXPLORER
system (United Imaging Healthcare), represents a quantum leap in
PET/CT imaging capabilities. Offering unparalleled sensitivity
and comprehensive body coverage, this technology has redefined
diagnostic accuracy and patient care. In this supplement, 3 leading
institutes in China, including Peking University Cancer Hospital
(8), Sun Yat-Sen University Cancer Center (9), and Henan Provin-
cial People’s Hospital, Zhengzhou University (10), share their
unique clinical experience and insights on total-body PET in their
clinical practice, including disease distribution, patient selection
workflow, scanning protocol, and several enhanced clinical appli-
cations, along with challenges encountered in routine clinical prac-
tice. The 3 articles delve into the bottleneck that impedes the full
use of total-body PET in China, accompanied by suggested
! May 2024
solutions. Additionally, state-of-the-art total-body PET and its
potential roles in pharmaceutical research are explored in these
articles.
With the rapid development and extraordinary advancements of
nuclear medicine in China over the past few years, the findings
reported by the Chinese clinical and research community hold
high value for the global community. Beyond the high-quality
studies performed at leading institutions, China’s vast population
of 1.4 billion offers a unique resource for scientific and clinical
investigations. This large demographic includes many patients
with rare diseases, presenting numerous opportunities for future
collaborations and international multicenter studies. Consequently,
with the continuously increasing scientific and clinical caliber of
research personnel and clinicians in China, we firmly believe that
nuclear medicine studies from the Chinese community will signifi-
cantly benefit the global nuclear medicine community.
Taken together, over the past 70 years, nuclear medicine in China
has achieved tremendous progress, benefiting millions of patients
annually. Despite this success, challenges such as shortages of radio-
isotope supplies and lack of radiopharmaceuticals remain (16). How-
ever, the future potential of nuclear medicine in China is enormous.
There are more than 3,000 tertiary hospitals, yet only a third of them
currently provide nuclear medicine services. The implementation of
the mid- and long-term development plan (2021–2035) for medical
isotopes is set to significantly promote the clinical application of
radiopharmaceuticals and advance the research and development of
new radiopharmaceuticals. By 2035, we anticipate overcoming the
current shortages, with independent innovation in radiopharmaceuti-
cals flourishing and more advanced, high-quality equipment being
produced domestically. The scale of nuclear medicine is expected to
increase 3–4 times from today, serving over 10 million patients annu-
ally in China. Through continuous efforts, nuclear medicine is poised
to play a pivotal role in improving and enhancing the quality of life
and health care for the Chinese population.
In summary, this JNM supplement offers a timely overview of
the current status of nuclear medicine in China, detailing signifi-
cant advances in research and development, as well as the clinical
translation of novel radiopharmaceuticals. It aims to inform and
inspire future international collaborations and multicenter studies,
underscoring our belief that this special issue will significantly
boost JNM’s global impact over time. As the guest editors of this
special issue, we sincerely hope you find enjoyment and value in
reading this supplement, discovering information that benefits
both your research activities and your daily clinical practice. We
are confident that through shared knowledge and collective effort,
nuclear medicine in China will play an increasingly vital role in
global health care, improving the quality of life and treatment out-
comes for patients around the world.
DISCLOSURE
This work is supported by the National Natural Science Founda-
tion of China (82071961). Weibo Cai declares a conflict of interest
with the following corporations: Actithera, Inc., Rad Source Tech-
nologies, Inc., Portrai, Inc., rTR Technovation Corp., and Four
Health Global Pharmaceuticals Inc. No other potential conflict of
interest relevant to this article was reported.
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INTRODUCTION ! Chen et al. 3S
Fibroblast Activation Protein Inhibitor Tracers and Their
Preclinical, Translational, and Clinical Status in China
Liang Zhao*1,2, Fei Kang*3, Yizhen Pang1,2, Jianyang Fang4,5, Long Sun1,2, Hua Wu1,2, XiaoLi Lan6, Jing Wang3, and
Haojun Chen1,2
1
Department of Nuclear Medicine, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen,
China; 2Minnan PET Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen,
China; 3Department of Nuclear Medicine, Xijing Hospital, Fourth Military Medical University, Xi’an, China; 4State Key Laboratory of
Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China; 5Center for Molecular
Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, China; and 6Department of Nuclear
Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

illuminated the potential of FAP-targeted radioligands for therapeu-

Quinoline-based fibroblast activation protein (FAP) inhibitors (FAPIs)
have recently emerged as a focal point in global nuclear medicine,
underscored by their promising applications in cancer theranostics
and the diagnosis of various nononcological conditions. This review
offers an in-depth summary of the existing literature on the evolution
and use of FAPI tracers in China, tracing their journey from preclinical
to clinical research. Moreover, this review also assesses the diagnos-
tic accuracy of FAPI PET for the most common cancers in China,
analyzes its impact on oncologic management paradigms, and inves-
tigates the potential of FAP-targeted radionuclide therapy in patients
with advanced or metastatic cancer. This review also summarizes
studies using FAPI PET for nononcologic disorders in China. Thus,
this qualitative overview presents a snapshot of China’s engagement
with FAPI tracers, aiming to guide future research endeavors.
Key Words: fibroblast activation protein inhibitors; radionuclide
therapy; tumor diagnosis; tumor management
J Nucl Med 2024; 65:4S–11S
DOI: 10.2967/jnumed.123.266983
tic interventions. Moreover, FAPI radiotracers have shown diagnos-
tic utility in various nonmalignant pathologies, advancing the
understanding of structural refinement and prompting expanded clin-
ical investigations.
China’s focus on FAPI-centric research has been remarkable.
Since an inaugural research article published in 2020 (3), Chinese
studies have substantially contributed to the discourse, evidenced
by the 421 articles written by Chinese authors and identified via a
PubMed search until October 10, 2023 (keywords: ‘FAPI’ OR
‘fibroblast activation protein inhibitor’ AND ‘China’; 1 retraction
and 2 corrections were excluded); these articles account for 50%
of the global FAPI-centric literature (421/822). Chinese research
has mainly focused on tumor types that have a notably high inci-
dence rate in China, such as gastric cancer, liver cancer, and naso-
pharyngeal cancer. The aim of this review was to cohesively
collate and present the preclinical, translational, and clinical evolu-
tion of FAPI tracers in the Chinese academic landscape.

PRECLINICAL AND TRANSLATIONAL DEVELOPMENTS

T
IN CHINA

he tumor microenvironment, a critical component of tumor
tissue, is enriched with cancer-associated fibroblasts, which are
prominent entities in various solid tumors. Fibroblast activation
protein (FAP), a type II transmembrane serine protease, is a dis-
tinct cancer-associated fibroblasts marker with sparse expression
in healthy tissues. In contrast, its expression in cancerous tissues
correlates with tumor invasiveness, metastatic potential, and prog-
nosis. More than 90% of epithelial tumors exhibit elevated FAP
expression, making it a promising target for cancer imaging
modalities (1). A seminal contribution from the University of Hei-
delberg in 2018 introduced a series of FAP inhibitors (FAPIs) for-
mulated explicitly for tumor imaging; this breakthrough garnered
rapid international recognition and prompted nuclear medicine insti-
tutions globally to explore its implications (2). The ensuing research
underscored the diagnostic efficacy of FAPIs in malignancies and
Received Oct. 31, 2023; revision accepted Jan. 29, 2024.
For correspondence or reprints, contact Haojun Chen (leochen0821@foxmail.
com), Jing Wang (13909245902@163.com), or Xiaoli Lan (xiaoli_lan@hust.edu.cn).
*Contributed equally to this work.
COPYRIGHT ! 2024 by the Society of Nuclear Medicine and Molecular Imaging.
FAPI-04 and FAPI-46 are the most commonly used FAPI tracers
in clinical investigations, with molecular weights of approximately
873 and 886, respectively. The small structure of FAPI enables it
to rapidly bind to the FAP target. However, it also swiftly detaches,
resulting in its rapid elimination from the body. Consequently, vari-
ous modifications have been explored to enhance tumor uptake and
retention of FAPI molecules for radioligand therapies. Multimeriza-
tion is commonly used to optimize target molecules, particularly
for developing radiolabeled arginine-glycine-aspartate (RGD) pep-
tides; a similar approach was used to optimize FAPI molecules.
In 2022, Zhao et al. developed the first FAPI dimer (4). In pre-
clinical models, the FAPI dimer showed 2- to 3-fold-higher tumor
uptake and prolonged tumor retention than FAPI-46 when radiola-
beled with 68Ga. In addition, the antitumor efficacy of the FAPI
dimer labeled with 177Lu was augmented in FAP-positive tumor
xenografts (5). Pang et al. were the first to develop a FAPI tetramer
that further increased tumor tissue uptake (6). However, the FAPI
tetramer also demonstrated increased uptake in some healthy
organs, particularly the liver and kidney; this feature may be a
double-edged sword for theranostic applications. Moreover, the
177
Lu-labeled FAPI tetramer had better tumor uptake and antitumor

4S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65 ! No. 5 (Suppl. 1) ! May 2024

efficacy than the dimer and monomer in tumors with moderate uptake of 18F-FAPT in the gallbladder was lower than that of 18F-
FAP expression. Thus, radioligand therapy with the FAPI tetramer FAPI-42 (16). Therefore, 18F-FAPT may perform better than 18F-
might be more suitable than that with the FAPI dimer for tumors FAPI-42 in detecting biliary duct system cancers. Figure 1 shows
with moderate to mild FAP expression. However, among the multi- the structure of various individual FAPI molecules developed by
meric FAPI variants in China, only 68Ga-DOTA-2P(FAPI)2 has been Chinese researchers.
translated into clinical investigations (4). In healthy volunteers, the Given the development of several modified FAPI tracers, the
68
Ga-DOTA-2P(FAPI)2 effective dose is 1.19E202 mSv/MBq, FAPI variant choice should be anchored to specific diagnostic or
comparable to that of 68Ga-FAPI-04 (1.64E202 mSv/MBq) and therapeutic applications, complemented by a meticulous assess-
slightly higher than that of 68Ga-FAPI-46 (7.80E203 mSv/MBq) ment of the potential benefits and limitations of each option.
(4). In 3 patients with cancer (21 lesions), tumor uptake was reported
to be 2- to 3-fold higher with 68Ga-DOTA-2P(FAPI)2 than with CLINICAL DEVELOPMENTS IN CHINA
68
Ga-FAPI-46 (SUVmax, 8.1–39.0 vs. 1.7–24.0; P , 0.001).
Tumor Diagnosis
Heterobivalent probes targeting FAP and other molecular tar-
Since Chen et al. introduced the use of the FAPI tracer in
gets have also been developed. For instance,68Ga-FAPI-RGD, a
patients with various cancers in Xiamen, China, in 2020 and
heterobivalent molecule targeting FAP and integrin avb3, showed
highlighted its diagnostic potential (3), imaging-based FAPI
enhanced tumor uptake and image contrast compared with 68Ga-
research for cancer in China has surged, with hundreds of studies
labeled FAPI-02 and cyclic RGDfK monomers in preclinical mod-
emerging. For instance, a study by Chen et al. at The First Affili-
els (7). In clinical translational studies, 68Ga-FAPI-RGD exhibited
ated Hospital of Xiamen University included 75 patients who had
promising diagnostic performance equal to or even surpassing that
various cancer types and who underwent paired 68Ga-FAPI-04 and
of 18F-FDG in patients with various cancer types, particularly 18
F-FDG PET/CT; Chen et al. reported that 68Ga-FAPI-04 PET/CT
lung, esophageal, and ovarian cancers (7,8). Other heterobivalent
had better diagnostic efficacy than 18F-FDG PET/CT, particularly
probes that target FAP and prostate-specific membrane antigen
in detecting liver, peritoneum, and brain metastases (3). Subse-
have shown high tumor accumulation in preclinical models (9,10),
quently, several studies further compared 68Ga- or 18F-labeled
although clinical data for FAPI–prostate-specific membrane anti-
FAPI and 18F-FDG PET/CT across tumor types (Table 1). To pro-
gen are still lacking.
Another strategy to enhance tumor uptake and retention of FAPI vide a more accurate reflection of the current status of FAPI
is to extend its circulation in the blood by conjugating it with other research in China, we use an arrangement based on anatomic
moieties, such as albumin-binding moieties. For instance, Wen et al. regions, from the top to the bottom of the human body, followed
reported that a FAPI variant modified with an albumin binder, trun- by sections on mesenchymal tissue origin tumors and lymphoma.
cated Evans blue (denoted as EB-FAPI), showed significantly Jiang et al. (17) and Chen et al. (18) preoperatively assessed
improved tumor uptake and retention compared with FAPI-02 (11). metastatic lymph node detection in head and neck squamous cell
Furthermore, when radiolabeled with 177Lu, EB-FAPI remarkably carcinoma and oral squamous cell carcinoma, finding that 68Ga-
inhibited tumor growth in U87MG tumor–bearing mice. Other FAPI-04 had performance superior to that of 18F-FDG in PET/CT.
albumin-binding moieties, including the 4-(p-iodophenyl) butyric However, both modalities exhibited equivalent effectiveness for
acid moiety, 4-p-chlorophenyl butyric acid, lauric acid, and pal- assessing primary tumors (17,18). In addition, Gu et al. explored
mitic acid, have also been conjugated with FAPI molecules to
enhance tumor uptake and retention (12,13). Of the FAPI modifica-
tions used to prolong circulation in the blood, only EB-FAPI has
been translated for clinical use—for radioligand therapy in patients
with refractory cancers. Further details are available in the “Clinical
Developments in China” section.
In addition to modifying FAPI to improve tumor uptake and
retention, efforts are ongoing in China to facilitate FAPI radiolabel-
ing with various radionuclides. China has more SPECT scanners
than PET scanners. Thus, modifying FAPI molecules for labeling
with 99mTc and, thus, SPECT imaging might be better suited for
China’s current conditions. In this regard, Ruan et al. developed a
FAPI-derived ligand that incorporated D-proline (called DP-FAPI)
(14). This ligand was radiolabeled with 99mTc to produce 99mTc-
DP-FAPI, which exhibited a high tumor-to-background ratio for
SPECT imaging. In a subsequent translational study, quantitative
SPECT/CT using 99mTc-DP-FAPI demonstrated favorable tumor
uptake in 3 patients with gastrointestinal tumors. In addition, Yang
et al. developed a FAP-targeting ligand that incorporated an
organosilicon-based fluoride acceptor and a DOTAGA chelator,
enabling the molecules to be labeled with radionuclides—including
18
F, 68Ga, and 177Lu—for theranostic pairing (15). A common limi-
tation of 18F-labeled FAPI tracers is their intense hepatobiliary
physiologic uptake; Huang et al. developed a glycopeptide-
containing FAPI tracer (called FAPT) to address this issue (16). In FIGURE 1. Structures of FAP-targeted radiotracers used in clinical prac-
both preclinical and translational clinical studies, the physiologic tice in China.

FAPI TRACERS IN CHINA ! Zhao et al. 5S

 TABLE 1
Summary of Representative Oncologic Studies with FAPI PET/CT in China

Tumor type FAPI agent(s) Study Year No. of patients

68
Head and neck squamous cell carcinoma, Ga-FAPI-04 Jiang et al. (17) 2023 77
oral squamous cell carcinoma
Chen et al. (18) 2022 36
68
Head and neck cancer of unknown primary Ga-FAPI-04 Gu et al. (19) 2022 18
origin
68
Nasopharyngeal carcinoma Ga-FAPI-04 Zhao et al. (20) 2021 45
68
Metastatic thyroid cancer Ga-FAPI-04 Fu et al. (21) 2022 35
68
Breast cancer Ga-FAPI-04 Zheng et al. (22) 2023 34
68
Lung cancer Ga-FAPI-04 and Wang et al. (23) 2022 34
18
F-FAPI-04
Zhou et al. (24) 2022 74
Wei et al. (25) 2023 68
68
Gastrointestinal cancer, including Ga-FAPI-04 and Liu et al. (26) 2022 35
18
esophageal cancer, gastric cancer, F-FAPI-74
colorectal cancers, liver cancer, biliary
tract cancer, and pancreatic cancer
Lin et al. (27) 2022 56
Pang et al. (28) 2021 35
Guo et al. (29) 2021 34
Lan et al. (30) 2022 18
Chen et al. (31) 2023 34
Xu et al. (32) 2023 112
Shi et al. (33) 2021 17
Zhang et al. (34) 2022 30
Qin et al. (35) 2022 20
68
Recurrent soft-tissue sarcoma Ga-FAPI-04 Gu et al. (36) 2022 45
18
Gastrointestinal stromal tumors F-FAPI-42 Wu et al. (37) 2022 35
68
Lymphoma Ga-FAPI-04 Chen et al. (38) 2023 186

the use of FAPI PET/CT in head and neck cancer of unknown pri-
mary origin and with negative 18F-FDG findings, reporting that
68
Ga-FAPI-04 PET/CT successfully located the primary tumor in
7 of 18 patients (19). Moreover, in a study involving 39 patients with
newly diagnosed nasopharyngeal carcinoma, Zhao et al. reported a
significantly higher SUVmax with 68Ga-FAPI-04 PET/CT than with
18
F-FDG PET/CT in primary tumors (16.18 vs. 10.11; P , 0.001),
regional lymph nodes (11.42 vs. 7.37; P , 0.001), and bone and vis-
ceral metastases (6.94 vs. 3.11; P , 0.001), resulting in the detection
of more positive lesions (especially for skull base and intracranial
involvement) (20). Another study focused on metastatic differentiated
thyroid cancer, comparing the diagnostic accuracy of 68Ga-FAPI-04
and 18F-FDG in 35 participants (21). Among the 35 participants,
68
Ga-FAPI-04 PET/CT demonstrated higher uptake in metastatic
lymph nodes and pulmonary metastases than 18F-FDG. Consequently,
68
Ga-FAPI-04 PET/CT exhibited enhanced sensitivity compared
with 18F-FDG PET/CT in detecting neck lesions (65/78 vs. 51/78;
P 5 0.01) and distant metastases (87/110 vs. 65/110; P , 0.001).
To date, only 1 research article investigating FAPI and breast
cancer in China has been published; the study included 34 patients
with newly diagnosed breast cancer (22). Consistent with the obser-
vations for most solid tumors, primary tumor uptake of the radio-
tracer and the N stage evaluation were better with 68Ga-FAPI-04
than with 18F-FDG. A positive correlation was also observed
between the SUVmax of 68Ga-FAPI and the pathologic grade of the
primary lesions and the patient’s final stage (P , 0.001).
Regarding lung cancer, Wang et al. (23) and Zhou et al. (24)
reported higher tumor uptake and tumor-to-background ratios for
68
Ga-FAPI PET/CT than for 18F-FDG PET/CT in detecting pri-
mary tumors, positive lymph nodes, and bone lesions, with all
comparisons having a significance level of P , 0.01. Intriguingly,
in a study involving 68 patients with lung cancer, Wei et al.
reported contrasting results: the tumor-to-background ratios
derived from 18F-FAPI-04 PET/CT were lower than those derived
from 18F-FDG PET/CT in depicting primary tumors, but the
tumor-to-background ratios were higher with 18F-FAPI-04 PET/CT
than with 18F-FDG PET/CT in depicting metastatic lymph nodes
and bone metastases (25). Despite the variations, these studies sug-
gested that 18F-FAPI-04 PET/CT may offer diagnostic accuracy
superior to that of 18F-FDG PET/CT.
Numerous studies have shown that 68Ga- or 18F-labeled FAPI
PET/CT is better than 18F-FDG PET/CT at detecting primary and
metastatic lesions in various digestive tumors, including esopha-
geal, gastric, duodenal, colorectal, liver, biliary tract, and pancreatic
cancers (26–33). For instance, a study involving 34 patients with
histologically confirmed gastric signet ring cell carcinoma across 4

6S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65 ! No. 5 (Suppl. 1) ! May 2024

medical centers demonstrated that 68Ga-FAPI-04 PET had better
radiotracer uptake, tumor-to-background ratios, and diagnostic
accuracy than 18F-FDG PET in detecting primary or recurrent
tumors and metastatic lesions (Fig. 2) (31). Notably, lesion sites in
which 18F-FDG was advantageous over 68Ga-FAPI-04 were not
present. In addition to PET/CT, multisequence imaging using 68Ga-
FAPI-04 PET/MRI has proven effective in identifying lesions in
pancreatic cancer, especially in cases of obstructive inflammation
and minuscule liver metastases (34). Qin et al. reported that multise-
quence MRI was advantageous for interpreting metastatic lesions in
the liver, uterus, rectum, bones, and ovaries in a cohort of 20 patients
with gastric cancer (35). Consequently, multisequence MRI with
FAPI PET could enhance the evaluation of soft-tissue lesions.
On the basis of recent studies conducted by nuclear medicine
scientists in China, FAPI PET/CT has considerable potential for
imaging sarcomas, a type of cancer with intense FAP expression
in tumor cells. In 1 study of 45 patients with recurrent soft-tissue
sarcoma and presenting with 282 local relapses and distant
metastases, Gu et al. reported that 68Ga-FAPI-04 PET/CT iden-
tified more lesions (275/282) than 18F-FDG PET/CT (186/282),
with superior sensitivity, specificity, and diagnostic accuracy
(P , 0.001) (36). Another study assessed 35 patients with recurrent or
metastatic gastrointestinal stromal tumors, finding that 18F-FAPI-42
PET/CT detected more tumor lesions (85/106) than 18F-FDG PET/CT
(57/106), with a particularly pronounced difference in the detection of
liver metastases (42/48 vs. 16/48; P , 0.001) (37). These findings
underscore the potential use of FAPI PET/CT as an emergent and
effective imaging modality for monitoring the recurrence of soft-tissue
sarcomas and gastrointestinal stromal tumors.
Although the superiority of FAPI PET over 18F-FDG PET has
been underscored for various malignancies, the clinical scenario is
reversed for lymphoma. In a cohort of 186 participants presenting
with 5,980 lymphoma lesions, 18F-FDG PET/CT identified more
nodal lesions (4,624 vs. 2,196) and extranodal lesions (1,304 vs.
845) than 68Ga-FAPI PET/CT. Thus, the staging accuracy based
on the 18F-FDG PET results was more precise than that based on
the 68Ga-FAPI-04 PET results (98.4% vs. 86.0%) (38).
The National Cancer Center in China names lung, colorectal,
stomach, liver, breast, esophagus, thyroid, pancreas, prostate, and
18 68
FIGURE 2. F-FDG and Ga-FAPI PET imaging of 8 representative patients with gastric signet ring
cell carcinoma. 68Ga-FAPI PET outperformed 18F-FDG PET in detecting primary tumors (patients 3, 7,
17, 19, and 33; solid black arrows), local recurrences (patient 12; blue arrows), abdomen lymph node
metastases (patients 12, 19, and 27; green arrows), bone metastases (patients 17, 19, and 27), and
peritoneal metastases (patients 29 and 33; dotted black arrows). (Adapted with permission of (31).)
cervical/uterine cancers as the top 10 cancers on the basis of their inci-
dence rates (39). Although the number of FAPI PET studies has
surged in various types of cancer, studies on its clinical application for
prostate and cervical/uterine cancers remain nascent, with few case
studies being reported—highlighting the urgent need for comprehen-
sive research in this area. In addition, FAPI PET imaging is not with-
out pitfalls. High uptake and similar retention of FAPI tracer are seen
in malignant disease and inflammatory processes, leading to potential
false-positive findings without careful imaging interpretation. How-
ever, this issue could be partly overcome by 18F-FDG PET, in which
the delayed scan may help differentiate inflammation from malignancy
because inflammatory processes normally show rapid washout and, in
general, low avidity. In addition to that in inflammatory disease,
increased FAPI uptake in other nononcological conditions (including
degenerative disease, fibrotic lesions, and tuberculosis) implies that
radiologists should exercise extreme caution and that integrating these
and other imaging findings with clinical data is essential for a compre-
hensive evaluation (40). Therefore, it would be meaningful to generate
evidence for FAPI PET to better characterize tumor biology or in can-
cer types in which 18F-FDG shows shortcomings rather than replicat-
ing the entire volume of data available with 18F-FDG.
Impact on Tumor Management
FAPI PET/CT has garnered attention for its favorable tumor-to-
background contrast and detection rate in primary and metastatic
tumors across most cancer types. Consequently, enhanced detection
could improve clinical tumor–node–metastasis (TNM) staging
compared with traditional imaging methods, paving the way for
optimized therapeutic strategies (20,23,28,41). For instance, imag-
ing with 68Ga-FAPI-04 PET/CT resulted in TNM upstaging in 6 of
23 patients with pancreatic cancer (26.1%) compared with imaging
with 18F-FDG (41). Crucially, these staging changes influenced
clinical management decisions for 2 of these patients (8.7%). Simi-
larly, in a study in which 68Ga-FAPI-04 PET/CT was compared
with contrast-enhanced CT, 68Ga-FAPI-04 PET/CT resulted in
TNM upstaging in 5 of 23 patients (21.7%) and prompted changes
in the therapeutic approach for 1 patient (4.3%) (41).
The prognostic value of FAPI PET is another pivotal dimension
to consider in oncologic management. Clinical oncologists may
use this prognostic parameter to identify
patients at higher risk of residual disease or
relapse, allowing more frequent monitoring
and implementation of more aggressive treat-
ment regimens. Zhao et al. first reported that
the gross tumor volume (GTV) determined
via FAPI PET (GTVFAPI) was an indepen-
dent prognostic indicator for progression-free
survival and overall survival in 34 patients
who had esophageal squamous cell carci-
noma and were undergoing definitive che-
moradiotherapy (Fig. 3A) (42). Intriguingly,
Hu et al. found that higher baseline tumor-to-
background ratios of blood (i.e., the ratio of
the SUVmax of the primary tumor to the
SUVmean of the blood) on 18F-FAPI-04
PET/CT scans correlated with a poor
response to concurrent chemoradiotherapy
in patients with locally advanced esopha-
geal squamous cell carcinoma (P 5 0.046)
(43). Additionally, in a study of 37 patients
with surgically treated pancreatic ductal
FAPI TRACERS IN CHINA ! Zhao et al. 7S

FIGURE 3. Kaplan–Meier plots showing overall survival for 45 patients
with unresectable esophageal squamous cell carcinoma (A) and 37
patients with resectable pancreatic ductal adenocarcinoma (B), stratified
by GTVFAPI. Definition of GTVFAPI is consistent with that of FAPI-avid tumor
volume (FTV). (Adapted with permission of (42) and (44).)
adenocarcinoma, Ding et al. reported that the SUVmax derived from
68
Ga-FAPI-04 PET/CT was a significant independent prognostic
factor for recurrence-free survival (hazard ratio, 2.46; P , 0.05)
(44). Moreover, GTVFAPI (also called FAPI-avid tumor volume in
their article) correlated with overall survival (hazard ratio, 12.82;
P , 0.05) (Fig. 3B) (44). Furthermore, Wu et al. examined the
prognostic significance of 68Ga-FAPI PET/CT in patients who had
unresectable hepatocellular carcinoma and were undergoing com-
bined PD-1 inhibitor and lenvatinib treatment (45), finding that
higher GTVFAPI (also called FAPI-avid tumor volume in their
article) was an independent predictor of shorter progression-free
survival (hazard ratio, 3.88 [95% CI, 1.26–12.01]; P 5 0.020)
and overall survival (hazard ratio, 5.92 [95% CI, 1.19–29.42];
P 5 0.035). Prognostic insights from FAPI PET can be instrumen-
tal in refining the treatment approach and follow-up strategies for
oncology patients, potentially improving their clinical outcomes.
Radiotherapy is the cornerstone treatment for most cancers.
Integrating 18F-FDG PET/CT into radiotherapy planning has sig-
nificantly enhanced the accuracy of outlining target volumes for
numerous cancers, notably head, neck, and lung cancers. Simi-
larly, there is a growing interest in the potential of FAPI PET to
fine-tune radiotherapy planning. A recent study of PET/CT-guided
complementary contouring of contrast-enhanced CT–based GTV
in 21 patients with esophageal cancer underscored the adaptability
of FAPI PET in this domain (46). When 20% and 30% were used
for FAPI SUVmax thresholds, the revised GTV expanded in 4 of
21 participants (19%). Interestingly, a tighter threshold of 40% for
FAPI SUVmax expanded the GTV in only 2 participants, highlight-
ing the nuances of FAPI PET for refining radiotherapy strategies
depending on the uptake parameters. However, there is a notice-
able gap in Chinese research on the utility of FAPI PET in radio-
therapy planning for other malignancies.
External-beam radiotherapy is the first-line treatment for naso-
pharyngeal carcinoma, and 68Ga-FAPI PET/CT seems to better
delineate tumors than 18F-FDG PET/CT because of its superior
tumor-to-background ratio and enhanced lesion detectability (20).
However, 2 studies compared 68Ga-FAPI PET/CT with MRI eva-
luations, finding that 68Ga-FAPI PET/CT upstaged the T stage in
13 of 47 and 4 of 39 patients and understaged the T stage in 2 of
47 and 2 of 39 patients (20,47). These disparities underscore that
although FAPI PET/CT holds promise, it should be viewed as a
complementary tool that acts synergistically with other imaging
modalities. Nonetheless, this combined approach could reduce
uncertainties and inconsistencies in anatomic tumor delineation.
8S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65 ! No. 5 (Suppl. 1)
Overall, these findings highlight the potential of 68Ga-FAPI
PET/CT as a diagnostic tool and critical component for shaping per-
sonalized and effective treatment pathways for patients with cancer.
However, there is a dearth of early-response evaluations with FAPI
PET. Crucial aspects that need to be addressed are the extent and
duration of FAPI uptake in postsurgery areas or tumors treated with
radiation (48). Differentiation of viable tumor lesions from fibrotic or
inflammatory processes may be challenging in patients who under-
went FAPI PET/CT for therapy response evaluation, particularly
those who underwent surgical resection and radiation therapy.
Radionuclide Therapy Targeting FAP
In recent years, radionuclide-targeted therapy has emerged as a
potential therapeutic alternative for patients with advanced and
metastatic cancer, especially those for whom multiple lines of ther-
apy have failed. Notably, targeted radiopharmaceuticals, including
177
Lu-DOTATATE and 177Lu-labeled prostate-specific membrane
antigen, have shown considerable promise—extending survival in
patients with specific tumor types, such as neuroendocrine tumors
and prostate cancer (49). However, some therapy-related radionu-
clides, including 177Lu, 90Y, and 225Ac, are import dependent. For
instance, self-produced 177Lu only meets 5% of the domestic
demand, and other commonly used medical isotopes rely on
imports. In addition, therapy-related radiopharmaceuticals have not
been approved by the National Medical Products Administration
(although the U.S. Food and Drug Administration has approved
#60 radiopharmaceuticals for clinical use, whereas China has
approved #30) (50). To date, only 5 publications by Chinese
nuclear medicine physicians, including 4 case reports and only 1
clinical research article, have reported on 177Lu-FAPI radioligand
therapy (Table 2; Fig. 4). Two distinct cases, 1 with nasopharyn-
geal carcinoma and the other with radioiodine-refractory differenti-
ated thyroid cancer, were treated with 177Lu-FAPI-46. The former
underwent 1 cycle, and disease progression occurred; the latter
received 4 cycles, resulting in stable disease (51,52). Furthermore,
reports from the Affiliated Hospital of Southwest Medical Univer-
sity indicated that 177Lu-FAP-2286 was used for 1 patient with
lung squamous cell carcinoma and 1 patient with recurrent bladder
cancer, and both achieved a partial response after treatment
(53,54). Moreover, a dose escalation trial conducted at The First
Affiliated Hospital of Xiamen University and involving 12 patients
with metastatic radioiodine-refractory thyroid cancer showed prom-
ising results with 177Lu-EB-FAPI (denoted as 177Lu-LNC1004)
(55). This first-in-humans trial, using a 3 1 3 dose escalation design
over a 6-wk treatment cycle, reported a mean whole-body effective
dose of 0.17 6 0.04 (mean 6 SD) mSv/MBq. Impressively, the
treatment exhibited high 177Lu-EB-FAPI uptake and retention, cul-
minating in a mean absorbed tumor dose of 8.50 6 12.36 Gy/GBq.
The outcomes, based on the RECIST criteria, were as follows: 25%
(3/12) partial response, 58% (7/12) stable disease, and 17% (2/12)
progressive disease; these data signified overall objective response
and disease control rates of 25% and 83%, respectively.
Despite the promising preliminary findings for 177Lu-EB-FAPI
in China, comprehensive prospective randomized controlled trials
should be conducted in the coming years. In studies focusing on
FAP-targeted radionuclide therapy, striking the right balance
between the rate of clearance of the drug and the time it resides in
the tumor is imperative. Concurrently, balancing the physical half-
life of the radioisotope and the biologic half-life of the ligand is
critical for achieving a high therapeutic efficacy with a robust
safety profile. Distinctively, FAP-targeted radionuclide therapy
! May 2024
 zeroes in on tumor-associated fibroblasts, emitting rays that irradi-
ate neighboring malignant tumor cells through the “cross-fire”

Thrombocytopenia (grade 4 in 1
effect, inducing cell death. This approach differs from other radio-

events in all treatment cycles

patient each) (CTCAE v5.0)

Treatment-related adverse

(grade 3 and grade 4 in 1

nuclide therapies that directly target tumor cells. Additionally,

patient), hematotoxicity
understanding the intricacies of the tumor microenvironment is

Pain flare-up
crucial. Bao et al. reported that 177Lu-DOTAGA.(SA.FAPi)2 in

None

None

None
combination with poly(ADP-ribose) polymerase inhibitors signifi-
cantly enhanced therapeutic efficacy in a preclinical triple-
negative breast cancer model (56). That study indeed opens a new
direction for combining 177Lu-labeled FAPIs with conventional
antitumor drugs (56). In future endeavors, enhancing therapeutic
outcomes could involve integrating FAP radionuclide therapy with
conventional antitumor therapy and immunotherapy.

Nontumor Diagnoses

stable disease (7 patients),

Partial response (3 patients),
Progressive disease, mixed

Activated fibroblasts are also found in conditions involving

Response (RECIST)

progressive disease (2
chronic inflammation, fibrosis, and scar formation, suggesting that
FAPI PET/CT may have broad applications for nononcologic con-
Summary of Representative Studies of FAPI Radioligand Therapy in China

ditions, especially systemic autoimmune and rheumatic immune

Partial response

Partial response

diseases in which activated fibroblasts are essential. To date, FAPI

Stable disease

PET/CT has been used to detect lesions and evaluate therapeutic

response

patients)

responses in several nononcological diseases in China. For

instance, Luo et al. conducted a prospective study comparing
68
Ga-FAPI-04 PET/CT and 18F-FDG PET/CT in 26 patients with
IgG4-related disease (57). 68Ga-FAPI-04 had significantly higher
3.33 GBq (6 patients),
Median injected activity

4.99 GBq (3 patients)

uptake than 18F-FDG in the involved pancreas, bile duct, liver,

5.55 GBq (cumulative:

2.22 GBq (3 patients),

and salivary glands (P , 0.01). Additionally, 68Ga-FAPI PET/CT

detected the involvement of 13.2% of organs (18/136) in 50.0% of
3.7 GBq

7.0 GBq

7.4 GBq

the patients (13/26). Lesion uptake using FAPI PET has also been
22.25 GBq)

positively correlated with disease stage or severity in patients with

TABLE 2

various conditions, such as renal fibrosis (58), interstitial lung dis-

eases (59), Crohn disease intestinal lesions (60), and rheumatoid
arthritis (61). When used appropriately, FAP-targeting tracers
offer significant advantages and an effective, noninvasive diagnos-
cycle(s)/patient

tic strategy for the aforementioned diseases. The potential of FAPI

treatment
No. of

PET in evaluating the therapeutic response has been exclusively

CTCAE v5.0 5 Common Terminology Criteria for Adverse Events Version 5.0.
1

assessed in preclinical arthritis studies, suggesting its utility in

monitoring treatment responses in rheumatoid arthritis (62).

PERSPECTIVES AND FUTURE DIRECTIONS

Lu-FAP-2286

Lu-FAP-2286

Lu-EB-FAPI
Lu-FAPI-46

Lu-FAPI-46
FAPI agent

FAPI tracers were first reported by a team at the University of

Heidelberg in Germany in 2018. Since then, their use in the
nuclear medicine field has rapidly gained traction, but FAPI
177

177

177
177

177

remains in its developmental phase in China. Although advances

in preclinical research have improved FAPI uptake and prolonged
Recurrent bladder
cell carcinoma

tumor retention, few studies have translated modified FAPI tracers

Nasopharyngeal

Lung squamous
Thyroid cancer

Thyroid cancer
Tumor type

into clinical applications. Chinese nuclear medicine scientists have

carcinoma

reported impressive findings on the diagnostic capabilities of FAPI

cancer

PET for various tumor types. However, many of these studies

were constrained by limited patient populations and lacked corrob-
orative histopathologic results. Despite the promising diagnostic
prowess of FAPI, which sometimes rivals or surpasses 18F-FDG,
patients
No. of

most conclusions have been drawn from single-center studies with

12
1

relatively small sample sizes. Hence, any assertion that FAPI can
replace 18F-FDG is premature, and FAPI should be considered a
Fu H et al. (55)
Rao et al. (54)

complementary tool with specific indications. Interestingly, FAP is

Fu et al. (51)

Fu et al. (52)

Li et al. (53)

not exclusive to tumor tissues; it is also present in certain nontu-

mor lesions. This duality broadens the clinical utility of FAPI
Study

PET for specific nontumor diseases. However, this necessitates

extreme prudence from nuclear medicine specialists and radiolo-
gists to accurately differentiate tumors from inflammatory disease.

FAPI TRACERS IN CHINA ! Zhao et al. 9S

 addition to the high-quality study performed
at some leading institutions in China, the 1.4-
billion population of China can also be
further explored for various scientific and
clinical investigations. With such a large pop-
ulation base, there are many different types
of rare disease with significant number of
patients (e.g., Ig-G4 related disease, cardiac
amyloidosis, cancer of unknown primary
origin, gastrointestinal cancer, and biliary–
pancreatic cancer), which will definitely
provide numerous opportunities for future
potential cooperation as well as international
multicenter studies. Therefore, with the ever
increasing scientific and clinical caliber of
FIGURE 4. Representative PET maximum-intensity projections showcasing patients with meta- research personnel and clinicians in China,
static solid cancer both at baseline and after targeted FAP radionuclide therapy. (Adapted with per- we strongly believe the FAPI-related studies
mission of (51) (A: metastatic nasopharyngeal carcinoma), (52) (B: metastatic thyroid cancer), (53) from Chinese community will greatly benefit
(C: recurrent bladder cancer), (54) (D: lung squamous cell carcinoma), and (55) (E: metastatic thyroid the worldwide FAPI community.
cancer). F is from our unpublished data (metastatic medullary thyroid cancer).
In conclusion, FAPI PET imaging raises
exciting opportunities with ease of patient
Currently, most FAPI tracers use 68Ga, with scant research on 18F preparation. Rapid uptake and high tumor-to-background ratio allows
and 99mTc labeling. Given the longer half-life of 18F (109.8 vs. early imaging. Given the large volume of evidence with 18F-FDG in
68.0 min), superior spatial resolution, and more abundant cyclotron diagnosis, prognostication, and response assessment, FAPI-based
production, applying 18F-radiolabeled FAPI variants should be fur- PET imaging may be better approached, at least initially, as a com-
ther explored. Additionally, the ubiquity of SPECT/CT machines plementary agent to 18F-FDG with specific applications. Chinese
compared with PET/CT and PET/MRI devices in Chinese hospi- nuclear medicine experts are poised to collaborate with international
tals makes 99mTc-labeled FAPI a convenient imaging modality for peers, ushering in a groundbreaking phase in the convergence of
future clinical applications. radionuclide tumor diagnosis and treatment. We expect that through
China has only 1 recorded application of FAPI PET for target unremitting and collaborative efforts, FAPI-derived radiopharmaceu-
volume delineation in radiotherapy planning. In contrast, European ticals will play a crucial role in improving and enhancing the quality
studies have expanded this to include head and neck cancers, lung of human life and health care worldwide.
cancers, adenoid cystic carcinomas, pancreatic cancers, and glio-
mas, suggesting future growth areas (13). However, a larger DISCLOSURE
patient pool and consistent threshold standards are essential for
No potential conflict of interest relevant to this article was
future studies. Moreover, early evidence suggests a correlation
reported.
between parameters derived from FAPI PET and patient prognosis
for certain tumors, potentially aiding patient stratification and fos-
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FAPI TRACERS IN CHINA ! Zhao et al. 11S
Translational PET Imaging of Nectin-4 Expression in
Multiple Different Cancers with 68Ga-N188
Jianhua Zhang*1, Xiaojiang Duan*1, Xueqi Chen*1, Zhuochen Zhang1, Hongwei Sun1, Jiayin Shou1, Guangyu Zhao1,
Jianxin Wang2, Yongsu Ma2, Yinmo Yang2, Xiaodong Tian2, Qi Shen3,4, Wei Yu3,4, Zhisong He3,4, Yan Fan1, and
Xing Yang1,5–7
1
Department of Nuclear Medicine, Peking University First Hospital, Beijing, China; 2Department of Hepatobiliary and Pancreatic
Surgery, Peking University First Hospital, Beijing, China; 3Department of Urology, Peking University First Hospital, Beijing, China;
4
National Research Center for Genitourinary Oncology, Institute of Urology, Peking University, Beijing, China; 5Department of
Central Laboratory, Peking University First Hospital, Beijing, China; 6Key Laboratory for Research and Evaluation of
Radiopharmaceuticals (National Medical Products Administration), Beijing, China; and 7International Cancer Institute, Peking
University Health Science Center, Beijing, China

Nectin cell adhesion molecule 4 (nectin-4) is a transmembrane protein

overexpressed on a variety of cancers and plays an important role in
oncogenic and metastatic processes. The nectin-4–targeted anti-
body–drug conjugate enfortumab vedotin has been approved for
treating locally advanced or metastatic urothelial cancer, but the effi-
cacy in other types of cancer remains to be explored. The aim of
this study was to evaluate the feasibility of nectin-4–targeted PET
imaging with 68Ga-N188 as a noninvasive method to quantify mem-
branous nectin-4 expression in multiple tumor types—an approach
that may provide insight for patient stratification and treatment selec-
tion. Methods: Sixty-two patients with 16 types of cancer underwent
head-to-head 68Ga-N188 and 18F-FDG PET/CT imaging for initial stag-
ing or detection of recurrence and metastases. Correlation between
lesion SUVmax and nectin-4 expression determined by immunohisto-
chemistry staining was analyzed in 36 of 62 patients. Results: The
SUVmax of 68Ga-N188 had a positive correlation with membranous
nectin-4 expression in the various tumor types tested (r 5 0.458; P 5
0.005), whereas no association was observed between the SUVmax and
cytoplasmic nectin-4 expression. The detection rates for patient-based
analysis of 68Ga-N188 and 18F-FDG PET/CT examinations were com-
parable (95.00% [57/60] vs. 93.33% [56/60]). In patients with pancreatic
cancer, 68Ga-N188 exhibited a potential advantage for detecting resid-
ual or locally recurrent tumors; this advantage may assist in clinical
decision-making. Conclusion: The correlation between nectin-4–
targeted 68Ga-N188 PET imaging and membranous nectin-4 expres-
sion indicates the potential of 68Ga-N188 as an effective tool for select-
ing patients who may benefit from enfortumab vedotin treatment. The
PET imaging results provided evidence to explore nectin-4–targeted
therapy in a variety of tumors. 68Ga-N188 may improve the restaging of
pancreatic cancer but requires further evaluation in a powered, pro-
spective setting.
Key Words: nectin-4; 68Ga-N188; enfortumab vedotin; PET/CT
J Nucl Med 2024; 65:12S–18S
DOI: 10.2967/jnumed.123.266830
Received Oct. 9, 2023; revision accepted Jan. 31, 2024.
For correspondence or reprints, contact Xing Yang (yangxing2017@bjmu.
edu.cn).
*Contributed equally to this work.
COPYRIGHT ! 2024 by the Society of Nuclear Medicine and Molecular Imaging.
N ectin cell adhesion molecule 4 (nectin-4), formerly known as
poliovirus receptor–like 4, is a type I transmembrane protein and
belongs to the nectin family of immunoglobulinlike adhesion
molecules (1,2). Overexpression of nectin-4 has been identified in
a variety of cancers, including bladder, breast, ovarian, and pan-
creatic tumors. Enfortumab vedotin (EV), an antibody–drug conju-
gate targeting nectin-4, was recently approved by the U.S. Food
and Drug Administration and the European Medical Agency for
its efficacy in treating locally advanced or metastatic urothelial
cancer (UC) (3,4). The efficacy of EV in other solid tumors
remains to be explored. The presence of nectin-4 expression has
been observed both on cell membranes and in the cytoplasm of
tumor cells, with the membrane expression as the biologic premise
for EV binding to achieve therapeutic effects (1,5). A recent study
showed that nectin-4 membranous expression decreases with dis-
ease progression and that low nectin-4 expression in metastatic
biopsies may indicate resistance to EV (6). A shorter progression-
free survival for patients who have metastatic tumors with lower
nectin-4 expression after receiving EV was also reported (6).
There is a potential urgent need for noninvasive methods to iden-
tify patients with high levels of membranous nectin-4 expression
for personalized EV therapy.
Recently, we developed a nectin-4–targeted radiotracer, 68Ga-
N188, for PET/CT imaging of nectin-4 expression (7). Such
agents can overcome the limitations of biopsy for detecting hetero-
geneous biomarker expression and achieve dynamic assessment of
nectin-4 expression noninvasively. In the pilot study, 68Ga-N188
detected nectin-4-expressing lesions in 14 UC patients, with a pos-
itive correlation between lesion SUVmax and nectin-4 expression
determined by immunohistochemical (IHC) staining.
Besides UC, nectin-4 expression has been reported in multiple
other types of cancer, and it is of interest to explore 68Ga-N188
PET in those tumor types. Such investigation may help to further
validate this imaging method in clinical settings and provide
insight on nectin-4 expression patterns across different cancer
types—information that could help to promote the application of
EV in treating cancers other than UC. We initiated this study and
explored the utility of nectin-4–targeted PET in 16 types of pri-
mary tumors and recurrent/metastatic relapses in 62 patients.
Nectin-4 expression in the tumors of 36 patients was determined
with IHC. We further evaluated the correlation between SUVmax

12S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65 ! No. 5 (Suppl. 1) ! May 2024
of PET imaging and membranous nectin-4 expression. The initial
results are presented in a head-to-head comparison with 18F-FDG
PET and suggest that 68Ga-N188 can be an effective method for
detecting cancer and quantifying membranous nectin-4 expression.
MATERIALS AND METHODS
Patients
This prospective, single-center study was conducted at Peking Uni-
versity First Hospital and was approved by the institutional review
board (approval number 2022-301). The study was registered at
ClinicalTrials.gov (NCT05593107). All participants were consecu-
tively recruited for enrollment from August to December 2022 and
provided written informed consent.
Inclusion criteria were as follows: adult patients aged 18 y and
older, patients who had pathologically confirmed cancer or for whom
cancer was highly suspected and patients who were referred for cancer
restaging, patients who underwent both 18F-FDG and 68Ga-N188
PET/CT scans within 1 wk, and patients who agreed to be followed up
for pathologic and imaging results. Exclusion criteria were as follows:
female patients who were pregnant or lactating, female patients who
planned to become pregnant within 6 mo, and patients who were
unable to provide written informed consent.
Radiopharmaceutical Preparation
18
F-FDG was provided by Atom High-Tech Co., Ltd. 68Ga-N188
was prepared according to a previously reported procedure (7).
Briefly, 3 mL of 0.05 M HCl solution containing [68Ga]GaCl3 (518–
1,665 MBq), 200 mL of 1.0 M sodium acetate, and 100 mg of N188
were heated at 90" C for 10 min. After being cooled to room tempera-
ture, the solution was extracted with an activated Sep-Pak Light C18
Cartridge (Waters Corp.), and 68Ga-N188 was eluted with 0.6 mL of
80% ethanol aqueous solution. After purification and sterilization,
308–962 MBq of 68Ga-N188 could be obtained with a radiochemical
yield of 53.9% 6 5.9% (mean 6 SD) (not decay corrected, n 5 30)
and a radiochemical purity of greater than 99%, as analyzed by radio–
high-performance liquid chromatography.
PET/CT Imaging Protocol
All participants fasted for 6 h before 18F-FDG PET/CT examination
and 18F-FDG was administered intravenously (range of 3.70–5.18
MBq/kg) at serum glucose levels of less than 130 mg/dL. No special
preparation was required before 68Ga-N188 PET/CT imaging. The
injected dose for 68Ga-N188 was 2.22–2.96 MBq/kg. PET/CT acquisi-
tions (uMI780; United Imaging Health Care) were performed 40–60
min after injection from head to midthigh. Low-dose, noncontrast CT
(tube voltage of 120 kV, tube current of 100 mA/s, and matrix of 512
3 512) was performed for attenuation correction and anatomic refer-
ence. A total of 4 or 5 PET bed positions were acquired with a matrix
of 192 3 192 and 1.5 min/bed position. All PET data were recon-
structed using the ordered-subset expectation maximization algorithm
with 2 iterations and 20 subsets. 18F-FDG and 68Ga-N188 PET/CT
images were analyzed at a postprocessing workstation (uExceed, ver-
sion R001; United Imaging Health Care).
PET/CT Imaging Analysis
Both 18F-FDG and 68Ga-N188 PET/CT images were reviewed and
evaluated independently by 2 accredited nuclear medicine physicians
with more than 10 y of experience. Any disagreement was resolved by
comprehensive discussion for consensus. The lesions were considered
visually positive when the focal accumulation of 68Ga-N188 and 18F-
FDG was higher than that in adjacent background tissue, except for
suspected physiologic or benign radiotracer uptake. For 68Ga-N188
imaging, physiologic radioactivity was expected in the kidneys and
IMAGING NECTIN-4 EXPRESSION IN CANCER
bladder. The numbers of lymph nodes and distant metastases were
counted and recorded, with a maximum of 10 lesions recorded within
a given organ or region. For semiquantitative analysis, the SUVmax
normalized to body weight was automatically calculated and recorded
for each lesion.
Histopathologic results were used as the gold standard for the final
diagnosis. Follow-up clinical and conventional imaging examinations
(ultrasound, CT, or MRI) for at least 3 mo were considered the refer-
ence standard for participants without pathologic results. Tumor TNM
stage was determined with the TNM classification system (8) for
patients undergoing initial staging.
IHC Staining
Sections of paraffin-embedded tumor specimens were obtained
from surgically resected tumor or biopsy specimens. Samples were
dewaxed and pretreated with antigen retrieval solution (1:50 dilution;
ZSGB-Bio Inc.) for 20 min in a microwave oven. Samples were
stained for nectin-4 (1:1,000 dilution; ab189514; Abcam) and detected
using a ZSGB-BioDAB IHC Detection Kit (ZSGB-Bio Inc.). The pro-
portion of stained cells was captured with MShot Digital Imaging Sys-
tem V9.0 (MShot).
The IHC results for nectin-4 expression were independently
reviewed by 2 pathologists who were blinded to the clinical informa-
tion and PET/CT imaging results. Both visualized staining intensity
and proportion of positive tumor cells were evaluated. Both cytoplas-
mic nectin-4 expression and membranous nectin-4 expression were
scored. The final nectin-4 expression staining was scored as 4 catego-
ries: 0 (no expression), 1 (weak expression), 2 (moderate expression),
and 3 (strong expression).
Statistical Analysis
All statistics were analyzed using SPSS software (version 27.0.1;
IBM Corp.). Quantitative data were presented as the mean 6 SD. The
lesion detection rates of 68Ga-N188 and 18F-FDG PET/CT imaging
were compared using the McNemar test. The differences in tumor
radioactivity between the 2 imaging examinations were evaluated
using the paired-sample t test or the Wilcoxon signed rank test. The
Spearman rank correlation coefficient was applied for the correlation
between lesions’ SUVmax and nectin-4 expression. A P value of less
than 0.05 was considered statistically significant.
RESULTS
Participant Characteristics
Participant characteristics are shown in Table 1. The flow chart
of the study is presented in Figure 1. Sixty-two patients (29 female
and 33 male) were included, with a median age of 62 (range, 32–
86), and underwent paired 68Ga-N188 and 18F-FDG PET/CT
examinations. A total of 16 types of malignancies were included,
with the majority being pancreatic cancer (n 5 19; 30.6%) and
urothelial carcinoma (n 5 18; 29.0%), followed by ovarian cancer
(n 5 6; 9.7%) and cervical cancer (n 5 3; 4.8%).
All patients tolerated 68Ga-N188 and 18F-FDG well, and no
adverse effects were reported. Among these patients, 40 of 62
were included for initial staging, and the diagnosis was histologi-
cally confirmed. The other 22 patients had a prior history of
tumors and underwent PET/CT for restaging of tumor recurrence
and metastases. Detailed information about the 62 enrolled
patients is given in Supplemental Table 1 (supplemental materials
are available at http://jnm.snmjournals.org).
! Zhang et al. 13S
 TABLE 1
Summary of Participant Characteristics

Characteristic Value Percentage

Participants 62 100
Staging 40 64.5
Restaging 22 35.5
Demographics
Sex
Female 33 53.2
Male 29 46.8
Age (y) Mean 6 SD,
FIGURE 1. Flowchart of participant enrollment and study design.
60 6 13
(range, 32–86)
Pathologic type of tumor cholangiocarcinoma are shown in Figure 3. The primary liver lesions
Pancreatic cancer 19 30.6 were identified clearly by both 68Ga-N188 and 18F-FDG PET/CT
Urothelial carcinoma 18 29.0 imaging.
Ovarian cancer 6 9.7 Correlations of SUVmax and Nectin-4 Expression
Cervical cancer 3 4.8 The nectin-4 expression of primary and metastasis samples
Breast cancer 2 3.2 from 36 patients was evaluated and is shown in Supplemental
Colon cancer 2 3.2
Figure 2 and Supplemental Table 2. A distinct positive correlation
was evident between SUVmax and membranous nectin-4 expres-
Intrahepatic 2 3.2
cholangiocarcinoma sion (r 5 0.458; P 5 0.005), as shown in Figure 4, whereas no
significant correlation was found between SUVmax and cytoplas-
Non–small cell lung 2 3.2
cancer mic nectin-4 expression (r 5 0.033; P 5 0.847). Figure 5 shows
representative correlated images of 68Ga-N188 PET/CT (patient
Cutaneous malignant 1 1.6
melanoma 21 vs. patient 61) and IHC staining (upper row: membranous
nectin-4 expression with a score of 3; lower row: membranous
Cutaneous squamous 1 1.6
cell carcinoma nectin-4 expression with a score of 0).
Endometrial carcinoma 1 1.6 Comparison of Detection Rates
Esophageal cancer 1 1.6 The imaged cohort included the 40 patients who presented for
Hepatocellular 1 1.6 initial staging and the other 22 patients who presented for resta-
carcinoma ging, as described earlier. Forty-five primary tumors were identi-
Solid pseudopapillary 1 1.6 fied in the 40 patients undergoing initial staging (1 patient with
tumor of pancreas urothelial carcinoma and 1 patient with intrahepatic cholangiocar-
Thyroid cancer 1 1.6 cinoma had multiple presumed primary tumors), and 12
Uterine 1 1.6 residual/local recurrent tumors were identified in the 22 patients
carcinosarcoma undergoing restaging. Overall, 93 lymph nodes and 63 distant
metastases were detected across all cases. The patient-based and
lesion-based comparison results for rates of detection of 68Ga-
68
N188 and 18F-FDG PET/CT are shown in Table 2.
Imaging Manifestations of Ga-N188 in Various Tumors For the patient-based comparison, 68Ga-N188 and 18F-FDG
The average SUVmax of 68Ga-N188 PET/CT in the different PET/CT examinations yielded comparable detection rates (95.00%
tumor types (60/62 participants) is shown in Figure 2, and the rep-
resentative maximum-intensity-projection images from 68Ga-N188
PET/CT imaging are displayed in Supplemental Figure 1. One
patient (patient 41) who presented for UC initial staging was
excluded because the postoperative pathology was negative while
the biopsy pathology was positive. Considering clinical and patho-
logic results, the small tumor might be removed with the initial
biopsy. In another UC patient (patient 49), there was no tumor
local recurrence or distant metastasis after surgery, chemotherapy,
and immunotherapy, and he was also excluded.
As shown in Figure 2, the highest average SUVmax was observed
in intrahepatic cholangiocarcinoma, urothelial carcinoma, and
cutaneous squamous cell carcinoma, followed by cervical cancer,
esophageal cancer, endometrial carcinoma and pancreatic cancer. FIGURE 2. Average SUVmax of 68
Ga-N188 PET/CT in 60 cases of 16
Representative images from a patient (patient 52) with intrahepatic tumor types.

14S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65 ! No. 5 (Suppl. 1) ! May 2024
FIGURE 3. 68Ga-N188 PET/CT and 18F-FDG PET/CT images in 59-y-old
woman with intrahepatic cholangiocarcinoma before treatment (patient
52). Lesions were clearly visible on both maximum-intensity-projection
images. Axial CT images showed large lesions in right liver lobe with het-
erogeneously increased radioactivity of 68Ga-N188 (SUVmax, 5.2) and 18F-
FDG (SUVmax, 15.9) on axial PET and PET/CT fusion images (arrows).
[57/60] vs. 93.33% [56/60]), with no statistical difference. For 2 par-
ticipants, the results obtained over follow-up were confirmed to be
true-negative results, as mentioned earlier (participants 41 and 49).
For lesion-based comparison, 18F-FDG detected all 45 primary
tumors (100.00% [45/45]), and 68Ga-N188 identified 39 primary
tumors (86.67% [39/45]) (P 5 0.031). The 6 tumors missed by
68
Ga-N188 belonged to 4 types, including urothelial carcinoma,
intrahepatic cholangiocarcinoma, cervical cancer, and hepatocellu-
lar carcinoma.
For the 12 residual and locally recurrent tumors, 68Ga-N188
detected all 12 tumors (100.00% [12/12]), but 18F-FDG failed to
identify 4 of them (66.67% [8/12]) (P 5 0.125). Interestingly, these
4 lesions were all pancreatic tumors in patients undergoing restaging,
including 1 with postoperative recurrence (patient 18) and 3 with
residual lesions after adjuvant chemotherapy (patients 19, 29, and
30), and the results were further confirmed by follow-up imaging.
Representative images from a patient with pancreatic cancer after
treatment (patient 29) are shown in Figure 6. A residual tumor in the
head and uncinate process of the pancreas with increased 68Ga-N188
accumulation but no 18F-FDG uptake was noted.
Among the 104 lymph nodes detected by 68Ga-N188 and 18F-
FDG PET/CT examinations, 93 positive and 11 negative lymph
nodes were defined according to the pathologic and follow-up
results. 18F-FDG PET/CT demonstrated higher detection rates
than 68Ga-N188 PET/CT (94.62% [88/93] vs. 76.34% [71/93]
[P , 0.001] for lymph node metastases and 96.83% [61/63] vs.
71.43% [45/63] [P , 0.001] for distant metastases).
The sensitivity and accuracy of 18F-FDG PET/CT were higher
than those of 68Ga-N188 PET/CT (P , 0.001 and P 5 0.002,
respectively), and 68Ga-N188 PET/CT exhibited higher specificity
than 18F-FDG PET/CT (63.64% [7/11] vs. 36.36% [4/11]),
although differences did not reach statistical significance (P 5
0.250) (Table 3).
Changes in Tumor Staging and Management
In 58 of 62 patients, agreement on TNM staging or restaging
was obtained on the basis of 68Ga-N188 and 18F-FDG PET/CT.
The staging or restaging of 2 patients (patients 1 and 59) with pan-
creatic cancer was upstaged by 68Ga-N188 PET/CT compared
with 18F-FDG PET/CT for 1 metastatic peripancreatic node (N1
misjudged as N0) (patient 59) and multiple liver metastases (M1
IMAGING NECTIN-4 EXPRESSION IN CANCER
FIGURE 4. Correlation between membranous nectin-4 expression and
SUVmax.
misjudged as M0) (patient 1) recorded as negative by 18F-FDG
PET/CT (Supplemental Fig. 3). In contrast, 18F-FDG PET/CT
upstaged 1 patient with intrahepatic cholangiocarcinoma (patient 8)
and 1 patient with ovarian cancer (patient 47). For the former,
68
Ga-N188 detected only 1 of the liver lesions and missed involve-
ment in multiple regional lymph nodes (T1bN0M0 for 68Ga-N188
vs. T2N1M0 for 18F-FDG). For the latter, 1 metastatic lymph node
in the right cardiophrenic angle was staged as M1 by 18F-FDG
examination but missed by 68Ga-N188 PET/CT imaging.
Of note is that 68Ga-N188 detected 2 paraaortic lymph node
metastases in 1 patient with bladder cancer (patient 10) that were
negative on 18F-FDG PET/CT imaging (Fig. 7). Because of the
presence of liver metastasis, the TNM stage of this patient was not
changed by the additional finding. However, the identification of
additional lesions may provide complementary value for therapeu-
tic decision-making in clinical practice.
DISCUSSION
The present study serves as a pilot trial of using 68Ga-N188, a
radiotracer targeting nectin-4 overexpression, in 16 types of can-
cers besides UC (7). The positive correlation between membra-
nous nectin-4 expression by IHC and lesion SUVmax by PET/CT
was confirmed; this approach may offer a noninvasive evaluation
method for the selection of patients suitable for individualized and
precision therapy based on EV treatment. Furthermore, a head-to-
head comparison of 68Ga-N188 and 18F-FDG was performed to
evaluate their detection ability and diagnostic value.
Overexpression of nectin-4 has been reported to be involved in
the processes of angiogenesis by upregulating vascular endothelial
growth factor, tumor cell proliferation, and metastatic spread by
activating the phosphatidylinositol-3 kinase/Akt pathway as well
as the epithelial–mesenchymal transition—related signaling path-
way (9–12). The level of nectin-4 expression is upregulated in
over 90% of UC (13,14), making it a robust biomarker for target-
ing UC for diagnosis and treatment. EV showed very promising
clinical results for treating UC and was recently approved by the
U.S. Food and Drug Administration and the European Medical
Agency (3,4). Recently, different histologic and molecular sub-
types of UC were reported to exhibit marked heterogeneity of
nectin-4 expression (2,15–17). Nectin-4 status also varied among
! Zhang et al. 15S
 liver and bone metastasis in animal models
(20). To improve on the pharmacokinetic
properties of antibodies and facilitate trans-
lational research, a low-molecular-weight
PET imaging agent, 68Ga-N188, based on a
high-affinity bicyclic peptide scaffold, was
recently reported by our group. In a first-in-
humans study, it demonstrated a suitable
safety profile and pharmacokinetics in 2
healthy volunteers and 14 patients with UC.
The sensitivity of 68Ga-N188 in that study
was 88.1%, with high specificity, showing
the potential to quantitatively image nectin-
4 expression (7). We subsequently initiated
the study in this article to investigate the
imaging properties of 68Ga-N188 in broader
cancer types in a head-to-head comparison
FIGURE 5. Correlation of 68Ga-N188 PET/CT images and IHC staining. (A) 68Ga-N188 PET/CT with 18F-FDG.
images in 86-y-old man with urothelial carcinoma (patient 21). Left renal pelvis and proximal ureter In the present study, similar pharmaco-
tumors (arrows) showed substantial radioactivity from 68Ga-N188 (SUVmax, 4.8) and strong membra- kinetics were observed for 68Ga-N188 in
68
nous nectin-4 expression (score, 3). (B) Ga-N188 PET/CT images in 39-y-old man with hepatocellular
carcinoma (patient 61). Large tumor in right liver lobe (arrows) showed low and diffuse radioactivity
the 62 patients tested with various cancer
68
of Ga-N188 (SUVmax, 2.1). Negative membranous nectin-4 expression (score, 0) but moderate types, consistent with our early results for
cytoplasmic nectin-4 expression (score, 2) were observed on IHC image. UC (7). We were able to collect 36 tumor
samples from the patients and performed
IHC staining for broader cancer types.
different metastases, which resulted in mixed response rates to treat- Interestingly, with a sample size larger than that in our previous
ment by EV (6). For example, neuroendocrine and stroma-rich sub- study of UC (7), the SUVmax of lesions in 68Ga-N188 imaging
types of UC commonly have lower nectin-4 expression levels than the was found to positively correlate only with nectin-4 membranous,
luminal and basal molecular subtypes (15). Among the nonurothelial but not cytoplasmic, expression. On the basis of recent findings
histologic types of bladder cancer, only a small proportion of small reported by Kl€ umper et al. (6), several metastatic UC tissues
cell neuroendocrine carcinomas, adenocarcinomas/urachal carcino- expressed highly heterogeneous levels of membranous nectin-4, a
mas, and squamous cell carcinomas showed high nectin-4 expression result that highlights the importance of evaluation of nectin-4
(18). Nectin-4 expression has also been observed in multiple cancer expression status before initiation of EV treatment. Decreasing or
types besides UC, including metastatic colorectal, breast, and ovarian loss of membranous nectin-4 expression has been observed in a
cancers; however, the expression levels varied greatly, with consider- considerable fraction of patients receiving EV treatment, with dis-
able heterogeneity (1,2). Those issues create a barrier for selecting ease progression, and may indicate an unfavorable response to EV
patients most likely to respond to EV treatment. A noninvasive nuclear and a poor prognosis. Performing multiple assessments to evaluate
imaging method to quantify nectin-4 expression could be an ideal the dynamic changes in membranous nectin-4 expression in dis-
solution. ease progression over time is important. Although pathologic
Two radiolabeled antibodies for in vivo evaluation of nectin-4 biopsy could be applied, the status of nectin-4 cannot be ade-
expression have been reported in the preclinical setting. 99mTc- quately reflected by IHC in 1 biopsy, considering the interlesional
HYNIC-mABNectin-4 for immuno-SPECT imaging showed good and intralesional tumor heterogeneity of nectin-4 expression and
performance in the diagnosis of triple-negative breast cancer for the possible dynamic changes in expression levels. The findings of
guiding nectin-4–targeted treatment (19). AGS-22M6, radiola- positive correlation between 68Ga-N188 imaging and nectin-4
beled with 89Zr, was developed as an immuno-PET agent and suc- membranous expression confirmed the feasibility of noninvasively
ceeded in detecting nectin-4 expressing primary tumors as well as and quantitatively accessing tumor burden and nectin-4 status in

TABLE 2
Rates of Detection of 68Ga-N188 and 18F-FDG for Patient-Based and Lesion-Based Comparisons
68 18
Comparison Tumor or metastasis Ga-N188* F-FDG* P

Patient based 95.00 (57/60) 93.33 (56/60) 1.000

Lesion based Primary tumors 86.67 (39/45) 100.00 (45/45) 0.031
Residual/recurrent tumors 100.00 (12/12) 66.67 (8/12) 0.125
Lymph node metastases 76.34 (71/93) 94.62 (88/93) ,0.001
Distant metastases 71.43 (45/63) 96.83 (61/63) ,0.001

*Data are reported as percentages of cases, with numbers of cases in parentheses.

16S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65 ! No. 5 (Suppl. 1) ! May 2024
FIGURE 6. 68Ga-N188 PET/CT and 18F-FDG PET/CT images in 62-y-old
man with pancreatic cancer after chemotherapy plus radiotherapy (patient
29). Axial CT images showed soft-tissue mass in head and uncinate pro-
cess of pancreas (arrows). Mass with increased radioactivity of 68Ga-
N188 (SUVmax, 3.4) was observed on axial PET and PET/CT fusion
images. In contrast, no abnormal 18F-FDG uptake of mass (SUVmax, 3.2)
was noted on corresponding PET/CT images (arrows).
the whole body using PET imaging. On the basis of the imaging
results, we think it might be possible to guide personalized treat-
ment strategies by applying multiple 68Ga-N188 examinations to
evaluate membranous nectin-4 expression before and after the ini-
tiation of EV treatment.
Similarly, favorable detection rates were found for 68Ga-N188
and 18F-FDG. Compared with 68Ga-N188, 18F-FDG showed
higher rates of detection of primary tumors, lymph nodes, and dis-
tant metastases, as well as higher sensitivity and accuracy for
lymph node involvement. Higher specificity of lymph node metas-
tasis was obtained with 68Ga-N188, although not statistically sig-
nificant, because of the 18F-FDG avidity for some benign lesions.
In the present study, false-positive lesions caused by 18F-FDG
avidity in mediastinal and hilar lymph nodes, pulmonary infection,
arthritis, and Warthin tumor displayed low 68Ga-N188 activity.
Therefore, 68Ga-N188 could be applied as an effective comple-
ment to 18F-FDG PET/CT imaging, reducing false-positive results.
The SUVmax of 68Ga-N188 in 16 different types of tumors from
62 patients were compared. In UC (n 5 16) and pancreatic cancer
(n 5 19), with relatively large sample sizes, high SUVmax was
observed, consistent with previous findings of high levels of
nectin-4 expression. As shown in Figure 3, the highest average
SUVmax of 68Ga-N188 was for the primary lesions of 2 intrahepa-
tic cholangiocarcinomas. Low background radioactivity in the
TABLE 3
Diagnosis of Lymph Node Involvement by 68Ga-N188 and
18
F-FDG
68 18
Parameter Ga-N188* F-FDG* P imaging could thus act as a predictor for clinical outcomes in pan-
Sensitivity 76.34 (71/93) 94.62 (88/93) ,0.001
Specificity 63.64 (7/11) 36.36 (4/11) 0.250
Accuracy 75.00 (78/104) 88.46 (92/104) 0.002
*Data are reported as percentages of cases, with numbers of
cases in parentheses.
IMAGING NECTIN-4 EXPRESSION IN CANCER
FIGURE 7. 68Ga-N188 PET/CT and 18F-FDG PET/CT images in 84-y-old
man with urothelial carcinoma after treatment with transurethral resection
of bladder tumor plus pelvic radiotherapy (patient 10). Metastatic liver
lesions could be identified from both maximum-intensity-projection
images. Axial CT images revealed small paraaortic lymph node with obvi-
ously increased 68Ga-N188 accumulation (SUVmax, 4.3), whereas no
abnormal 18F-FDG uptake (SUVmax, 2.2) was noted on corresponding
PET/CT images (arrows).
liver helped to improve the tumor-to-liver ratio, making it possible
to detect primary liver tumors and liver metastases clearly.
Six patients with ovarian serous carcinoma showed moderate
radioactivity with 68Ga-N188 PET/CT imaging. Discordant
nectin-4 expression in different histologies of ovarian cancer has
been reported. High nectin-4 expression was seen in about one-
half of ovarian serous carcinomas and one-third of ovarian mucin-
ous carcinomas, but only cytoplasmic localization was reported
for nectin-4 staining (21); this finding might account for the mod-
erate uptake observed in the present study. Moreover, nectin-4 has
been identified as a key gene associated with poor prognosis in
high-grade serous ovarian cancers that involve extensive perito-
neal involvement, that is, miliary tumors (22). In the present study,
the increased and extensive radioactivity distribution related to
widespread peritoneal involvement was also noted on 68Ga-N188
imaging (patient 43 in Supplemental Fig. 1), whereas only peritoneal
metastatic masses were revealed by 18F-FDG PET/CT imaging.
In the evaluation of residual/recurrent tumors of pancreatic can-
cer, the rates of detection of 68Ga-N188 and 18F-FDG were
100.00% and 66.67%, respectively. Four residual or recurrent pan-
creatic tumors were negative on 18F-FDG imaging but positive on
68
Ga-N188 imaging. 68Ga-N188 also upstaged the TNM stage in
another 2 pancreatic cancer patients with additional lymph node
and liver metastases that were missed by 18F-FDG. 68Ga-N188
could be advantageous over 18F-FDG in restaging of pancreatic
cancer lesions after neoadjuvant chemotherapy and surgery; this
notion still needs to be further confirmed with larger sample sizes
and more data. In addition, high levels of nectin-4 expression in
pancreatic cancer have been reported to be associated with poor
postoperative prognosis and early relapse (23,24). 68Ga-N188
creatic cancer. Close follow-up and active surveillance or treat-
ment are reasonable suggestions for pancreatic cancer patients
with positive 68Ga-N188 findings. The results of an ongoing
follow-up study addressing the application of 68Ga-N188 in pan-
creatic cancer will be important.
Several limitations of the present study must be acknowledged.
First, the small sample size restricted in-depth analysis of 68Ga-
N188 performance in multiple cancer types, and current results
! Zhang et al. 17S
may be underpowered. The lesion SUVmax may not be representa-
tive of cancer types with a limited number of cases. Further studies
powered to meaningful endpoints are needed, as are studies that
more completely explore the role of 68Ga-N188 as an imaging bio-
marker. In addition, the relatively short follow-up period of the
patients in the present study is not sufficient for further analysis of
nectin-4 expression and prognosis.
CONCLUSION
A positive correlation between membranous nectin-4 expression
by IHC and SUVmax on nectin-4–targeted 68Ga-N188 PET/CT imag-
ing was observed in a study of 62 patients with 16 different types of
cancer, suggesting the potential to apply 68Ga-N188 for selecting
patients suitable for individualized and precision EV therapy and
monitoring of membranous nectin-4 expression during disease pro-
gression. Nectin-4–targeted diagnosis and therapy may be extended
to cancer other than UC. A head-to-head comparison of 68Ga-N188
and 18F-FDG was performed in a variety of tumor types. Further
investigation is needed to confirm the potential advantages of 68Ga-
N188 PET, such as restaging of pancreatic cancer.
DISCLOSURE
This work was funded by the National Natural Science Founda-
tion of China (grants 92059101 and 22277002 to Xing Yang), Bei-
jing Natural Science Foundation (grant Z220014 to Xing Yang),
and National High Level Hospital Clinical Research Funding (Sci-
entific and Technologic Achievements Transformation Incubation
Guidance Fund Project of Peking University First Hospital grant
2023CX02 to Jianhua Zhang). No other potential conflict of inter-
est relevant to this article was reported.
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! May 2024
Melanin-Targeting Radiotracers and Their Preclinical,
Translational, and Clinical Status: From Past to Future
Xiao Zhang*1–3, Zhaoguo Lin*1–3, Yuan Feng1–3, Fei Kang4, Jing Wang4, and Xiaoli Lan1–3
1
Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan,
China; 2Hubei Key Laboratory of Molecular Imaging, Wuhan, China; 3Key Laboratory of Biological Targeted Therapy, Ministry of
Education, Wuhan, China; and 4Department of Nuclear Medicine, Xijing Hospital, Fourth Military Medical University, Xi’an, China
Melanin is one of the representative biomarkers of malignant mela-
noma and a potential target for diagnosis and therapy. With advance-
ments in chemistry and radiolabeling technologies, promising strides
have been made to synthesize radiolabeled melanin-binding molecules
for various applications. We present an overview of melanin-targeted
radiolabeled molecules and compare their features reported in preclini-
cal studies. Clinical practice and trials are also discussed to elaborate
on the safety and validity of the probes, and expanded applications
beyond melanoma are reviewed. Melanin-targeted imaging holds
potential value in the diagnosis, staging, and prognostic assessment of
melanoma and other applications. Melanin-targeted radionuclide ther-
apy possesses immense potential but requires more clinical validation.
Furthermore, an intriguing avenue for future research involves expand-
ing the application scope of melanin-targeted probes and exploring
their value.
Key Words: melanin; malignant melanoma; nuclear medicine; PET;
clinics
J Nucl Med 2024; 65:19S–28S
DOI: 10.2967/jnumed.123.266945
M
elanin is a natural organic biopolymer that is formed by the
polymerization of phenolic complexes through quinones (1). Mela-
nin pigment is present in various organs and tissues of humans and
animals, such as the retina, substantia nigra, skin, and hair (2). It
also accumulates in certain diseases, with melanoma being the most
prominent example. Melanoma is a highly aggressive tumor with
limited diagnostic and treatment options (3). Exploring melanin as
a potential target for diagnosing and treating melanoma shows
promise in the management of melanoma. Melanin has various
properties, such as light absorption, paramagnetism, and electron
exchange (4), and it plays roles in photoprotection, antioxidation,
photothermal conversion, and metal chelation (5). Benefiting from
these properties of melanin, multimodality imaging and integrative
therapy may be useful to target melanin (6). For example, melanin
strongly binds metal ions, such as chelated Fe31, which is observed
as T1 hyperintensity on MRI (7). Melanin shows an exceptionally
broad spectrum of ultraviolet–visible absorption, which can pro-
duce photoacoustic effects for photoacoustic imaging (PAI). It also
Received Oct. 26, 2023; revision accepted Jan. 31, 2024.
For correspondence or reprints, contact Jing Wang (13909245902@163.com)
or Xiaoli Lan (lxl730724@hotmail.com).
*Contributed equally to this work.
COPYRIGHT ! 2024 by the Society of Nuclear Medicine and Molecular Imaging.
MELANIN-TARGETING RADIOTRACERS
has high photothermal conversion efficiency used for photothermal
therapy (8). However, the hyperintense T1 signal is unspecific, and
PAI with photothermal therapy is limited by the penetration depth.
Nuclear medicine techniques use decaying radioisotope–labeled
probes to locate and characterize specific biologic processes at the
molecular level in vivo and can achieve precise imaging and ther-
apy. The rapid development of chemistry and radiolabeling technol-
ogy has led to the synthesis of melanin-binding molecules and the
use of radionuclides to label molecules used for radiotargeted imag-
ing and therapy, which has generated multiple breakthroughs (9).
Advances in genetic bioengineering have led to the establishment
of various cells that can be transfected to produce melanin, which
serves as an exogenous biomarker when the transfected cell is
implanted in the body (10). These developments impel melanin-
targeting applications to be more extensive. The explorations of
radiotracers and melanin-produced reporter genes have gradually
increased and become a hot spot in recent years (11–15).
Here we present an overview of melanin-targeted radiolabeled
molecules and compare their features in mice bearing melanoma
tumors. Melanin-targeted imaging for exogenous melanin pro-
duced by implanted transfected cells is discussed. We focus on
melanin-targeting tracers and their preclinical, translational, and
clinical status and present our perspective for broadening their
applications.
MELANIN-TARGETING MOLECULES FOR NUCLEAR
MEDICINE IMAGING
Discovery of Strong Affinities Between Certain Drugs
and Melanin
In 1968, chlorpromazine (an antipsychotic derivative of pheno-
thiazine) was the first radiolabeled molecule reported to bind mel-
anin to visualize human malignant melanoma and metastases
(16). In 1972, 35S and 14C were used to label chlorpromazine and
chloroquine (an antimalaria drug), respectively (17). In the
1990s, other compounds also became known to bind with mela-
nin, such as adiphenine (an inhibitor of nicotinic receptors) and
methylene blue (18,19). These molecules display 2 similar chem-
ical structures at physiologic pH: an aromatic or heteroaromatic
ring and a protonated amine (Fig. 1). There is always a space
linker between the 2 main groups. Further studies focused on the
synthesis and selection of the best structures exhibiting these
characteristics. The structures and characteristics of typical mole-
cules are summarized in Figure 2 and Table 1 (detailed informa-
tion is in Supplemental Fig. 1 and Supplemental Table 1
[supplemental materials are available at http://jnm.snmjournals.
org]), respectively (20–25).
! Zhang et al. 19S

FIGURE 1. Example of melanin-binding molecules, showing chemical
interactions between benzopyrazine, picolinamide, and benzamide deriva-
tives and melanin fragment.
Structures with a Benzene Ring and Tertiary or
Secondary Amine
In 1991, N-(2-diethylaminoethyl)-4-iodobenzamide (BZA), with
a benzamide structure and tertiary amine, was identified and
showed a high affinity to melanin pigment (26). When labeled with
125
I, it demonstrated high uptake in melanotic tumor tissue of
melanoma-bearing mice by scintigraphy. The favorable results led
to several investigations into the structure with a benzamide and
amine group (27,28). Some reports investigated the binding mecha-
nism of benzamide derivatives to melanin, ruling out receptor–
ligand interaction and covalent bond correlation (29,30). Further
research showed that electrostatic forces and hydrophobic interac-
tions may play a role in the binding mechanism (Fig. 1). An ionic
interaction is produced between the protonated cation on the tertiary
amine and the carboxylates of melanin. The aromatic ring binds
with the heteroaromatic ring through a p-interaction (18).
To retain the acting groups, studies initially focused on radioiodine-
labeling molecules (31–34). However, the detection rate of lesions by
these probes is limited to the resolution of SPECT. PET imaging
probes were thus further developed (35). Garg et al. (36) and Ren et al.
(37) successfully synthesized the same probe, N-[2-(diethylami-
no)ethyl]-4-[18F]fluorobenzamide ([18F]FBZA). Ren et al. (37) per-
formed in vivo small-animal PET and found significant [18F]FBZA
uptake (6.47 6 2.16 percentage injected dose per gram of tissue [%ID/
g]) in B16F10 tumors at 1 h (Fig. 3). However, synthesis of this probe
is complex with low radiochemical yield. In later studies, N-(2-diethy-
laminoethyl)-4-[18F]fluoroethoxybenzamide, [18F]AlF-NOTA-BZA,
and N-(2-diethylaminoethyl)-4-[2-(2-(2-[18F]fluoroethoxy)ethoxy)-
ethoxy]benzamide were obtained with easier synthesis methods
(38–40). N-(2-diethylaminoethyl)-4-[18F]fluoroethoxybenzamide
and N-(2-diethylaminoethyl)-4-[2-(2-(2-[18F]fluoroethoxy)ethoxy)-
ethoxy]benzamide showed higher uptake values (8.66 6 1.02 and
8.31 6 1 %ID/g at 1 h, respectively) in tumors containing melanin
than did [18F]FBZA but also higher uptake values in tumors without
melanin. Thus, the various 18F-labeling benzamide derivatives
exhibit different in vivo pharmacokinetics.
The preceding studies focused on modifying the benzene ring to
improve radiochemical yield, melanin-targeting ability, or pharma-
cokinetic properties. Some researchers focused on the aliphatic
amine group. Pyo et al. (13) changed the N-substituents of the
amine group from ethyl to methyl to synthesize N-(2-(dimethylami-
no)ethyl)-4-[18F]fluorobenzamide, which resulted in rapid and
prolonged retention in melanoma, as well as the highest uptake
among benzamide derivatives (13.00 6 3.90 %ID/g at 1 h). Liu et al.
(41) constructed an aliphatic probe, N-(2-(diethylamino)ethyl)-2-
20S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65
[18F]fluoropropanamide, that contains only a tertiary amino group.
Tumor uptake (4.39 6 0.51 %ID/g at 1 h) was lower than that of
[18F]FBZA, but only by an electrovalent bond with melanin, and it
quickly decreased to 2.65 6 0.48 %ID/g at 2 h. This suggests that
the aromatic ring structure is necessary for building the melanin-
targeted PET probe.
Nicotinamide and Picolinamide Derivatives for Melanin
In addition to benzamide, nicotinamide and picolinamide have the
chemical properties for binding to melanin and can be synthesized by
a nucleophilic substitution reaction in a single step. Liu et al. (42) pre-
pared a series of iodonicotinamides based on N-2-diethylaminoethyl-
4-iodobenzamide, and N-(2-(diethylamino)ethyl)-5-[123I]iodonicoti-
namide displays high tumor uptake and rapid clearance from the
body. It is probable that the hydrophilic character of the pyridine moi-
ety of the nicotinamides versus the aryl moiety of the benzamide ana-
logs contributed to improved urinary excretion of the nicotinamides.
Greguric et al. (43) synthesized various structures of 18F-nicotinamide
probes, and N-[2-(diethylamino)ethyl]-6-[18F]fluoronicotinamide
showed the highest target-to-nontarget ratio (up to 40 at 3 h). Chang
et al. (44) reported that [131I]iochlonicotinamide showed rapid and
sustained uptake in pigmented melanoma, coupled with consistent
improvement in the target-to-background ratio.
Liu et al. (45) synthesized 3 18F-pyridine amides, and N-[2-
(diethylamino)ethyl]-5-[18F]fluoropicolinamide ([18F]P3BZA) (46)
has the greater advantages, such as higher tumor-to-muscle ratios
and good stability in vivo. This tracer, with an additional fluor-
oalkyl moiety, has high lipophilicity and tends to display
FIGURE 2. Structures of representative melanin-targeting molecules for
nuclear medicine imaging. Isotopes used to label molecules are indicated in
red. Benzene ring structure is shown in green. Nicotinamide and picolinamide
ring structures are indicated in blue. Benzopyrazine is shown in peach. Mole-
cules reported in Chinese studies are marked with blue boxes. [123I]MEL008
5 N-(2-(diethylamino)ethyl)-5-[123I]iodonicotinamide; [125I]/[18F]4 5 125I- and
18
F-labeled N-[2-(diethylamino)ethyl]-4-fluoro-3-iodobenzamide; [18F]DMFB
5 N-(2-(dimethylamino)ethyl)-4-[18F]fluorobenzamide; [18F]DMPY2 5 N-(2-
(dimethylamino)ethyl)-5-[18F]fluoropicolinamide; [18F]FPDA 5 N-(2-(diethyla-
mino)ethyl)-2-[18F]fluoropropanamide; [18F]MEL050 5 N-[2-(diethylami-
no)ethyl]-6-[18F]fluoronicotinamide; 4-[11C]MBZA 5 4-11C-methoxy N-(2-
diethylaminoethyl) benzamide; BZA-BAT 5 N-diethylaminoethyl-4-[8-
methyl-3-(3-methyl-3-thio-1-azabutyl)-8-thio-2,6-oxoazanonyl]benzamide;
ICF15002 5 N-(12-ethyl-1-fluoro-3,6,9-trioxa-12-azatetradecan-14-yl)-6-
iodoquinoxaline-2-carboxamide; IFNABZA 5 iodofluoronicotinamide
benzamide.
! No. 5 (Suppl. 1) ! May 2024
 TABLE 1
Main Characteristics of Radiolabeled Melanin-Targeting Molecules

Highest
Specific tumor
Radiochemical Radiochemical activity Time uptake
Representative probe LogP yield (%) purity (%) (GBq/mmol) point (h)* (%ID/g) Reference

[125I]BZA — 45 .95 1.33 3 1023 1 6.75 6 0.67 (26)

125
[ I]11 — 85–95 — — 1 5.21 6 0.51 (33)
[123I]IMBA 1.419 80–98 — — 1 6.7 (34)
[125I]PAB — 78–94 — 66.6 1 3.87 6 0.47 (32)
123
[ I]MEL008 1.55 6 0.03 30–80 .95 .2,000 1 7.8 6 1.7 (42)
5-[131I]IPN 0.03 6 0.03 55 6 5 .98 5.45–6.55 1 16.37 6 3.32 (80)
[18F]FBZA 1.7† 50 .95 132–166 1 6.47 6 2.16 (37)
[18F]DMFB — 15–30 — .5.5 1 13.00 6 3.90 (13)
18
[ F]AlF-NOTA-BZA 21.96 20–35 .95 60–80 0.25 6.67 6 0.91 (39)
4-[18F]FEBZA — 53 6 14 .99 321.9 6 40.7 1 8.66 6 1.02 (38)
[18F]FPBZA 20.48 40–50 .97 30–40 0.5 10.37 6 1.13 (40)
[18F]MEL050 1.1 35–45 .99 150–220 2 9.4 6 1.6 (43)
18 ‡
[ F]P3BZA 20.17 6 0.03 9.5 6 1.9 .95 100–150 2 16.97 6 3.28 (45)
[18F]DMPY2 — 15–20 — .7.6 1 24.86 6 2.30 (12)
[18F]PFPN 20.69 6 0.02 44.68 6 5.99 .99 120–195 1 19.52 6 1.69 (48)
[18F]FPDA — 79.8 6 13.5 .99 20–40 1 4.39 6 0.51 (41)
18
[ F]4 — 5 .99 8–14 1 6.77 6 1.90 (50)
[125I]4 — 73 .99 4–12 1 9.7 6 2.6 (50)
[18F]ICF15002 — 21 .99 45–53 1 14.05 6 1.42 (51)
[125I]40 — 8 96.3 5.2 3 1023 24 23.5 6 1.4 (52)
[99mTc]TcN-BZA-BAT§ 20.3 .40 .92 — 1 0.43 6 0.16 (54)
99m
[ Tc]TcO-Cf 0.64 .95 — — 3 1.34 6 0.46 (55)
[99mTc]Tc-12 — 70 — — 6 4.35 6 0.92 (56)
[99mTc]4b — 28.4 99 — 1 3.39 6 0.5 (57)
[99mTc]2 3.5 60–98 — — 1 4.95 6 1 (59)
99m
[ Tc]Tc1 0.53 6 0.01 .95 — — 1 2.17 6 0.42 (58)
[68Ga]Ga-SCN-NOTA-BZA 23.25 6 0.05 80–85 .97 10 1 1.57 6 0.66 (61)
[68Ga]Ga-SCN-DOTA-PCA 23.7 .80 .97 8.9 1 2.51 6 0.5 (60)
[68Ga]Ga-H-2 22.37 6 0.07 98 6 2 .95 4.32 0.5 4.19 6 1.79 (62)

*Time point (h) of highest tumor uptake.

†
Values were obtained from Garg et al. (36).
‡
Values were obtained from Xu et al. (48).
§
The syn isomer.
— 5 no value mentioned in article; [125I]11 5 N-(2-ethylaminoethyl)-4-[125I]iodobenzamide; [123I]IMBA 5 N-(2-diethylaminoethyl)-3-
[ I]iodo-4-methoxybenzamide; [125I]PAB 5 N-(2-(piperidin-1-yl)ethyl)-4-[125I]iodobenzamide; [123I]MEL008 5 N-(2-(diethylamino)ethyl)-5-
123

[123I]iodonicotinamide; 5-[131I]IPN 5 N-(2-(diethylamino)ethyl)-5-[131I]iodopicolinamide; [18F]DMFB 5 N-(2-(dimethylamino)ethyl)-4-

[18F]fluorobenzamide; 4-[18F]FEBZA 5 N-(2-diethylaminoethyl)-4-[18F]fluoroethoxybenzamide; [18F]FPBZA 5 N-(2-diethylaminoethyl)-4-[2-
(2-(2-[18F]fluoroethoxy)ethoxy)ethoxy]benzamide; [18F]MEL050 5 N-[2-(diethylamino)ethyl]-6-[18F]fluoronicotinamide; [18F]DMPY2 5 N-(2-
(dimethylamino)ethyl)-5-[18F]fluoropicolinamide; [18F]FPDA 5 N-(2-(diethylamino)ethyl)-2-[18F]fluoropropanamide; [18F]4 5 18F-labeled
N-[2-(diethylamino)ethyl]-4-fluoro-3-iodobenzamide; [125I]4 5 125I-labeled N-[2-(diethylamino)ethyl]-4-fluoro-3-iodobenzamide; ICF15002 5
N-(12-ethyl-1-fluoro-3,6,9-trioxa-12-azatetradecan-14-yl)-6-iodoquinoxaline-2-carboxamide; [125I]40 5 N-[2-[ethyl(4-fluorobut-2-ynyl)ami-
no]ethyl]-6-[125I]iodoquinoxaline-2-carboxamide; BZA-BAT 5 N-diethylaminoethyl-4-[8-methyl-3-(3-methyl-3-thio-1-azabutyl)-8-thio-2,6-
oxoazanonyl]benzamide; PCA 5 procainamide.
Detailed information and structures of molecules are shown in Supplemental Fig. 1 and Supplemental Table 1.

MELANIN-TARGETING RADIOTRACERS ! Zhang et al. 21S

 created another innovative melanin-targeting
probe, [131I]iodofluoronicotiamide benza-
mide, by combining benzamide with nicotin-
amide. It exhibited lower initial tumor uptake
(5.84 6 1.80 %ID/g at 1 h) but displayed
more stable tumor retention (5.17 6 1.53
%ID/g at 48 h) than [131I]iochlonicotinamide
(13.48 6 1.77 %ID/g at 1 h and 1.51 6 0.31
%ID/g at 48 h, respectively) (44).

Melanin-Targeting Molecules Labeled

with Radioactive Metal Nuclides
99m
Tc is inexpensive, convenient, and
easily labeled. While considering the pre-
ceding results, several 99mTc complexes,
based on the structural elements of benza-
mide (54–56), and benzamide analogs (57)
were reported for melanoma. Most showed
relatively high radiochemical yield but
FIGURE 3. Representative images of radiolabeled melanin-targeting molecules. PET/SPECT imag- exhibited limited affinity for the pigmented
ing shows mice bearing melanoma at different time points after injection of 18F-labeled tracers (A) tumor with moderate tumor uptake. 99mTc-
(12,37,45), 125/131/123I-labeled tracers (B) (42,52,80), and 68Ga-labeled tracers (C) (60–62). Red arrows
labeled probes ([99mTc]Tc1 and [99mTc]2)
indicate tumors. [123I]MEL008 5 N-(2(diethylamino)ethyl)-5-[123I]iodonicotinamide; [125I]40 5 N-[2-
125 18
[ethyl(4-fluorobut-2-ynyl)amino]ethyl]-6-[ I]iodoquinoxaline-2-carboxamide; [ F]DMPY2 5 N-(2- with a single tertiary amino group were
18 131 131
(dimethylamino)ethyl)-5-[ F]fluoropicolinamide; 5-[ I]IPN 5 N-(2-(diethylamino)ethyl)-5-[ I]iodopicoli- also investigated but did not display ideal
namide; PCA 5 procainamide. (Reprinted with permission of (12,45,52,60–62,80) and from (37,42).) uptake (2.17 6 0.42, 4.95 6 1 %ID/g at
1 h) in the melanoma tumors (58,59). The
chelating agents have a high hydrophilic
nonspecific binding to normal organs, such as high concentrations property, which can influence the physiologic properties of radiola-
in the liver (4.71 6 1.47 %ID/g at 1 h). Researchers optimized the beled bioactive molecules.
68
structure with a short-chain polyethylene glycol (triethylene gly- Ga is easily obtained from a 68Ge/68Ga generator without the
18 need for a medical cyclotron and has been the subject of attention in
col) to generate N-(2-diethylaminoethyl)-5-(2-(2-(2-[ F]fluor-
oethoxy)ethoxy]ethoxy) picolinamide ([18F]PFPN) (47), which recent years. Several molecules labeled by 68Ga were also devel-
led to reduced liver uptake (2.27 6 0.45 %ID/g at 1 h) and oped to bind with melanin (60,61). The tumor uptake values of
68
improved pharmacokinetics (logP 5 20.69 6 0.02) (48). Pyo et al. Ga-labeled benzamide derivatives were lower than that of
18
(12) also changed the N-substituents of the amine group to methyl [ F]FBZA (6.47 6 2.16 %ID/g at 1 h) (37). Radiolabeled benza-
and synthesized N-(2-(dimethylamino)ethyl)-5-[18F]fluoropicoli- mide derivatives undergo transport mediated by passive diffusion
namide, exhibiting the highest uptake (24.86 6 2.30 %ID/g at 1 h) through the cell membrane to interact with melanin in the cytosol.
in B16F10 tumors among reported nicotinamide and picolinamide The passive diffusion was positively correlated with the lipophili-
derivatives. city of the compounds. The 68Ga-labeled benzamide derivatives
displayed lower logP values, implying fewer lipophilic properties
Fluorinated and Iodinated Matched-Pair Radiotracers and than 18F-labeled benzamide derivatives. These results may indicate
Benzopyrazine Derivatives that radioactive metal nuclides are not ideal for labeling melanin-
Based on the highly favorable results using radiohalogenated targeting small molecules for the use of a hydrophilic chelating
aromatic and heteroaromatic analogs (49), researchers investigated agent. Wang et al. (62) investigated a dimer strategy to further
a new approach consisting of using iodinated and fluorinated improve the tumor-binding capacity. The researchers labeled
matched-pair radiotracers targeting melanin and offering the poten- pyridine-based benzamide dimers with 68Ga to produce [68Ga]Ga-
tial for both diagnosis via SPECT (123I or 125I) or PET imaging H-2 but with poor tumor uptake (2.89 6 0.42 %ID/g at 1 h). Lin
(124I or 18F) and therapy (131I). Billaud et al. (50) developed several et al. (63) combined self-assembling peptides with PFPN but
fluoroaromatic, fluoroheteroaromatic, iodoaromatic, and iodoheter- obtained only modest enhancements in tumor retention. These find-
oaromatic derivatives of N-(2-diethylaminoethyl)-6-iodoquinoxa- ings affirm the conclusion that metallic nuclides are not suitable for
line-2-carboxamide (ICF01012), and 125I- and 18F-labeled N-[2- labeling melanin-targeting small molecules.
(diethylamino)ethyl]-4-fluoro-3-iodobenzamides provided good
in vitro and in vivo stability and quite similar tumor uptake at 1 h CLINICAL APPLICATIONS OF MELANIN-TARGETING IMAGING
after injection. The researchers also synthesized a series of iodoben- Melanin-Targeting Imaging for Melanoma in the Clinic
zopyrazine derivatives with various side chains bearing fluorine Several clinical studies have been conducted to investigate the
(51,52). The results showed that N-(12-ethyl-1-fluoro-3,6,9-trioxa- clinical value of melanin-targeted radiotracers (Table 2) (64–67).
12-azatetradecan-14-yl)-6-iodoquinoxaline-2-carboxamide and N- [125I]BZA and N-(2-diethylaminoethyl)-2-[123I]iodobenzamide are
[2-[ethyl(4-fluorobut-2-ynyl)amino]ethyl]-6-[125I]iodoquinoxaline- 2 radiotracers that have been extensively studied. Both showed high
2-carboxamide exhibited high tumoral uptake and favorable kinetics sensitivity and specificity in detecting melanoma lesions in early
and thus are good candidates for both SPECT/PET imaging and tar- clinical trials (68–70). In a study involving 110 patients with a his-
geted radionuclide therapy (TRT) of melanoma. Chen et al. (53) tory of malignant melanoma, [123I]BZA scintigraphy showed high

22S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65 ! No. 5 (Suppl. 1) ! May 2024
 TABLE 2
Summary of Representative Clinical Studies of Melanin-Targeted Radiotracers

Year Phase, NCT no. Purpose Tracer Dose Time point Population Patients (n) Country Reference

1993, 1998 Phase II DEE [123I]BZA 130 MBq 20–24 h Cutaneous and ocular 110, 48 France (68,69)
melanoma, ocular
melanoma
1994 — DEE (S)-[123I]IBZM 205 MBq 2, 4, and 24 h Melanoma 11 Italy (64)
1997 — DEE [123I]IMBA 200–300 MBq 2, 4, and 22 h Diagnosed or suspected 3 Germany (34)
metastatic melanoma
1997 — DEE [123I]BZA 170 MBq 4–5 h Suspected ocular 14 Belgium (65)
melanoma and ocular
naevi
1998 — * [123I]IBZM 185 MBq 2–5 h and 1 d Melanoma 21 Germany (66)
123
1998 — DEE [ I]/[131I]MTB 135–560 MBq 1–120 h Melanoma 11 U.K. (67)
123
2002, 2004 Phase II DEE [ I]BZA2 130–185 MBq 2, 4, and 6 h Cutaneous melanoma, 25, 40 France (31,70)
ocular melanoma
2013 Phase III DEE [123I]BZA2 2 MBq/kg 4h Cutaneous and ocular 87 France (71)
melanoma
2019 IIT, NCT03033485 Safety and [18F]P3BZA 3.1 MBq/kg 10 min and 1 h Healthy volunteers, 6, 5 China (72)
dosimetry patients with
evaluation, suspected melanoma
DEE
2022 IIT, NCT04747561 Safety and [18F]PFPN 3.0–5.4 MBq/kg 1 and 3 h Healthy volunteers, 5, 21 China (73)
dosimetry patients with
evaluation, suspected or
DEE confirmed melanoma
2023 IIT, NCT05645484 Prognosis [18F]PFPN 3.0–5.4 MBq/kg 2–3 h Melanoma 76 China (47)
evaluation
2023 IIT, NCT05963035 DEE [18F]PFPN 3.0–5.4 MBq/kg — Clear cell sarcoma 3 China (75)
188
2013 Phase Ia and Ib, Safety and [ Re]Re-6D2 370 MBq, — Stage III or IV metastatic 13 and 7† Israel (88)
NCT00399113 and dosimetry 740–2,220 MBq† melanoma
NCT00734188 evaluation,
TEE
2014 — Safety and [123I]/[131I]BA52 235 6 62 MBq, 10 min; 4, 24, Metastatic, treatment- 26, 9 for therapy Germany (27)

MELANIN-TARGETING RADIOTRACERS
dosimetry 3,900 6 2,000 MBq‡ and 48 h§ resistant melanoma

!
evaluation,
TEE

*Aim of study was to examine mechanisms of IBZM accumulation clinically and histologically.
†
13 patients were enrolled in phase Ia study, and 7 patients were enrolled in phase Ib study.
‡

Zhang et al.
Diagnostic dose, therapeutic dose.
§
Imaging time point of [123I]BA52.
NCT 5 National Clinical Trial; DEE 5 diagnosis efficiency evaluation; — 5 not available; IBZM 5 2-hydroxy-3-iodo-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]benzamide; [123I]IMBA
5 N-(2-diethylaminoethyl)-3-[123I]iodo-4-methoxybenzamide; MTB 5 methylene blue; [123I]BZA2 5 N-(2-diethylaminoethyl)-2-[123I]iodobenzamide; IIT 5 investigator-initiated trial; TEE 5

23S
therapy efficacy evaluation; [123I]/[131I]BA52 5 benzo(1,3)dioxolo-5-carboxylicacid(4-(2-diethylaminoethylcarbamoyl)-2-[123I]/[131I]iodo-5-methoxyphenyl)amide.
 that was missed in [18F]FDG PET (Fig. 5),
suggesting the imaging potential of
[18F]PFPN in lesions other than melanoma
that contain melanin. Zhang et al. (75) also
evaluated the feasibility of [18F]PFPN PET
in clear cell sarcoma. Despite the scarcity
of studies, some of which involve a limited
number of patients, these findings indicate
fresh prospects for the applications of tar-
geted melanin imaging.

MELANIN-TARGETING MOLECULES
FOR RADIOTHERAPY

TRT with Small Molecules

The successful use of radiolabeled
benzamide and its analogs in melanoma
imaging indicates these melanin-binding
FIGURE 4. Representative images of [18F]PFPN and [18F]P3BZA PET in healthy volunteers and
molecules are promising candidates for
melanoma patients (72,73). Maximum-intensity projection (MIP) images were acquired with
[18F]PFPN (A) and [18F]P3BZA (B) PET from healthy female volunteers. Moderate [18F]P3BZA uptake TRT. Some of these probes have been
was observed in regional obsolete lymph nodes that showed calcification in chest. (C) Man who had assessed for therapeutic efficacy in mice,
surgical resection of choroidal melanoma underwent [18F]PFPN PET/MR and [18F]FDG PET/CT imag- and these studies are summarized in Sup-
ing. [18F]PFPN PET demonstrated capability to detect more lesions (indicated by arrowheads and plemental Table 2 (22–25). Joyal et al. (49)
arrows) than [18F]FDG PET. (D) MIP images of melanoma patient showed higher [18F]P3BZA uptake
18 synthesized N-(2-diethylamino-ethyl)-4-(4-
than [ F]FDG in melanoma lesions (arrows) at 60 min after injection. (Reprinted from (72,73).)
fluoro-benzamido)-5-[131I]iodo-2-methoxy-
benzamide ([131I]MIP-1145). In vivo stud-
diagnostic efficiency, with a sensitivity of 81%, accuracy of 87%, ies showed that the uptake of [131I]MIP-1145 in melanin-containing
and specificity of 100% (68). However, in a multicenter phase III SK-MEL-3 human melanoma xenografts remained at 5.91 %ID/g at
clinical study involving 87 participants conducted by Cachin et al. 24 h. A single dose of [131I]MIP-1145 to mice bearing SK-MEL-3
(71) (Supplemental Fig. 2), the sensitivity of N-(2-diethylami- melanoma led to a striking suppression of tumor growth, with
noethyl)-2-[123I]iodobenzamide in diagnosing melanoma metasta- substantial tumor regression observed with multiple doses.
ses was notably lower, at 39%, than the 87% for [18F]FDG. Its [131I]ICF01012 is one of the most extensively studied radiotracers
relatively poor performance may be attributed partly to the low res- that showed potent antitumor effects in both murine and human
olution of SPECT imaging. pigmented melanoma in therapeutic experiments (76,77). In highly
Two 18F-labeled small molecular probes targeting melanin, pigmented B16BL6 models, a single dose of 14.8–22.2 MBq of
[18F]P3BZA and [18F]PFPN, were the first to enter clinical trials in [131I]ICF01012 was sufficient for effective treatment (78). In con-
China. The safety and tolerance profiles of the 2 probes have been trast, less pigmented SK-MEL-3 tumors required 3 doses of 25
well established in healthy volunteers (72,73). Biodistribution in MBq to achieve effective radiotherapy (79).
healthy volunteers revealed that both tracers rapidly clear from the In a study in China, Xu et al. (80) successfully synthesized N-(2-
bloodstream, facilitating effective image contrast (Fig. 4). Both (diethylamino)ethyl)-5-[131I]iodopicolinamide and applied it to
[18F]P3BZA and [18F]PFPN showed significant accumulations in treatment of melanoma. Two doses of 18.5 MBq administered to
the kidneys and bladder, indicating predominant renal clearance. mice with B16F10 melanoma resulted in notable suppression of
[18F]P3BZA exhibited higher liver uptake than [18F]PFPN at vari- tumor growth and extended median survival (24 vs. 16 d in control).
ous time points, possibly because of its higher hydrophobic nature. No hematologic toxicity was observed during the treatment. In
In an evaluation of diagnostic efficacy, Zhang et al. (73) conducted a investigations of the highest absorbed dose in the liver, blood tests
comparative study of [18F]PFPN and [18F]FDG in 21 melanoma and histopathologic examinations revealed no discernible damage
patients. The results showed that [18F]PFPN detected more metastases to the liver, underscoring its safety.
than [18F]FDG and showed excellent contrast, particularly in the brain
and liver (Fig. 4). The research group then conducted a study to
TRT with Peptides and Antibodies
investigate the prognostic value of [18F]PFPN PET in a cohort of 76
18 Melanin-binding deca- or heptapeptides (4B4 or AsnProAsnTrpGly-
melanoma patients (47). The results revealed that [ F]PFPN PET out-
18 ProArg) were labeled with 188Re and demonstrated antimelanoma
performed [ F]FDG PET in terms of prognostic capabilities for pre-
activity (81,82) with relatively quick clearance in tumor tissue.
dicting both death and disease progression. Thus, melanin-targeting
Melanin-binding murine or humanized antibodies, 6D2, 8C3, and
imaging may be useful to further understanding of melanogenesis in
h8C3, displayed high affinity for melanin, showing the potential for
melanoma development, progression, and treatment.
melanoma treatment, especially when antibodies were labeled with
Expanding Applications Beyond Melanoma a-emitter 213Bi (83–86). However, there is an antigen barrier during
Researchers in China have conducted initial investigations into melanin-targeted radioimmunotherapy that hinders deeper penetration
the application of [18F]PFPN PET in tumors beyond melanoma. In of antibodies into the melanoma (87). Therefore, more efforts are
a case report (74), [18F]PFPN PET effectively visualized pigmented required in preclinical investigations for deeper understanding of the
epithelial adenomas with a size of at least 5 mm in the corpus ciliare complexities involved in melanin-targeted radioimmunotherapy.

24S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65 ! No. 5 (Suppl. 1) ! May 2024
 and functions and can be used as a specific biomarker in other
fields. Some researchers have used genetic engineering to transfect
nonpigment cells so that they produce melanin. This technology
broadens the potential of melanin-targeted applications.

Tyrosinase Reporter System

Tyrosinase is the rate-limiting enzyme in the melanin synthesis
pathway. Many studies have transfected the tyrosinase gene to non-
pigment cells to produce melanin. Because of the various character-
istics of melanin, transfected cells that express melanin can be
analyzed by multimodality imaging. In 1997, Weissleder et al. (90)
transfected the tyrosinase gene into mouse nonpigment cells (fibro-
blasts and human embryonal kidney cells). Transfected cells had a
higher 111In-binding capacity and markedly higher signal intensity
in MRI than nontransfected cells. Qin et al. (10) further used
[18F]P3BZA as a PET reporter probe for tyrosinase. After transfection
of MCF-7 cells, melanin expression was successfully monitored by

FIGURE 5. Representative [18F]PFPN PET and CT images of pigmented

epithelial adenomas and clear cell sarcoma. (A) Patient who reported
worsening vision and eye pain for more than 3 mo. MRI revealed
4.1 3 3.7 3 5.0 mm lesion in corpus ciliare with slightly reduced
T1-weighted signals. [18F]PFPN showed high activity (SUVmax, 7.1), sug-
gesting melanin expression. Subsequent pathology confirmed pigmented
epithelial adenoma (74). (B) Patient with history of clear cell sarcoma sur-
gery underwent [18F]PFPN PET scan for recurrence detection. [18F]PFPN
PET found hepatic metastatic lesions , 1.0 cm missed with [18F]FDG (75).
T1WI/FS 5 T1-weighted imaging/fat-suppressed; T2WI/FS 5 T2-weighted
imaging/fat-suppressed. (Reprinted from (74,75).)

Clinical Applications of Melanin-Targeting Therapeutic Probes

In the field of melanin TRT, both antibodies and small-molecule
drugs have undergone initial assessments in clinical trials. Mier
et al. (27) conducted a pioneering human study using benzo(1,3)-
dioxolo-5-carboxylicacid(4-(2diethylaminoethylcarbamoyl)-2-
[131I]iodo-5-methoxyphenyl)amide and established the safety and
efficacy of small molecule–based TRT. Notably, 3 of 5 patients
who received doses ranging from 4.3 to 6.6 GBq of benzo(1,3)-
dioxolo-5-carboxylicacid(4-(2diethylaminoethylcarbamoyl)-2-
[131I]iodo-5-methoxyphenyl)amide survived beyond 2 y, a stark
contrast to untreated or underdosed patients with an average over-
all survival of roughly 3 mo, heralding a promising future for
benzamide-based TRT. [188Re]Re-6D2 was also investigated in
phase Ia and Ib studies to evaluate the safety, pharmacokinetics,
dosimetry, and antitumor activity (88). However, transient human
antimouse antibody responses were observed in 60% (9/15) of FIGURE 6. (A) Scheme of tetracycline-controlled transactivator tyrosi-
the patients. Additional clinical trials involving melanin-targeted nase (TYR) reporter system and molecular imaging applications.
[18F]P3BZA PET (B), MRI (C), and photoacoustic (D) 3-modality imaging
radiotracers are under way (89).
was used to monitor survival, distribution, and function duration of trans-
fected stem cells in myocardial infarction area (14). Dopa 5 3,4-dihydroxy-
MELANIN AS AN EXOGENOUS BIOMARKER phenylalanine; Dox 5 doxycycline; MSCs 5 mesenchymal stem cells;
PDT 5 photodynamic therapy; PTT 5 photothermal therapy; TetIIP 5
Melanin-targeted molecules have displayed promising applica- tetracycline-inducible promoter; Ubi-TetR 5 ubiquitin promoter–tetracycline
tions in melanoma. However, melanin has multiple characteristics repressor. (Reprinted with permission of (14).)

MELANIN-TARGETING RADIOTRACERS ! Zhang et al. 25S

[18F]P3BZA at the cellular level and in vivo. The system showed high
sensitivity for PAI and featured good contrast on T1-weighted images,
demonstrating the feasibility of a single reporter for 3-modality imag-
ing. It has the superiority to avoid the complexity of the construction
of multiple reporter gene fusions and uncontrollable expression.
In addition to applications in tumor imaging, the multifunctional
reporter gene was used in myocardial infarction in a study in China
(14). The researchers successfully transferred the tyrosinase gene
into bone marrow mesenchymal stem cells (Fig. 6), which were
used to treat myocardial infarction. PAI, MRI, and [18F]P3BZA
PET 3-modality imaging were used to monitor the survival, distri-
bution, and function duration of the transfected stem cells in the
myocardial infarction area. The results demonstrated the myocar-
dial infarction site with clear signals on PET, MRI, and PAI for at
least 28 d, suggesting the use of melanin as an exogenous biomarker
was a feasible and reliable method.
Tetracycline-Controlled Transactivator Tyrosinase
Reporter System
Virus-mediated tyrosinase gene transfection into cells may have
the risk of changing the growth rate, signal transduction pathways,
and other cellular behaviors. An inducible system is an effective
method for controlling genetic expression (91). Paproski et al. (92)
used the tetracycline-controlled transactivator system to control the
expression of the tyrosinase gene, with doxycycline as the inducer.
Researchers used this system for inducible expression of the tyrosi-
nase gene in vivo, and the induced melanin-expressing tumors
showed strong signals in multiwavelength PAI (93).
A study in China used the inducible system to achieve multimodal
imaging of PET, MRI, and PAI (94). Transfected MDA-MB-
231 cells produced melanin under the induction of doxycycline,
which was detected with sensitivity by [18F]P3BZA and PAI. Theo-
retically, after being transfected to produce melanin, nonpigment
cells can be used in melanin TRT. However, gene editing of cells is
complex, time-consuming, and limited by uncontrollable immunoge-
nicity, gene mutation, gene expression time, and gene expression
amount. Ongoing development of genetic engineering technology
and efforts to improve and optimize these techniques are required for
future clinical applications.
EXPERIENCES IN CHINA AND FUTURE PERSPECTIVES
Researchers have been studying probes targeting melanin since
approximately the mid-20th century, and these efforts are ongoing.
Small molecules, peptides, and antibodies exhibit distinct character-
istics and trade-offs in terms of pharmacokinetics and biologic
effects. Over the past decade, researchers in China have made substan-
tial efforts in the development and application of melanin-targeting
probes, providing findings and insights for further research in this field.
In terms of design, probes based on nicotinamide and picolina-
mide structures exhibit higher tumor uptake and more desirable
tumor retention than benzamide derivates. Research groups world-
wide, including those in China, have proved the effectiveness of
in vivo imaging and therapeutic efficacies (12,43,48). Furthermore,
the development of iodofluoronicotinamide benzamide, containing
nicotinamides with benzamides, is a novel approach, and combina-
tions of the 2 structures may be effective (53).
With regard to probe optimization, polyethylene glycolation is
considered effective for optimizing pharmacokinetics, as demon-
strated by [18F]PFPN. Polyethylene glycolation strategies enhance
the probe’s hydrophilicity, reducing uptake in nontarget organs and
providing better imaging contrast. To enhance tumor retention,
26S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65 ! No. 5 (Suppl. 1)
self-assembling peptide strategies may prove somewhat effective
(63). Another novel attempt involves dimerizing the melanin-
targeting portion to enhance tumor uptake (62). Various strategies
have yielded unsatisfactory results, confirming that 68Ga may not
be the optimal choice for labeling such molecules. These approaches
can offer inspiration for designing therapeutic probes that require
enhanced and prolonged tumor uptake, and the effectiveness of these
strategies needs validation in probes labeled with isotopes other than
radioactive metal nuclides.
Clinical trials for [18F]P3BZA and [18F]PFPN as 18F-labeled
melanin-targeting molecule probes have been pioneered in China
(72,73). Detailed in vivo studies conducted in healthy volunteers
have robustly affirmed the safety and tolerability of these probes.
Compared with the traditional imaging agent [18F]FDG, these
probes exhibit superior imaging performance, highlighting their
significant value in melanoma diagnosis and staging. Furthermore,
melanin-targeted imaging has shown potential value in assessing
the prognosis of melanoma patients. This suggests that using the
imaging parameters of such probes may aid in roughly quantifying
melanin and assessing the melanin burden in disease, thereby offering
better understanding of the role of melanogenesis in disease progres-
sion. Although these results are promising, some patients may have
less pigmented or amelanotic melanoma or lesions with diminishing or
absent melanin during disease progression and treatment. This under-
scores the importance of using melanin-targeted imaging probes to
select appropriate patients before embarking on melanin TRT.
The imaging capabilities of melanin-targeted probes have been
validated for other melanin-containing diseases, such as pigmented
epithelial adenomas and clear cell sarcoma (74,75), in preliminary
studies. This suggests a broader range of potential applications for
melanin-targeted probes beyond melanoma. Another promising
application of melanin-targeted probes is tyrosinase reporter gene
imaging. This strategy offers the potential for noninvasive, repeti-
tive, long-term tracking of cells, with the prospect of extending
applications to cell therapy, such as chimeric antigen receptor
T cells.
In summary, preclinical and clinical data collectively support the
promising prospects of melanin-targeted probes. Given the unique
binding characteristics of these probes to melanin, both well-
structured design and appropriate radionuclide selection are para-
mount in their development. Melanin-targeted imaging holds
potential value in the diagnosis, staging, and prognostic assess-
ment of melanoma. The excellent imaging capabilities of melanin-
targeted probes also demonstrate significant potential for use in
TRT. However, clinical validation remains limited, necessitating
further exploration and concerted efforts to transition from bench
to bedside. Furthermore, an intriguing avenue for future research
involves expanding the application scope of melanin-targeted
probes and exploring their value in other domains.
DISCLOSURE
This work was financially supported by the National Natural Sci-
ence Foundation of China (grants 82372026 and 82030052). No
other potential conflict of interest relevant to this article was
reported.
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! May 2024
Landscape of Nuclear Medicine in China and Its Progress
on Theranostics
Weidong Yang*1, Fei Kang*1, Yue Chen2, Zhaohui Zhu3, Feng Wang4, Chunxia Qin5, Jin Du6, Xiaoli Lan5, and
Jing Wang1
1
Department of Nuclear Medicine, Xijing Hospital, Fourth Military Medical University, Xi’an, China; 2Department of Nuclear
Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, China; 3Department of Nuclear Medicine, Peking Union
Medical College Hospital, Beijing, China; 4Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University,
Nanjing, China; 5Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and
Technology, Wuhan, China; and 6China Isotope and Radiation Corporation, Beijing, China

MILESTONES OF NUCLEAR MEDICINE IN CHINA

Nuclear medicine in China started in 1956 and, with the rapid develop-
ment of the economy and continuous breakthroughs in precision
medicine, has made significant progress in recent years. Almost
13,000 staff members in nearly 1,200 hospitals serve more than 3.9
million patients each year. Over the past decade, the radiopharma-
ceutical industry has developed rapidly, with the initial formation of a
complete industrial chain of production of various radiopharmaceuti-
cals for both clinical use and basic research. Advanced equipment
such as PET/CT scanners is being manufactured domestically and
even installed abroad. Recently, research into screening and synthe-
sizing new target probes and their translation into the clinic has gained
more attention, with various new tracers with potential clinical value
being thoroughly studied. Simultaneously, 68Ga- and 177Lu-labeled
tumor-targeted probes and others have been implemented for thera-
nostics in an increasing number of hospitals and would be helped by
approval from the National Medical Products Administration. Over the
next 10–20 y, with the launch of the Mid- and Long-Term Develop-
ment Plan for Medical Isotopes (2021–2035) by the Chinese govern-
ment, there is great potential for nuclear medicine in China. With the
rise in independent innovation in manufacturing, the shortage of radio-
pharmaceuticals will be effectively curtailed. We anticipate that the
scale of nuclear medicine will at least double by 2035, covering all
high-grade hospitals and leading to the aim of “one county, one
department” in China.
Key Words: nuclear medicine; China; theranostics; radiopharmaceuti-
cals; equipment
J Nucl Med 2024; 65:29S–37S
DOI: 10.2967/jnumed.123.266968
In 1956, the first training course for isotope usage in Xi’an,
Shaanxi Province, marked the beginning of nuclear medicine in
China. Since then, nuclear medicine has started to enter clinical
practice and serve patients. In the 1980s, its growth accelerated
with the implementation of China’s reform and opening-up policy.
The Nuclear Medicine Branch of the Chinese Medical Association
(Chinese Society of Nuclear Medicine) was established in 1980,
and the following year, the Chinese Journal of Nuclear Medicine
was published. It was renamed the Chinese Journal of Nuclear
Medicine and Molecular Imaging in 2012 and has been published
monthly since 2017. The first SPECT machine was introduced in
1983, and the first clinical PET machine was installed in 1995. By
the 21st century, nuclear medicine had developed tremendously in
China. PET/CT scanning was introduced to clinical practice in
2002, and PET/MRI started to operate in 2012. PET/CT equip-
ment manufactured by United Imaging Healthcare was installed at
Fujita University, Japan, in 2017, marking the internationalization
of nuclear medicine instruments manufactured in China. In 2021,
the National Atomic Energy Agency, together with 7 other depart-
ments, including the Ministry of Science and Technology and the
Ministry of Public Security, officially released the Mid- and Long-
Term Development Plan for Medical Isotopes (2021–2035), which
aims to rapidly promote the further development of nuclear medi-
cine in China.
STATUS OF CURRENT NUCLEAR MEDICINE

During the past decade, the state of nuclear medicine has greatly
improved in China. Detailed information is available from the Chi-

W ith nearly 70 years of development, nuclear medicine in

China has significantly progressed. A relatively complete nuclear
medical system has formed, which plays a critical role in both clini-
cal medicine and medical research. With the development of thera-
nostics, nuclear medicine in China will go into a new era and keep
moving forward rapidly.
Received Oct. 30, 2023; revision accepted Mar. 25, 2024.
For correspondence or reprints, contact Xiaoli Lan (hzslxl@163.com) or
Jing Wang (13909245902@163.com).
*Contributed equally to this work.
COPYRIGHT ! 2024 by the Society of Nuclear Medicine and Molecular Imaging.
nese Society of Nuclear Medicine, which conducts a national sur-
vey of the nuclear medicine industry every 2 y. Unfortunately,
because of the coronavirus disease 2019 pandemic, the survey
scheduled for 2022 was not conducted as planned. According to
the most recent survey, in 2020, there were 1,148 departments in
China engaged in nuclear medicine–related work, with 273 new
departments (a 31.2% increase) since 2010 (1,2). Nuclear medicine
professional staffing increased by 83.9% (12,578 in 2020 vs. 6,838
in 2010), as shown in Figure 1A. An increase of more than twice
that in the number of nuclear medicine departments clearly indicates
the scale of expansion of nuclear medicine. The main growth has
been in SPECT/CT scanners, which have increased from 555 in
2010 to 903 in 2020; PET/CT scanners have more than doubled
over 10 y (133 PET or PET/CT machines in 2010 vs. 427 in 2020;

PROGRESS OF NUCLEAR MEDICINE IN CHINA ! Yang et al. 29S


FIGURE 1. State of nuclear medicine in China. (A) Growth in number of
departments and staff in nuclear medicine. (B) Number of SPECT/CT
scanners and PET/CT scanners. (C–F) Applications of PET/CT (C),
PET/MRI (D), SPECT/CT (E), and radionuclide therapy (F) in 2020. 99Tc-
MDP 5 99mTc-methylene diphosphonate.
Fig. 1B). Surprisingly, numbers have doubled again in the past 3 y,
with more than 800 PET/CT machines and almost 100 PET/MRI
scanners in daily use. According to the 14th Five-Year Plan, by the
end of 2025, the number will be doubled once more, with PET/CT
scanners increasing to more than 1,600 and PET/MRI scanners
increasing to more than 200.
In 2020, 849,942 PET/CT scans were performed, 5 times the
number performed 10 y ago (158,000 scans in 2010). More than
96.3% (818,367) of the 2020 PET/CT scans were for tumor imag-
ing, whereas 1.7% (14,753) were for neurologic investigation,
0.7% (4,846) were for cardiology, and all others were for a 68Ga-
or 11C-labeled probe (Fig. 1C). In addition, 14,095 patients under-
went PET/MRI in 2020: 81.9% (11,545) for tumors, 11.4%
(1,607) for neurologic disease, 1.2% (175) for cardiologic disease,
and all others for 68Ga- or 11C-labeled probes (Fig. 1D). In 2020,
2,514,142 SPECT scans were conducted, more than twice the
1,178,800 scans in 2010; of the 2020 scans, 63.1% (1,586,423)
were for skeletal system imaging using 99mTc-methylene dipho-
sphonate, 16% (402,262) were for endocrine system imaging, 12%
(301,697) were for urinary system imaging, and 4% (100,565)
were for circulatory system imaging (Fig. 1E). About 65% of the
hospitals or medical institutions that used SPECT radiopharmaceu-
ticals purchased 99mTc-labeled radiopharmaceuticals from central-
ized radiopharmacies; others purchased 99Mo/99mTc generators to
prepare 99mTc-labeled radiopharmaceuticals themselves.
Recently, almost 528,480 radionuclide treatments have been
conducted annually. The top 4 radionuclide types were 131I for
thyroid disease, around 45% (235,202); 32P/90Sr/90Y for skin
cancer, around 32% (169,603); 99Tc-methylene bisphosphonate
(99Tc-methylene diphosphonate, or Yunke [Chengdu Yunke Phar-
maceutical Co. Ltd.]), around 19% (98,355); and 125I particle
implantation, around 2% (12,718; Fig. 1F) (1,2). In recent years,
30S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65 ! No. 5 (Suppl. 1)
some medical institutions have begun to use 223Ra-dichloride for
the treatment of castrated prostate cancer patients with bone metas-
tases. Other therapeutic radiopharmaceuticals, such as 177Lu-
DOTATATE and 177Lu-labeled prostate-specific membrane antigen
(177Lu-PSMA), which have been approved in the United States but
yet not by the National Medical Products Administration (NMPA),
have also been prepared and investigated in clinical research for
neuroendocrine tumors and prostate cancer. Once treated with
radionuclides, patients should be followed up promptly to evaluate
the treatment response, modify the treatment plan if necessary, and
improve its effectiveness. The National Nuclear Medicine Quality
Control Center has set specific follow-up goals for hospitalized
patients such as those treated with 131I or patients with bone metas-
tases undergoing radionuclide treatment. For example, as required
by the National Nuclear Medicine Quality Control Center, hospital-
ized patients with bone metastases who underwent a SPECT/CT
scan should be followed up in no less than 50% of cases.
Currently, the percentage of patients undergoing nuclear medi-
cine examinations is still limited (0.28% of the population). One
of the most important reasons is that the public is unfamiliar with
nuclear medicine. The Chinese Society of Nuclear Medicine is
devoted to the promotion of knowledge and popularization of
nuclear medicine, and it has established an Information and Sci-
ence Popularization Working Committee with these aims. Nuclear
medicine experts have been organized periodically by the Chinese
Society of Nuclear Medicine to record videos, write papers, and
print pamphlets to introduce nuclear medicine to the public and
even to clinicians; organize academic lectures for physicians or
technicians; or dispatch experts to grassroots hospitals to assist in
promoting nuclear medicine technology.
PRODUCTION OF MEDICAL RADIOISOTOPES
After decades of development, the radiopharmaceutical industry
in China has made great progress, with a widespread supply of
multiple radioisotopes for clinical use and for research. 99mTc is
the most commonly used radioisotope for SPECT, accounting for
more than 90% of all SPECT imaging, and most 99mTc still
depends on international suppliers. The China Institute of Atomic
Energy has developed fission 99Mo production with an emphasis
on low-enriched-uranium targets (3–5) that is expected to improve
99m
Tc supply in the near future. 18F, the most commonly used
radioisotope in PET scanning, has been used daily for more than
900 PET scanners all over the country. About 120 hospitals or
medical institutions prepare their own 18F, and the rest purchase
it from radiopharmacies. 131I is the main radioisotope used in ther-
apy and is fully supplied domestically.
The rapid growth of the radiopharmaceutical industry has allowed
the production or supply of other clinically used radioisotopes,
including 125I, 198Au, 90Sr-90Y, 186Re, 153Sm, 161Tb, and 14C, and
the promotion of nuclear medicine in China. However, some com-
monly used radioisotopes still cannot be produced domestically. For
example, 68Ga, eluted from 68Ge/68Ga generators, is a popular PET
radioisotope label for PSMA, TATE, etc., that is not yet available
domestically. 68Ga/177Lu, a pair of radioisotopes used to label the
same probe, is ideal for theranostics, but 177Lu has to be purchased
from an international company such as Isotopen Technologien
M€ unchen. Recently and excitingly, the Mianyang Research Reactor
of the China Academy of Engineering Physics has developed tech-
nology and production facilities for 177Lu, successfully producing
no-carrier-added 177Lu (6). Small-batch production (at the curie
! May 2024
level) was achieved, and the product has been used in clinical trials
at some hospitals. Because there are 120 cyclotrons, Chinese
researchers are focused on novel medical isotopes with established
targets, which may help alleviate the shortage of radioisotope
supplies.
COMMERCIAL RADIOPHARMACEUTICALS
The radiopharmaceuticals commonly used in clinical practice,
such as 131I-sodium iodide oral solution, capsules for diagnostic
or therapeutic use (131I-sodium iodide), 125I as a brachytherapy
source, 99mTc-labeled radiopharmaceuticals (99mTc-methylene
diphosphonate, 99mTc-methoxyisobutylisonitrile, and 99mTc-
diethylenetriaminepentaacetic acid), 89Sr-chloride injection, 223Ra-
dichloride injection, and 90Y-resin microspheres, are commercially
available in China (data from https://www.nmpa.gov.cn). The
NMPA has approved 11 types of radionuclides, involving 33 radio-
pharmaceuticals. In addition to the companies producing radiophar-
maceuticals, holders of usage of radiopharmaceutical permission
license III can manufacture positron radiopharmaceuticals such as
18
F-sodium fluoride, 18F-FDG, and 11C-acetate that are approved
by the NMPA, and holders of license IV can synthesize or produce
radiotracers not yet approved by the NMPA.
In the past few years, various novel targets have been explored
worldwide as imaging or radionuclide therapy targets. Researchers
in China have been involved in developing radiopharmaceuticals
and in clinical translation for diagnosis and therapy. Tremendous
progress has been achieved; many new radiopharmaceuticals have
been thoroughly studied, and several are seen as potentially useful
radiopharmaceuticals that deserve commercial development, as
reviewed by Hu et al. (7) and Cui et al. (8). Eighty-eight pharmaceu-
tical companies qualified to produce radiopharmaceuticals are
engaged in translational development or commercialization of these
potential probes. Clinical trials are ongoing for 47 radiopharmaceuti-
cals. Of these, 15 are in stage I, 4 are in stage II, and 28 are in stage
III; 21 are for PET/CT imaging, 4 are for SPECT/CT imaging, and
all others are for radionuclide therapy. Most of them are focused on
oncology (79.2%), followed by neurology (16.7%) and all others
(about 4.1%; Fig. 2). Detailed information is presented for phase I
and II clinical trials in Table 1 and phase III trials in Table 2.
DOMESTIC ADVANCED EQUIPMENT
PET represents the most sophisticated equipment in nuclear
medicine, and its development in China can be traced back to the
work of a team at the Institute of High Energy Physics of the Chi-
nese Academy of Sciences. The first prototype was successfully
developed in June 1986, and preclinical images of a monkey’s
FIGURE 2. Commercial radiopharmaceuticals under development. (A)
Radiopharmaceuticals in different stages of clinic trial. (B) Indications for
radiopharmaceuticals under investigation.
PROGRESS OF NUCLEAR MEDICINE IN CHINA
brain were obtained. Unfortunately, it was not used for clinical
application or commercialization. The first domestic clinical PET
system was developed by Neusoft Healthcare in 2009, and the first
PET/CT scanner was developed by United Imaging Healthcare in
2014. The United Imaging Healthcare also produced the first
domestic PET/MRI scanner, which was installed in 2018.
Companies such as United Imaging Healthcare have quickly
developed PET/CT or PET/MRI machines. The quality and perfor-
mance of PET equipment have rapidly improved. The world’s first
total-body PET/CT machine (uEXPLORER; United Imaging Health-
care), which allows dynamic imaging, was launched in 2018. It can
obtain information about blood circulation throughout the body, pro-
viding a tool for studying physiology, as well as pathologic processes
in disease (9). The latest digital PET/CT machine, uMI Panorama
(United Imaging Healthcare), with a 2.9-mm National Electrical
Manufacturers Association PET resolution and sub–200-ps timing
resolution, provides extremely high-quality images (10).
Apart from dynamic imaging, whole-body PET/CT can signifi-
cantly reduce scan time and dosage injection. Zhang et al. (11) and
Hu et al. (12) showed that a fast PET protocol, with a 30- to 45-s
acquisition time in the total-body uEXPLORER PET/CT scanner,
could provide image quality equivalent to that of conventional digital
scans. Zhao et al. (13) explored the relationship of image quality,
lesion detection rate, and acquisition time in routine clinical practice
using different injection dosages and showed that optimal image
quality could be achieved with a dose reduction to a one-10th admin-
istered dose (0.37 MBq/kg) for total-body PET/CT. Short-duration
scanning may be helpful for patients who are unable to tolerate a
long scan, for example, because of severe cancer pain, and reducing
injection dosage is particularly beneficial in pediatric patients.
Medical cyclotrons producing positron radioisotopes for PET/CT
or PET/MRI have also played a critical role in nuclear medicine
development. A few years ago, cyclotrons in the Chinese market
relied on international companies; recently, domestic manufacturers
have begun to emerge. SiChuan Longevous Beamtech Co., Ltd.,
has the ability to expand to low-energy and high-energy accelera-
tors, including ion sources, with multispecification targets, shields,
and other components and unique technical advantages. In 2020,
Longevous-11 (Longevous Beamtech Co. Ltd.) became the first
commercial medical cyclotron produced in China.
RESEARCH AND FUNDING OF NUCLEAR MEDICINE
From 2013 to 2022, the total number of applications for projects
in the field of nuclear medicine and molecular imaging reached
2,949 in China, and 899 grants were supported by the National
Natural Science Foundation of China. The number of applications
and successful grants has steadily increased. Overall funding
increased from 20.9 million yuan (#$2.9 million) in 2013 to
59.5 million yuan (#$8.2 million) in 2022. Of the 899 approved
grants, 608 (69.3%) were for tumor studies and 269 (30.6%) were
for nontumor studies. Most research has focused on the develop-
ment of tumor-targeted molecular probes for precise imaging and
radionuclide therapy (14).
In the past decade, the National Natural Science Foundation of
China has responded to national funding directives and steadily
expanded funding for young researchers in nuclear medicine and
molecular imaging. The number of related projects and the total
funding have steadily increased, with diverse, often interdisciplin-
ary, projects. However, it is still necessary to strengthen funding
for major projects in this field. In recent years, the Chinese
! Yang et al. 31S
 TABLE 1
Radiopharmaceuticals Under Commercial Clinical Development or in Market Approval Process in China

Drug Company Phase Indication

NRT6003 injection
18
F-fusiruitai injection
18
F-fuxianyisu injection
18
F-florbetazine injection
18
F-florastamin injection
18
F-BF3-BPA injection
68
Ga-HX01 injection
68
Ga-natan recombinant
PD-L1 single-domain
antibody injection
Kit for preparation of HRS-
9815
HRS-9815 injection
99m
Tc-CNDG injection
131
I-IPA injection
131
I-actuximab injection
177
Lu-JH020002 injection
HRS-4357 injection
177
Lu-XT033
177
Lu-vipivotide tetraxetan
injection
NRT6008 injection
18
F-flutemetamol injection
18
F-florbetapir injection
90
Y-resin microspheres
188
Re-HEDP injection
Chengdu New Radiomedicine
Technology Co., Ltd.
Shanghai Lannacheng Biotechnology
Co., Ltd.
Yantai Lannacheng Biotechnology Co.,
Ltd.
HTA Co., Ltd.
HTA Co., Ltd.
Suzhou Boruichuanghe Biotechnology
Co., Ltd.
Suzhou Hexin Pharmaceutical
Technology Co., Ltd.
Suzhou Smartnuclide
Biopharmaceutical Co.
Tianjin Hengrui Pharmaceuticals Co.,
Ltd.
Tianjin Hengrui Pharmaceuticals Co.,
Ltd.
Beijing Shihong Drug Development
Center
Telix International Pty Ltd.; Grand
Pharmaceutical Co., Ltd., China
Shanghai Haikang Chinese Medicine
Technology Development Co., Ltd.
Bivision Biomedical Technology Co.,
Ltd.
Tianjin Hengrui Pharmaceuticals Co.,
Ltd.
Sinotau Pharmaceuticals Co., Ltd.
Advanced Accelerator Applications
USA, Inc., Novartis Co.
Chengdu New Radiomedicine
Technology Co., Ltd.; Chongqing
HuaPont Pharmaceutical
General Electric Pharmaceutical Co.,
Ltd., Shanghai
Nanjing Jiangyuan AMS Positron
Research and Development Co.,
Ltd.
Grandpharma Co., Ltd., China
Yantai Dongcheng Pharmaceutical
Group Co., Ltd.
I Therapy for primary and metastatic
liver cancer
I Diagnosis of PSMA-positive lesions in
prostate cancer patients
I Diagnosis of FAP-positive lesions in
solid tumor patients
I Diagnosis of Alzheimer disease related
to b-amyloid neuritic plaques
I Diagnosis of PSMA-positive lesions in
prostate cancer patients
I Diagnosis of brain tumor lesions
I Diagnosis of tumors that express avb3
or CD13 receptors
I PET imaging for assessment of PD-L1
expression levels in primary or
metastatic lesions of solid tumor
patients
I Diagnosis of PSMA-positive lesions in
prostate cancer patients
I
I Diagnosis of benign and malignant
tumors
I Therapy for glioblastoma
I Therapy for advanced malignant solid
tumor
I Therapy for mCRPC
I Therapy for mCRPC
I Therapy for mCRPC
II Therapy for mCRPC
I Therapy for pancreatic cancer
I and II Diagnosis of Alzheimer disease related
to b-amyloid neuritic plaques
II Diagnosis of Alzheimer disease related
to b-amyloid neuritic plaques
II Therapy for inoperable primary liver
cancer
II Palliation of bone pain caused by bone
metastases

BF3-BPA 5 boron trifluoride boronophenylalanine; CNDG 5 isonitrile deoxyglucosamine; IPA 5 4-L-iodophenylalanine; mCRPC 5
metastatic castration-resistant prostate cancer; HEDP 5 hydroxyethylidene diphosphonate.

32S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65 ! No. 5 (Suppl. 1) ! May 2024
 TABLE 2
Radiopharmaceuticals in Phase III of Commercial Clinical Development or Market Approval Process in China

Drug Company Indication

18
F-alfatide injection Jiangsu Shimeikang Pharmaceutical Tumor diagnosis
Co., Ltd.
18
F-APN-1607 injection Suzhou Xinxu Pharmaceutical Co., Ltd. Diagnosis and evaluation of
neurodegenerative diseases,
including Alzheimer disease and
cognitive impairment related to tau
protein pathology
18
F-florbetaben injection Tianjin HTA Isotope Medicine Co., Ltd. Diagnosis of Alzheimer disease related
to b-amyloid neuritic plaques
18
F-sodium fluoride injection Nanjing Jiangyuan AMS Positron Diagnosis of bone metastasis of
Research and Development Co., malignant tumor
Ltd.; HTA Co., Ltd.
6-18F-fluoro-L-dopa injection Jiangsu Huayi Technology Co., Ltd.; Imaging to visualize dopaminergic
HTA Co., Ltd. nerve terminals in striatum for
evaluation of suspected Parkinson
disease in adult patients
18
F-flortaucipir injection Beijing Xinhe Pharmaceutical Diagnosis and evaluation of
Technology Co., Ltd. neurodegenerative diseases,
including Alzheimer disease and
cognitive impairment related to tau
protein pathology
68
Kit for preparation of Ga-PSMA-11 Novartis Pharma AG/Advanced Diagnosis of PSMA-positive lesions in
Accelerator Applications USA, Inc., prostate cancer patients
Novartis Co.
68
Ga-PSMA-11 injection Telix Pharmaceuticals Inc., US
68
Kit for preparation of Ga-DOTATATE HTA Co., Ltd. Diagnosis of somatostatin receptor–
positive NETs in adults and children
68
Ga-DOTATATE injection HTA Co., Ltd.
68
Kit for preparation of Ga-edotreotide Tianjin Hengrui Pharmaceuticals Diagnosis of somatostatin receptor–
Co., Ltd. positive NETs in adults and children
68
Ga-edotreotide injection Tianjin Hengrui Pharmaceuticals
Co., Ltd.
99m
Tc-3PRGD2 injection Foshan Ruidiao Pharmaceutical Diagnosis of benign and malignant
Co., Ltd. lung tumors and lung lymph node
metastasis
99m
Tc-GSA injection Beijing Shihong Drug Development Diagnosis of function and morphology
Center of liver
99m
Tc-technetiumsulfur colloid injection HTA Co., Ltd. Diagnosis of primary tumor drainage
area lymph nodes in adult breast
cancer patients
123
I-ioflupane injection GE Pharmaceutical Co., Ltd., Shanghai Diagnosis of Parkinson disease
90
Y-glass microspheres Fangen Pharmaceutical Development Therapy for unresectable primary liver
Co., Ltd., Tianjin cancer
131
I-MIBG injection HTA Co., Ltd. Diagnosis of neuroblastoma and
pheochromocytoma
177
Lu-DOTATATE injection Advanced Accelerator Applications Therapy for neuroendocrine tumor
S.A.; Jingding Pharmaceutical
Research and Development Co.,
Ltd., Shanghai
177
Lu-DOTATATE injection HTA Co., Ltd. Therapy for neuroendocrine tumor
177
Lu-DOTATATE injection Sinotau Pharmaceuticals Co., Ltd. Therapy for neuroendocrine tumor
177
Lu-DOTATATE injection Tianjin Hengrui Pharmaceuticals Therapy for neuroendocrine tumor
Co., Ltd.
177
Lu-DOTATOC injection ITM Solucin GmbH Therapy for neuroendocrine tumor

APN 5 florzolotau; NETs 5 neuroendocrine tumors; GSA 5 galactosyl-human serum albumin; MIBG 5 metaiodobenzylguanidine.

PROGRESS OF NUCLEAR MEDICINE IN CHINA ! Yang et al. 33S

government has established several major scientific research pro- as 225Ac has been studied for labeling a somatostatin analog. A case
jects to develop new, high-quality equipment in nuclear medicine, report by Peng et al. (21) showed that 225Ac-DOTATATE could be
with total funding of 118 million yuan (#$16 million). used successfully for metastatic pheochromocytoma. Before treatment,
68
Ga-DOTATATE PET/CT showed multiple lesions with elevated
POTENTIAL OF NUCLEAR MEDICINE IN CHINA tracer uptake throughout the body; however, tracer uptake of almost all
Although nuclear medicine in China has improved significantly lesions was significantly reduced after 3 cycles of 225Ac-DOTATATE,
in the past few years, the coverage of nuclear medicine remains with a dose of approximately 7.4 MBq (0.2 mCi) per injection.
low. There are only 0.305 PET/CT scanners and 0.645 SPECT/CT
68
scanners for every 1 million Chinese people. Only 6.07 per 10,000 GA/177LU THERANOSTICS FOR PROSTATE CANCER
people have had a PET/CT scan, and just 3.79 per 10,000 people 177
Lu-PSMA treatment for prostate cancer has also undergone
have received radionuclide therapy annually. This is lower than in phase III clinical trials in 11 centers, and approval by the NMPA
the United States or European countries. However, Chinese nuclear is expected in 2025. Bu et al. (22) conducted a single-center study
medicine can remain at the forefront of international nuclear medi- evaluating the efficacy and safety of 177Lu-PSMA I&T in East
cine through the installation of PET/CT and PET/MRI scanners, Asian populations. Enrolled patients were selected by 68Ga-PSMA
the application of new radiopharmaceuticals, etc. In tight cooperation PET. After 2 or more cycles of 177Lu-PSMA I&T, 68Ga-PSMA
with international colleagues, theranostics such as 68Ga/177Lu-PSMA PET/CT was repeated to evaluate response to treatment. Six
and 68Ga/177Lu-fibroblast activation protein inhibitor (FAPI) are patients (15%) developed mild reversible xerostomia during
being rapidly developed and broadly explored in the clinic. Other follow-up, and 28 patients (70%) experienced grade 1–4 bone mar-
theranostics are also under investigation, and innovative radiophar- row dysfunction in this study. Changes in prostate-specific antigen
maceuticals may be commercialized in the near future. were assessed after therapy, with partial response in 25 patients
(62.5%), stable disease in 5 patients (12.5%), and progressive disease
PROGRESS IN THERANOSTICS IN CHINA
in 10 patients (25%). Quality of life, Karnofsky performance status,
As a promising clinical tool for personalized medicine, theranostics and pain were all significantly improved after treatment (P , 0.05).
has received great attention in China over the past decade. Probes spe- This study showed that 177Lu-PSMA I&T achieved favorable
cifically targeted to lesions can be labeled with different radionuclides, responses in East Asian populations.
177
including positron radionuclide labeling for PET imaging and b- or Lu-EB-PSMA-617 was developed to optimize the pharmaco-
a-emitter radionuclide labeling for radiation therapy. With typical kinetics, prolong tumor retention, and improve the efficacy of
theranostics, lesions detected by PET could be suited to radionuclide treatment. A dosimetry study showed that in comparable bone
therapy to effectively improve treatment. Serial clinical translational metastases (SUVmax, 10.0–15.0), the accumulated radioactivity of
studies of novel theranostics, such as 68Ga-, 177Lu-, or 225Ac-labeled 177
Lu-EB-PSMA-617 was about 3.02-fold higher than that of
177
probes for neuroendocrine tumors and prostate cancer, have been con- Lu-PSMA-617 (23,24). Furthermore, approximately 2.0 GBq
ducted in an increasing number of hospitals. of 177Lu-EB-PSMA for up to 3 cycles achieved a prostate-specific
antigen response, with hematologic toxicity comparable to that from
68
GA/177LU THERANOSTICS FOR NEUROENDOCRINE TUMOR 7.4-GBq doses of 177Lu-PSMA-617 for 4–6 cycles (Fig. 3) (25).
Using 68Ga-DOTATATE PET/CT imaging in patients with neu- 68
GA/177LU THERANOSTICS BY TARGETING FAP
roendocrine tumors at baseline and/or after several cycles of treat-
ment with 177Lu-DOTATATE has been widely explored in China. FAP is a type II transmembrane protein that is overexpressed in
177
Lu-DOTATATE treatment of neuroendocrine tumors is under- cancer-associated fibroblasts and therefore is a promising target
going phase III clinical trials. In addition to DOTATATE, Chinese for diagnosis and treatment of numerous malignant tumors.
researchers have designed new radiopharmaceuticals for clinical Radioisotope-labeled FAPI is under broad investigation in China.
studies that optimize the pharmacokinetics of 177Lu-DOTATATE. Baseline imaging by 68Ga-FAPI that demonstrates tumor FAP
177
Lu-DOTA-EB-TATE was designed by adding an Evans blue expression was used to select patients for radionuclide-targeted
motif to 177Lu-DOTATATE. As expected, 177Lu-DOTA-EB-TATE therapy. Fu et al. (26) showed that 177Lu-FAPI-46 was useful in
achieved a 7.9-fold increase in tumor dose, whereas the increased metastatic nasopharyngeal carcinoma and could be used for treat-
doses to the kidneys and bone marrow were 3.2- and 18.2-fold, ment of advanced radioiodine-refractory differentiated thyroid
respectively (15). In patients given a single
dose of 177Lu-DOTA-EB-TATE, as low as
0.66 6 0.06 GBq (17.8 6 1.7 mCi), 72.5%
of 40 neuroendocrine tumors with a diame-
ter of at least 2.0 cm showed a more than
15% decrease of SUVmax (16). Dose esca-
lations up to approximately 3.7 GBq/cycle
(100 mCi) for 3 cycles seemed to be well
tolerated, achieving a response rate of
48.3% and a disease control rate of 86.2%
(17–19). Moreover, the 177Lu-DOTA-EB-
TATE treatment, without amino acid infu-
FIGURE 3. Metastatic castration-resistant prostate cancer patients with whole-body metastases
sion, demonstrated a favorable safety profile treated with 177Lu-EB-PSMA at 1.85 GBq for each cycle, as shown with PSMA PET. (A–C) Patients
in neuroendocrine tumor patients (20). In treated with 1–3 cycles of 177Lu-EB-PSMA. After treatment, total-lesion PSMA (TLP), PSMA volume
addition to 177Lu, an a-particle emitter such (PSMA-VOL), and prostate-specific antigen (PSA) were significantly decreased.

34S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65 ! No. 5 (Suppl. 1) ! May 2024
cancer. Intense radiotracer uptake was observed in such metastatic
lesions on a 68Ga-FAPI PET/CT scan before and after therapeutic
scintigraphy. Follow-up examinations, after 4 cycles of 177Lu-
FAPI-46 treatment, revealed stable metastatic lesions (26). Several
structurally optimized FAPI probes are undergoing clinical
research to further improve the effectiveness of radionuclide-
labeled FAPI in the treatment of solid tumors. Fu et al. (27) further
produced 177Lu-EB-FAPI (177Lu-LNC1004) and treated patients
with metastatic radioiodine-refractory thyroid cancer, showing that
177
Lu-LNC1004 at 3.33 GBq/cycle was well tolerated, with high-
radiation-dose delivery to the tumor lesions, encouraging therapeu-
tic efficacy, and acceptable side effects. In addition to thyroid
carcinoma, Rao reported that 177Lu-FAPI-2286 was effective in
squamous cell lung cancer with systemic metastases (28). It may
be anticipated that 68Ga/177Lu-FAPI theranostics will be extended
to other solid carcinomas in an increasing number of hospitals.
THERANOSTICS FOR BONE METASTASIS
Bone is the most common site of distant metastasis of malignant
tumors. Bisphosphonate, an antibone absorbent, has been widely
used in cancer bone metastasis, but it has a limited inhibitory effect
on cancer cells, and in clinical practice, high doses of bisphospho-
nates often cause jawbone necrosis. However, ibandronate, an imid-
azole derivative and third-generation bisphosphonate, can be used
for treatment of bone metastasis. Wang et al. (29,30) independently
designed and developed a targeted diagnosis- and treatment-
integrated radiopharmaceutical, 68Ga/177Lu-DOTA-ibandronate. The
results in 18 cases of bone metastases showed that baseline 68Ga-
DOTA-ibandronate PET imaging had higher diagnostic efficacy for
bone metastases than did 99mTc-methylene diphosphonate SPECT.
Subsequent 177Lu-DOTA-ibandronate treatment showed that in
17 patients who experienced pain before treatment, 14 (82%)
achieved relief of bone pain. An 8-wk follow-up 68Ga-DOTA-iban-
dronate PET/CT showed partial remission in 3 patients, disease
progression in 1 patient, and stable disease in 14 patients (Fig. 4).
FIGURE 4. 66-y-old patient with prostate cancer and bone metastases who received 4 cycles of
therapy with 370 MBq of 177Lu-DOTA-ibandronate. (A) 68Ga-DOTA-ibandronate PET/CT image
before treatment. (B–E) 68Ga-DOTA-ibandronate PET/CT images after each cycle. After 4 cycles of
treatment, uptake of 68Ga-DOTA-ibandronate was significantly decreased. Arrows refer to metasta-
ses at L4-5 vertebra, and arrowheads refer to metastases at 10th rib on right side.
PROGRESS OF NUCLEAR MEDICINE IN CHINA
More recently, 177Lu-DOTA-ibandronate–targeted therapy has been
used for bone metastases from various tumors, including lung, breast,
prostate, thyroid, colon, and kidney, as well as neuroendocrine tumors
(31,32). Furthermore, ibandronate has been labeled with 225Ac, and
the clinical translation of 225Ac-labeled DOTA-ibandronate has shown
a potent response of bone metastases after 1 cycle of 225Ac-DOTA-
ibandronate therapy (33). All studies indicated that 68Ga/177Lu/225Ac-
DOTA-ibandronate provides a potential set of integrated radiopharma-
ceuticals with good prospects in the diagnosis and treatment of bone
metastases (32,34).
OTHERS
Additional theranostic agents based on different probes for
imaging and radionuclide therapy, such as 90Y-resin microspheres,
have been used clinically. 90Y radioembolization is a promising
approach for treating liver malignancies and received approval by
the NMPA on January 30, 2022. To conduct 90Y-resin micro-
sphere treatment, 99mTc-labeled macroaggregated albumin is first
administered to simulate the deposition of the 90Y-resin micro-
spheres in the patient and to calculate the required dose of 90Y.
Angiography is then repeated after 1–2 wk to facilitate the admin-
istration of the calculated dose of 90Y, and after treatment, the
patient undergoes a SPECT/CT or PET/CT scan for confirmation
of the distribution of the 90Y-resin microspheres to assess the effi-
cacy and safety profile. Feng et al. (35) and Li et al. (36) reported
the first case treated with 90Y-resin microspheres in China, and
since then, more than 100 patients have received 90Y-resin micro-
sphere treatment.
PROCEDURES AND CHALLENGES OF THERANOSTICS
Before novel theranostic radiopharmaceuticals can be used in
the clinic, applicants must comply with the requirements of good
clinical practice issued by the NMPA and must apply to the hospi-
tal ethics committee for approval. The ethics committee is respon-
sible for conducting a comprehensive evaluation of the scientific
rationale and procedures involved in the
clinical trial, as well as the risks and bene-
fits to patients. Trials will be approved
only when the design and implementation
of clinical trials comply with ethical regu-
lations, protecting the safety, health, and
other rights of patients. For radiopharma-
ceutical companies, a registration applica-
tion needs to be submitted to the NMPA,
which evaluates the value, safety, efficacy,
production processes, and quality control
of the radiopharmaceuticals. If the applica-
tion is approved, the NMPA will issue a
registration certificate, permitting commer-
cialization and use in the clinic. Several
radiopharmaceuticals have entered the
approval process, clinical trials, or the
marketing approval stage, and some of
these are expected to be approved in the
near future.
Interdisciplinary cooperation and col-
laboration between academia and industry
is essential for theranostics. Multidisciplin-
ary discussions by a combination of
nuclear medicine physicians, oncologists,
! Yang et al. 35S
urologists, and other relevant specialists about patient selection,
individual treatment plans, and response evaluation are required
before theranostics. In the development of radiotracers for thera-
nostics, multiple disciplines, such as biomedicine and radiochem-
istry, are required to work together to screen specific targets,
synthesize high-affinity probes, label with radionuclides, and
translate research into the clinic.
Researchers in hospitals or institutes and in commercial compa-
nies can all develop radiopharmaceuticals. Once radiotracers have
shown definite diagnostic or therapeutic effects, researchers in hos-
pitals or institutes can transfer their patents to companies for com-
mercialization. For example, 177Lu-DOTA-ibandronate, mentioned
earlier, has already had its patent transferred to the commercial com-
pany Kelun-Biotech for production. The patent for 18F-PFPN, devel-
oped by Lan et al. (37) in Union Hospital, Huazhong University of
Science and Technology, for melanoma PET/CT imaging, was
transferred to HighTech Atom Co., Ltd. Yang et al. at Peking Uni-
versity Cancer Hospital have successfully transferred several radio-
pharmaceutical patents to companies, and the latest PSMA-P137
was authorized to Yunnan Baiyao Group Co., Ltd., in August 2022
(38). In addition, researchers can commercialize radiotracers them-
selves. However, if commercial companies develop a potential
radiotracer with good preclinical results, they can collaborate with
researchers in hospitals for clinic trials for final NMPA approval.
The rapidly growing need for skilled professionals in nuclear
medicine remains a major challenge. China has established a com-
prehensive system to cultivate nuclear medicine professionals,
including undergraduate education and master’s and doctoral train-
ing. After graduating from medical colleges, students should
receive systematic training for 3 y, in accordance with the stan-
dardized training content and standards for nuclear medicine resi-
dent physicians issued by the National Health Commission.
However, because of great demand, the existing professional train-
ing system is still inadequate; therefore, doctors in other fields
have been enrolled to work in nuclear medicine, and continuing
education is essential for these specialists. As a new technology,
theranostics requires special training and has been limited to a few
specialist hospitals. Nuclear medicine physicians preparing to con-
duct theranostics can attend those specific hospitals for special
training and advance their knowledge through various academic
conferences or special lectures.
New technologies and radiopharmaceuticals for theranostics are
still relatively expensive for most Chinese patients, because they
are not yet covered by health care programs. For example, the 18F-
or 68Ga-labeled probe for PET/CT usually costs more than 5,000
yuan (#$691), and the 177Lu-labeled probe for radionuclide ther-
apy will be more expensive than PET/CT imaging. However, we
anticipate that with improvement of the technology and gradual
expansion of clinical applications, radiopharmaceutical prices will
be gradually reduced, becoming affordable for an increasing num-
ber of patients, and could be covered by health care programs in
the near future. If so, these will greatly promote the development
of theranostics.
THE FUTURE
Nuclear medicine in China has made tremendous progress in
the past 70 y. Millions of patients benefit each year from the devel-
opment of nuclear medicine; however, shortages of supplies of
radioisotopes and lack of radiopharmaceuticals persist. Neverthe-
less, the potential scope for future nuclear medicine in China
36S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65 ! No. 5 (Suppl. 1)
remains enormous; there are more than 3,000 tertiary hospitals,
the highest-ranked hospitals in China, yet only one third of them
provide nuclear medicine services at present. The issuing of
Healthy China 2030 and the Mid- and Long-Term Development
Plan for Medical Isotopes (2021–2035) by the Chinese govern-
ment resulted in a bright blueprint for Chinese nuclear medicine.
As planned, nuclear medicine will cover all tertiary hospitals and
be launched in another 2,000 hospitals throughout the country to
implement the “one county, one department” policy. We anticipate
that by the end of 2035, the shortage of radioisotopes and radiophar-
maceuticals will no longer exist. Independent innovation in radio-
pharmaceuticals will continuously emerge, and more advanced,
high-quality equipment will be produced by local companies. The
scale of nuclear medicine will be 3–4 times greater than it is today,
serving more than 10 million patients each year in China.
DISCLOSURE
No potential conflict of interest relevant to this article was
reported.
ACKNOWLEDGMENTS
We thank Xiang Zhou, Jiajun Ye, Xiang Li, and Lin Qiu for tech-
nical assistance.
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! Yang et al. 37S
Recent Advances in Radiotracers Targeting Novel
Cancer-Specific Biomarkers in China: A Brief Overview
Jingming Zhang*1,2, Fei Kang*3, Xiao Wang1, Xuejiao Chen1, Xing Yang1,4–6, Zhi Yang5,7, and Jing Wang3
1
Department of Nuclear Medicine, Peking University First Hospital, Beijing, China; 2Department of Nuclear Medicine, Beijing
Chao-Yang Hospital, Capital Medical University, Beijing, China; 3State Key Laboratory of Holistic Integrative Management of
Gastrointestinal Cancers, Department of Nuclear Medicine, Xijing Hospital, Fourth Military Medical University, Xi’an, China;
4
Department of Central Laboratory, Peking University First Hospital, Beijing, China; 5Key Laboratory for Research and Evaluation of
Radiopharmaceuticals (National Medical Products Administration), Beijing, China; 6International Cancer Institute, Peking University
Health Science Center, Beijing, China; and 7Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/
Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital and Institute, Beijing, China

methods for the accurate detection and quantification of these bio-

Radiopharmaceuticals play a critical role in nuclear medicine, provid-
ing novel tools for specifically delivering radioisotopes for the diagno-
sis and treatment of cancers. As the starting point for developing
radiopharmaceuticals, cancer-specific biomarkers are important and
receive worldwide attention. This field in China is currently experienc-
ing a rapid expansion, with multiple radiotracers targeting novel tar-
gets being developed and translated into clinical studies. This review
provides a brief overview of the exploration of novel imaging targets,
preclinical evaluation of their targeting ligands, and translational
research in China from 2020 to 2023, for detecting cancer, guiding tar-
geted therapy, and visualizing the immune microenvironment. We
believe that China will play an even more important role in the devel-
opment of nuclear medicine in the world in the future.
Key Words: China; radiopharmaceuticals; cancer-specific biomar-
kers; cancer diagnosis; cancer treatment
J Nucl Med 2024; 65:38S–45S
DOI: 10.2967/jnumed.123.266314
markers become significantly important for solving the clinical
demands for patient stratification (7).
Nuclear medicine imaging (PET/CT and SPECT) is an effective
method for detecting and staging cancers (8,9). It can provide
quantitative information about the level of expression of cancer-
specific biomarkers, thus facilitating clinical treatment decision-
making. The discovery of novel cancer-specific biomarkers and
the development of effective targeted radiopharmaceuticals are
essential for enriching the nuclear medicine imaging toolbox.
Over the last decades, China has shown rapid development in
these areas. Several early reviews have summarized various
aspects of this development (10,11). During the last 3 y, research-
ers in China have actively been continuing to contribute to the
development of novel nuclear imaging methods for assisting can-
cer theranostics. This review presents an updated summary with a
focus on radiotracers targeting novel biomarkers.

I
IMAGING AGENTS FOR CANCER DIAGNOSIS

n the era of precision medicine, cancers can be identified and
reclassified by specific molecular markers, which help to achieve
targeted diagnosis and treatment. In China, the incidence rate and
mortality of cancer continue to rise along with the aging of the
population (1). According to the official “Healthy China 2030”
planning outline, the overall early diagnosis rate and 5-y survival
rate of common cancers aim to be improved to greater than or
equal to 55% and 46.6%, respectively. The concepts of diagnosis
and therapy mediated by cancer-specific biomarkers are becoming
rapidly accepted. After the revelation of the pathogenesis of cancer
and its immune escape mechanism, various novel therapeutic
approaches, such as targeted therapies (2–5) and immunotherapies
(6), have been developed and have contributed greatly to the
advancement of oncology treatments. The success of these thera-
pies is highly dependent on the clear identification of the level of
expression of the key biomarkers within the tumor. Therefore,
Received Oct. 31, 2023; revision accepted Jan. 23, 2024.
For correspondence or reprints, contact Jing Wang (13909245902@163.
com) or Xing Yang (yangxing2017@bjmu.edu.cn).
*Contributed equally to this work.
COPYRIGHT ! 2024 by the Society of Nuclear Medicine and Molecular Imaging.
Cancer specifically overexpresses a range of proteins either in
tumor cells or in the microenvironment for promoting the growth
and invasion of tumors. These proteins provide characteristic
information about tumor tissues and make them ideal nuclear
imaging targets for cancer diagnosis. For example, radiopharma-
ceuticals targeting prostate-specific membrane antigen, a protein
highly overexpressed in prostate cancer and tumor neovasculature,
can be used for the accurate staging of prostate cancer (12). Fibro-
blast activation protein, which is specifically overexpressed in
cancer-associated fibroblasts, can be used as a pan-cancer target
for the diagnosis of a variety of tumors (13). Related studies have
been actively pursued in China. In addition to these well-known
targets, radiotracers targeting novel biomarkers are also under pre-
clinical and translational studies; these include some targets that
have been substantially developed worldwide (e.g., carbonic anhy-
drase IX (14), integrin avb6 (15,16), CD38 (17,18), epithelial cell
adhesion molecule (19), glypican 3 (20,21), carcinoembryonic
antigen–related cell adhesion molecule 5 (22), and integrin avb3
(23)) and some that have been pioneered mainly by Chinese
researchers (e.g., galectin (24), integrin a6 (25), and nectin cell
adhesion molecule 4 (nectin-4) (26,27)), as shown in Table 1. We
selected representative examples for a brief introduction.

38S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65 ! No. 5 (Suppl. 1) ! May 2024
 TABLE 1
Summary of Novel Radiopharmaceuticals Developed in China from 2020 to 2023

Target type Target Ligand Ligand type Stage Reference

68
Cancer diagnostic targets CAIX [ Ga]Ga-NY104 Small molecule Clinical 14
68
Galectin [ Ga]Ga-galectracer Small molecule Clinical 24
68
Integrin avb6 [ Ga]Ga-cycratide Peptide Clinical 15
68
[ Ga]Ga-DOTA-R01-MG Peptide Preclinical (16)
Integrin a6 [99mTc]Tc-RWY Peptide Clinical (early 25
phase 1)
68
Nectin-4 [ Ga]Ga-N188 Peptide Clinical 26
[99mTc]Tc-HYNIC-mAbNectin-4 Antibody Preclinical 27
68
CD38 [ Ga]Ga-NOTA-Nb1053 Single-domain antibody Preclinical 17
[99mTc]Tc-CD3813 Single-domain antibody Preclinical 18
18 18
CEACAM5 [ F]FB-Nb41 and [ F]FB-Nb41-ABD Single-domain antibody Preclinical 22
EpCAM [99mTc]Tc-NB4 Single-domain antibody Preclinical 19
18 68 68
Glypican 3 [ F]F-G2, [ Ga]Ga-NOTA-G2, and [ Ga]Ga- Single-domain antibody Preclinical 20
NOTA-ABDG2
[99mTc]Tc-HPG Peptide Preclinical 21
177
Integrin avb3 [ Lu]Lu-Palm-3PRGD2 Peptide Preclinical 23
124
Cancer therapeutic targets CLDN18.2 [ I]I-18B10(10 L) Antibody Clinical 48
89
[ Zr]Zr-DFO-TST001 Antibody Preclinical 47
124
[ I]I-5C9 Antibody Preclinical 46
68 18 64
Ga-, F-, and Cu-labeled hu19V3 Single-domain antibody Preclinical 49
89
Zr-labeled CLDN18.2 VHH, CLDN18.2 Single-domain antibody Preclinical 51
VHH-ABD, and CLDN18.2 VHH-Fc
89
[ Zr]Zr-hu7v3-Fc Single-domain antibody Preclinical 50
89
Death receptor 5 [ Zr]Zr-CTB006 Antibody Clinical 34
131 18
KRAS I- and F-labeled ARS-1620 Small molecule Preclinical 56
18
[ F]PFPMD Small molecule Clinical 57
18
LAT-1 [ F]FBY Small molecule Clinical 75
68
CDK19 [ Ga]Ga-IRM-015-DOTA Small molecule Preclinical 36
CDK4/6 [99mTc]Tc-tricine-TPPTS-L and [99mTc]Tc- Small molecule Preclinical 38
tricine-TPPMS-L
68
[ Ga]Ga-DOTA-palbociclib Small molecule Preclinical 37
c-Met [99mTc]Tc-HYNIC-YQ-M3 Peptide Preclinical 39
18
[ F]FPC Small molecule Preclinical 76
68
PARP [ Ga]Ga-DOTA-olaparib Small molecule Preclinical 77
68
PDGFRb [ Ga]Ga-DOTA-ZTRI Affibody (Affibody AB) Preclinical 40
[99mTc]Tc-HYNIC-YQGX-10 Peptide Preclinical 41
64
Trop2 [ Cu]Cu-NOTA-Himb1636 Antibody Preclinical 35
68
Cancer immunotherapy- CD8 [ Ga]Ga-NOTA-SNA006 Single-domain antibody Preclinical 78
related targets
68
[ Ga]Ga-NODAGA-SNA006 Single-domain antibody Clinical (early 61
phase 1)
68
Granzyme B [ Ga]Ga-grazytracer Small molecule Clinical 70
68
TIGIT [ Ga]Ga-GP12 Peptide Clinical 63
68
[ Ga]Ga-DOTA-DTBP-3 Peptide Preclinical 62
124
CD25 [ I]I-basiliximab Antibody Preclinical 79
64
ICAM-1 [ Cu]Cu-NOTA-ICAM-1 Antibody Preclinical 80
64
[ Cu]Cu-NOTA-aICAM-1/Fab Fab Preclinical 74
68 68 89
CD47 [ Ga]Ga-NOTA-C2, Ga- and Zr-labeled Single-domain antibody Preclinical 64
177
NOTA-ABDC2, and [ Lu]Lu-DOTA-ABDC2
18
STING [ F]F-DABI Small molecule Preclinical 66
18
[ F]FBTA Small molecule Preclinical 65
68
VLA-4 [ Ga]Ga-LLP2A Peptide Preclinical 81

CAIX 5 carbonic anhydrase IX; CEACAM5 5 carcinoembryonic antigen–related cell adhesion molecule 5; EpCAM 5 epithelial cell adhesion molecule;
LAT-1 5 large neutral amino acid transporter type 1; CDK19 5 cyclin-dependent kinase 19; CDK4/6 5 cyclin-dependent kinase 4/6; [18F]FPC 5 18F-radiolabeled
crizotinib derivative; PARP 5 poly(adenosine diphosphate–ribose) polymerase; PDGFRb 5 platelet-derived growth factor receptor b; Trop2 5 trophoblast
cell surface antigen 2; [18F]FBTA 5 18F-radiolabeled analog of STING agonist-benzothiophene derivative; VLA-4 5 very late antigen 4.

UPDATE ON RADIOPHARMACEUTICALS IN CHINA ! Zhang et al. 39S

Nectin-4
Nectin-4, also named poliovirus receptor–like 4, is a type I
transmembrane cell adhesion molecule of the nectin family (28). It
is expressed mainly in the embryo and placenta during fetal devel-
opment, with expression declining in adulthood. Upregulation of
nectin-4 was found in various cancer types, most commonly in
urothelial carcinoma, being present in 83% to 97% of tumor sam-
ples (28,29). The tumor-specific expression makes nectin-4 an
excellent theranostic target. An antibody–drug conjugate targeting
nectin-4, enfortumab vedotin (30), was the first such agent approved
by the U.S. Food and Drug Administration for treating locally
advanced and metastatic urothelial carcinoma (3). Recently, promis-
ing results were also observed when enfortumab vedotin was com-
bined with other types of immunotherapies (31).
The diagnostic value of the nectin-4–targeting method has not
been fully exploited. In principle, the cancer-specific expression of
nectin-4 could provide an imaging method for tumor detection. In
2022, Shao et al. developed a 99mTc-labeled antibody ([99mTc]Tc-
HYNIC-mAbNectin-4) for the detection of triple-negative breast
cancer (27). This radiotracer showed good detection capability and
high specificity for nectin-4–positive tumors, but the prolonged
blood circulation half-life of the antibody required over 24 h to
reach a good target-to-background contrast.
Low-molecular-weight agents can have good pharmacokinetics
and achieve good imaging contrast within 1 h. Recently, Duan et al.
constructed a novel nectin-4–targeting radiotracer ([68Ga]Ga-
N188) based on the bicyclic peptide scaffold BT8009 (26).
[68Ga]Ga-N188 specifically targeted nectin-4–expressing tumors
and was rapidly excreted by the kidneys. A translational study was
performed on 2 healthy volunteers and 14 patients with advanced
bladder cancer using uEXPLORER (United Imaging) total-body
PET/CT to determine the pharmacokinetics and tissue distribution
of the radiotracer (Fig. 1A). A good correlation between the organ
FIGURE 1. (A) Dynamic SUVmax of [68Ga]Ga-N188 in selected organs.
(B) SUVmax of [68Ga]Ga-N188 at lesions with different nectin-4 expression
levels (*** indicates P , 0.001). (C) [68Ga]Ga-N188 and [18F]FDG PET/CT
imaging of adrenal metastasis of urothelial cancer (top) and inflamed
lymph nodes (bottom). (D) Comparison of [68Ga]Ga-N188 PET/CT,
[18F]FDG PET/CT, and MRI of brain metastasis from urothelial cancer.
Lesions or inflamed lymph nodes are indicated by arrows. DCE-MRI 5
dynamic contrast-enhanced MRI; DWI 5 diffusion-weighted imaging;
T2WI 5 T2-weighted imaging. (Adapted with permission of (26).)
40S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65 ! No. 5 (Suppl. 1)
uptake and the nectin-4 expression level was confirmed (Fig. 1B).
High sensitivity and specificity could be achieved for bladder can-
cer detection, showing potential advantages for distinguishing
tumors from inflammatory lesions or organs with high [18F]FDG
uptake (Figs. 1C and 1D). A recent clinical study involving 62
patients with 16 types of cancer was performed to explore the clin-
ical application of [68Ga]Ga-N188 PET in multiple cancers; the
initial results demonstrated a detection rate comparable to that of
[18F]FDG PET, improved performance in the detection of residual
and recurrent tumors, and lymph node specificity, indicating the
potential utility of this method for cancer diagnosis in general.
Integrins
Integrins, as a class of cell adhesion transmembrane receptors,
are overexpressed in a wide range of cancer types and play a criti-
cal role in tumor progression (32). They normally exist as a het-
erodimer, consisting of an a-subunit and a b-subunit; there are no
less than 24 functionally distinct isoforms, categorized into 4 types,
including leukocyte cell adhesion integrins, RGD-binding integrins,
collagen-binding integrins, and laminin-binding integrins (33).
Integrin avb3 is a classical target and has attracted worldwide inter-
est for the development of tumor-targeting radiotracers. Recently, a
phase 3 clinical trial (NCT04233476) of [99mTc]Tc-3PRGD2 was
completed, with results that met both primary and secondary end-
points. It will hopefully be approved soon in China as a novel
radiopharmaceutical for cancer diagnosis; its approval could fill the
gap in radiopharmaceutical approvals during the last decade. Con-
sidering the low cost of SPECT, it may provide an affordable
method for people in developing countries or in other areas where
the installed PET base may limit access.
Novel radiopharmaceuticals targeting other integrins (e.g., integ-
rins avb6 and a6) have also been developed and evaluated in
clinical translational studies. Recently, Feng et al. reported a 68Ga-
labeled cyclic peptide, [68Ga]Ga-cycratide, based on the integrin
avb6–targeting RGDLATL sequence (15). Compared with linear
peptides, it showed a similar affinity for integrin avb6, with
improved serum stability and higher tumor uptake. The clinical
translational study in patients with pancreatic cancer showed that
[68Ga]Ga-cycratide had good pharmacokinetics and could be applied
to detecting pancreatic neoplastic lesions and postoperative recur-
rence (Fig. 2A). Gao et al. reported an integrin a6–targeted
radiotracer, [99mTc]Tc-RWY (25), and demonstrated its in vivo spe-
cificity in several preclinical animal models as well as its potential
for clinical application in 2 patients with breast cancer (Fig. 2B).
IMAGING AGENTS FOR GUIDING TARGETED THERAPY
Targeted therapy represents one of the most important mile-
stones for cancer treatment. Targeted small molecules or monoclo-
nal antibodies could serve as a “magic bullet” to selectively
deliver payloads to the key receptors or functional proteins that
promote cancer growth, proliferation, survival, and metastasis to
exert anticancer effects. Recently, targeted therapeutic agents
experienced accelerated approval for broad clinical applications;
these include sacituzumab govitecan for trophoblast cell surface
antigen 2 (2), olaparib for poly(adenosine diphosphate–ribose)
polymerase (4), and sotorasib for Kirsten rat sarcoma viral onco-
gene homologue (KRAS) (5). Because of their high specificity,
these drugs are effective only in cancer patients carrying the
related biomarkers. Assessment of the level of expression of these
biomarkers is crucial for patient stratification, and PET imaging
may provide an ideal tool for noninvasively quantifying biomarker
! May 2024

FIGURE 2. (A) [68Ga]Ga-cycratide and [18F]FDG PET/CT images of
patients with suspected or postsurgery recurrent pancreatic cancer.
Lesions are indicated by red arrows. (B) CT and [99mTc]Tc-RWY
SPECT/CT images in different planes (transverse, coronal, and sagittal) of
patient with breast cancer. Lesion is indicated by white arrow. Existence
of tumor cells and integrin a6 expression were confirmed by hematoxylin–
eosin (HE) staining result and integrin a6 immunohistochemistry (IHC)
staining result, respectively. (Adapted from (15,25).)
expression at a molecular level to guide accurate patient selection.
Great effort has been made in this direction; radiotracers for anti-
body–drug conjugate targets (e.g., death receptor 5 (34) and tropho-
blast cell surface antigen 2 (35)), protein kinase targets (e.g.,
cyclin-dependent kinase 19 (36), cyclin-dependent kinase 4/6
(37,38), c-Met (39), and platelet-derived growth factor b (40,41)),
and others are summarized in Table 1. Among them, the develop-
ment of radiotracers targeting biomarkers such as cyclin-dependent
kinase 19, claudin 18.2 (CLDN18.2), and KRAS is in the early
stages and has been pioneered mainly by Chinese scholars. Here
we further discuss 2 examples.
CLDN18.2
The CLDN18.2 protein is a tight junctional protein and is 1 of the
2 isoforms of claudin 18 protein (42). It has been found to have lim-
ited expression mainly in the tight junctions of differentiated gastric
mucosal epithelial cells, functioning in barrier maintenance and para-
cellular transport (43). Overexpression of CLDN18.2 has been iden-
tified in multiple malignancies, such as gastric cancer and pancreatic
cancer, making it an excellent therapeutic target (44). Monoclonal
antibodies and antibody–drug conjugates against CLDN18.2, such as
zolbetuximab, TST001, AB101, SYSA-1801, RC118, and CMG901,
have been evaluated in clinical trials to explore their safety and anti-
tumor activity in patients with advanced solid tumors (45).
The boost in CLDN18.2-targeted cancer therapeutics brings up
a demand for assessing CLDN18.2 expression for patient strati-
fication. Immuno-PET may provide a straightforward platform
for selecting patients and evaluating the treatment response.
Zhu’s group evaluated a series of immuno-PET imaging probes,
including [124I]I-5C9 (46), [89Zr]Zr-DFO-TST001 (47), and [124I]I-
18B10(10 L) (48), for the in vivo detection of CLDN18.2 expres-
sion in subcutaneous and orthotopic gastric cancer xenograft
models. [124I]I-18B10(10 L) was selected, and a first-in-humans
UPDATE ON RADIOPHARMACEUTICALS IN CHINA
translational study was performed to assess its safety and feasibility
for mapping CLDN18.2 expression in 17 patients, including
12 with gastric cancers, 4 with pancreatic cancers, and 1 with
cholangiocarcinoma. [124I]I-18B10(10 L) PET could detect most
CLDN18.2-overexpressing lesions with an acceptable dosimetry
profile and could monitor CLDN18.2 expression status before and
after CLDN18.2-targeted treatment (Fig. 3), demonstrating the fea-
sibility of CLDN18.2-targeted imaging.
To improve the pharmacokinetics, single-domain antibodies tar-
geting CLDN18.2 have been actively pursued, with the potential
advantages of better tumor penetration and faster tumor uptake than
those of conventional monoclonal antibodies. Wei et al. reported a
humanized single-domain antibody targeting CLDN18.2 (clone
hu19V3) and constructed radiotracers labeled with 68Ga,64Cu, and
18
F, which showed moderate tumor uptake with fast renal clearance
(49). Zhong et al. developed a humanized single-domain antibody
targeting CLDN18.2, fused it with human IgG1 Fc, and labeled it
with 89Zr to generate [89Zr]Zr-hu7v3-Fc (50). Compared with the
antibody, [89Zr]Zr-hu7v3-Fc was smaller and had a higher affinity,
resulting in better tumor penetration and faster tumor uptake. Hu
et al. developed a humanized single-domain antibody and fused it
with the albumin-binding domain or IgG1 Fc (51). The antibody
was radiolabeled with 89Zr and evaluated in preclinical models.
Biodistribution results at 12 h after injection showed that the addi-
tion of the albumin-binding domain or IgG1 Fc increased tumor
uptake by 34.6-fold or 40.7-fold, respectively. With all of the expe-
rience accumulated with functionalized single-domain antibodies
in preclinical settings, multiple translational studies are currently
under investigation.
KRAS
The KRAS gene is one of the most frequently mutated onco-
genes among the RAS GTPase family and one of the most com-
mon tumor driver mutations (52). The total proportion of the
KRAS mutation in tumors is about 30%; it is most common in
pancreatic cancer (60%–90%), colorectal cancer (30%–45%), and
lung cancer (20%–30%) (53). The G12C mutation of KRAS
(KRASG12C) damages the guanosine triphosphate hydrolysis medi-
ated by GTPase-activating protein, increases guanosine triphos-
phate–bound KRAS, and continuously activates the downstream
pathway for the occurrence and maintenance of cancer (54).
Therefore, it has been considered an important therapeutic target
for a wide range of cancers. KRASG12C-specific inhibitors may
FIGURE 3. Representative [124I]I-18B10(10 L) PET images of patient
before and after CLDN18.2-targeted therapy. Lesions are indicated by
arrows. After receiving CLDN18.2-targeted therapy, SUVmax of peritoneal
metastases decreased from 3.1, 3.2, and 4.2 to 0.7, 0.9, and 1.6, respec-
tively, and patient survived for up to 40 wk without progression. (Adapted
with permission of (48).)
! Zhang et al. 41S
provide an effective solution, and 2 inhibitors (sotorasib and ada-
grasib) have been approved for the treatment of advanced or meta-
static KRASG12C non–small cell lung cancer (5,55). The success
of the treatment is highly dependent on the existence of the muta-
tion, which is mainly determined by biopsy and tumor gene
sequencing. A noninvasive molecular imaging method could pro-
vide an ideal solution to overcome the limitations caused by tumor
heterogeneity.
In 2021, Zhang et al. reported a radiolabeled small molecule,
[131I]I-ARS-1620, for imaging of the KRASG12C status of tumors
in vivo (56). The in vivo imaging results showed that A549 tumors
with KRASG12C could be specifically detected at 1 h after injec-
tion, with a tumor-to-muscle ratio of 2.2 6 0.48 (mean 6 SD), and
no significant uptake was detected in either the KRASG12C-nega-
tive A549 tumor group or the ARS-1620 blocking group.
Recently, Li et al. reported another novel radiotracer derived
from AMG510 (sotorasib), [18F]PFPMD, for the PET imaging of
KRASG12C status in vivo (57). It can bind to KRASG12C with
higher selectivity than KRASWT (wild type), KRASG12D, or
KRASG12V. The PET imaging results showed significantly higher
uptake in KRASG12C mutated tumors than in non–KRASG12C
mutated tumors in a preclinical mouse model (3.93 6 0.24 %ID/g
vs. 2.47 6 0.26 %ID/g). A translational study was performed
with 5 healthy volunteers and 14 patients with non–small cell
lung cancer or colorectal cancer to assess safety, dosimetry,
and KRASG12C imaging capability. The results showed that
[18F]PFPMD was safe and primarily excreted through the kidney
and intestines (Fig. 4A). The SUVmax of tumors with KRASG12C
was higher than that of those without the mutation (Fig. 4B) in
FIGURE 4. (A) Representative [18F]PFPMD PET images of healthy volun-
teer at different time points after injection. (B) Representative [18F]PFPMD
PET/CT images of non–KRASG12C-expressing and KRASG12C-expressing
tumors in patients with non–small cell lung cancer and colorectal cancer.
KRAS mutation status of tumors was determined by amplification-
refractory mutation system polymerase chain reaction or targeted 425-
gene sequencing, with KRASG12C mutant lesions indicated by red arrows
and non-KRASG12C mutant lesions indicated by white arrows. (Adapted
from (57).)
42S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65 ! No. 5 (Suppl. 1)
both patients with non–small cell lung cancer (3.56 6 0.67 vs.
2.45 6 0.21) and patients with colorectal cancer (3.90 6 0.53 vs.
2.48 6 0.29), indicating the potential of this radiotracer for the
clinical evaluation of KRASG12C.
IMAGING AGENTS FOR VISUALIZING IMMUNE
MICROENVIRONMENT
Immunotherapy has brought revolutionary changes to cancer
management. Unlike other types of cancer therapy, immunother-
apy aims to activate the host immune system to exert anticancer
effects (58). This unique feature allows it to achieve a clinical
response to a wide range of cancer types (6). Immune infiltration
in the tumor microenvironment and the maintenance of its effector
functions are crucial for the efficacy of immunotherapy. However,
the high complexity and heterogeneity of the tumor microenviron-
ment result in variable therapeutic responses, and only a subset of
patients benefit from immunotherapy. Therefore, it is important to
develop reliable methods for patient stratification and monitoring
of the efficacy of immunotherapy. A variety of novel radiotracers
targeting immune-related biomarkers, such as programmed cell
death protein 1 (59), programmed cell death ligand 1 (60), CD8
(61), T-cell immunoreceptor with immunoglobulin and immunore-
ceptor tyrosine-based inhibition motif domain (TIGIT) (62,63),
CD47 (64), and stimulator of interferon genes (STING) (65,66),
have been developed for visualizing the immune microenviron-
ment and predicting or monitoring the treatment response. Some
of them, such as radiotracers targeting CD8, granzyme B, TIGIT,
CD47, and very late antigen 4, were developed on the basis of rel-
evant studies conducted outside China. In addition, some, such as
radiotracers targeting intercellular adhesion molecule 1 (ICAM-1)
and STING, were originally developed by Chinese researchers.
The progress made in this field in China during recent years is
summarized in Table 1, and 2 representative examples are dis-
cussed here.
Granzyme B
Granzyme B is a serine esterase mainly excreted by cytotoxic T
lymphocytes and natural killer cells. Within target cells, granzyme
B rapidly activates the caspase cascade reaction and triggers cell
apoptosis by inducing DNA fragmentation (67). Granzyme B
secretion is a key step in a variety of antitumor immunotherapies,
reflecting not only cytotoxic T-cell infiltration at the tumor site but
also the functional status of immune cells (68). Therefore, radio-
tracers targeting granzyme B secretion can provide a direct indica-
tion of the tumor-killing effect of immune cells and potentially
help to predict the response to immunotherapy (69).
In 2022, Zhou et al. developed a 68Ga-labeled peptidomimetic
agent, [68Ga]Ga-grazytracer, for granzyme B–targeted PET imag-
ing (70). Compared with the peptide-based PET imaging ligand
[68Ga]Ga-NOTA-GZP (69), [68Ga]Ga-grazytracer showed
improved potency and metabolic stability, which resulted in higher
tumor uptake and tumor-to-muscle ratio. The efficiency of
[68Ga]Ga-grazytracer in monitoring early tumor responses to
immune checkpoint inhibitors and adoptive T-cell transfer therapy
was investigated in preclinical mouse models. A positive relation-
ship between tumor uptake and therapeutic outcome was observed.
[68Ga]Ga-grazytracer PET could differentiate tumor pseudopro-
gression on immune checkpoint inhibitor treatment from true pro-
gression, demonstrating a potential advantage over [18F]FDG
PET. In addition, a clinical translational study of [68Ga]Ga-grazy-
tracer was performed. Patients undergoing immune checkpoint
! May 2024

FIGURE 5. [18F]FDG and [68Ga]Ga-grazytracer PET images of lung can-
cer patients treated with immunotherapy. [18F]FDG SUVmax of both
patients decreased after immunotherapy; however, patient with higher
[68Ga]Ga-grazytracer uptake (SUVmax, 4.1; tumor–to–blood pool SUVmax
ratio, 1.2) showed positive response (A), and patient with lower [68Ga]Ga-
grazytracer uptake (SUVmax, 2.0; tumor–to–blood pool SUVmax ratio, 0.8)
showed negative response (B). Red arrows indicate primary tumors.
(Adapted from (70).)
inhibitor treatment were imaged after treatment initiation. The
results showed that the treatment responders had higher granzyme
B PET tumor SUVmax and tumor–to–blood pool ratio than nonre-
sponders (Figs. 5A and 5B); these results were consistent with the
immunochemistry staining results. With the potential of [68Ga]Ga-
grazytracer having been demonstrated, a systematic clinical investi-
gation would have merit and is currently under way.
ICAM-1
ICAM-1, also known as CD54, is a member of the immunoglobu-
lin superfamily of adhesion molecules expressed mainly on endothe-
lial cells and leukocytes (71). It plays a key role in innate and
adaptive immune responses and promotes the activation and migra-
tion of lymphocytes by interacting with leukocyte integrins such
as lymphocyte function–associated antigen 1 and Mac1 (72,73).
Recently, Zhao et al. discovered that ICAM-1 played an important
role in the abscopal effect of tumor radiation therapy and that
ICAM-1–targeted imaging can be used for prediction of the
responses to radiation therapy in combination with immunotherapy
(74). Tumors were inoculated on both left and right flanks of
BALB/c mice, and only 1 was irradiated to mimic the clinical sce-
nario of a primary tumor and its metastatic lesions (Fig. 6A). Signifi-
cant upregulation of ICAM-1 in nonirradiated tumors with a smaller
change in tumor volume was identified by quantitative proteomic
analysis. Further mechanistic studies showed that ICAM-1 improved
the abscopal effect by increasing the infiltration and activation of
CD81 T cells within the tumor. A 64Cu-labeled ICAM-1–specific
PET imaging radiotracer, [64Cu]Cu-NOTA-aICAM-1/Fab, was con-
structed and succeeded in noninvasive monitoring of ICAM-1
expression levels and early prediction of the abscopal effect of
tumor radiotherapy in 4T1 and CT26 tumor–bearing mouse
models, with good contrast and specificity (Figs. 6B and 6C). The
feasibility of using ICAM-1 PET to predict the abscopal effect
during radiotherapy has been demonstrated, and a radioligand with
UPDATE ON RADIOPHARMACEUTICALS IN CHINA
FIGURE 6. (A) Schedule of x-ray radiotherapy (X-RT) and in vivo imaging
in 4T1 tumor–bearing mice. (B) Representative small-animal PET images
of [64Cu]Cu-NOTA-aICAM-1/Fab in 4T1 tumor–bearing mice at 6 h after
injection, with red circles indicating location of nonirradiated tumors.
(C) Growth curves of nonirradiated 4T1 tumors (** indicates P , 0.01).
%ID/g 5 percentage injected dose per gram; NIRF 5 near-infrared fluo-
rescence; V 5 tumor volume at day n; V0 5 tumor volume at day 0.
(Adapted with permission of (74).)
18 68
improved pharmacokinetics and suitable for F and Ga labeling
would facilitate translational research.
CONCLUSION
The last 3 y have witnessed the rapid development of radiophar-
maceuticals in China. A variety of novel tumor-related biomar-
kers, such as nectin-4, KRAS, CLDN18.2, and granzyme B,
have been exploited as targets for tumor diagnosis or prediction
of the treatment response, and progress has been made in the
development of high-quality ligands targeting these biomarkers.
For multiple radiotracers, first-in-humans clinical translation has
been achieved. Besides monoclonal antibodies and small mole-
cules, a variety of functionalized peptides and antibody fragments
(e.g., Fab and single-domain antibody) with suitable pharmacoki-
netics matching those of short–half-life nuclides (18F and 68Ga)
have also been actively pursued. In addition to diagnostic usage,
radionuclide therapy is another attractive application area for
nuclear medicine. Biomarkers with membrane localization, limited
expression in normal tissues, and upregulation in cancer are
ideal targets for radionuclide therapy application. Some of them,
such as integrin avb3, trophoblast cell surface antigen 2, CD47,
and CLDN18.2, have been tested in preclinical models for radio-
nuclide therapy. In addition, other biomarkers with good tumor
specificity and imaging potential, such as nectin-4, glypican 3,
integrin a6, epithelial cell adhesion molecule, and death receptor
5, can also be exploited for radionuclide therapy.
However, there are still limitations that may require further
efforts. First, the number of radiopharmaceuticals targeting innova-
tive targets remains low and needs to be further explored. Second,
the performance of innovative radiopharmaceuticals still needs sys-
tematic evaluation in well-designed prospective cohort studies.
With improved accessibility of screening methods (e.g., cyclic
peptide and single-domain antibody) and accumulated experience
! Zhang et al. 43S
(e.g., radiolabeling and patient management), greatly accelerated
development of and translational research on radiopharmaceuticals
are expected in China in the near future.
DISCLOSURE
This study was supported by National Natural Science Founda-
tion of China grants (92059101 and 22277002 to Xing Yang;
91959208, 92259304, and 82122033 to Fei Kang). No other poten-
tial conflict of interest relevant to this article was reported.
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! Zhang et al. 45S
The Role of Total-Body PET in Drug Development and
Evaluation: Status and Outlook
Xiangxi Meng1, Xiangxing Kong1, Lei Xia1, Runze Wu2, Hua Zhu1, and Zhi Yang1
1
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), National Medical Products
Association, Key Laboratory for Research and Evaluation of Radiopharmaceuticals, National Medical Products Association,
Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, China; and 2Beijing United Imaging
Research Institute of Intelligent Imaging, Beijing, China
Total-body PET, an emerging technique, enables high-quality simulta-
neous total-body dynamic PET acquisition and accurate kinetic analy-
sis. It has the potential to facilitate the study of multiple tracers while
minimizing radiation dose and improving tracer-specific imaging. This
advancement holds promise for enhancing the development and clini-
cal evaluation of drugs, particularly radiopharmaceuticals. Multiple
clinical trials are using a total-body PET scanner to explore existing
and innovative radiopharmaceuticals. However, challenges persist,
along with the opportunities, with regard to the use of total-body PET
in drug development and evaluation. Specifically, considerations
relate to the role of total-body PET in clinical pharmacologic evalua-
tions and its integration into the theranostic paradigm. In this review,
state-of-the-art total-body PET and its potential roles in pharmaceuti-
cal research are explored.
Key Words: total-body PET; radiopharmaceuticals; drug develop-
ment; pharmacology study
J Nucl Med 2024; 65:46S–53S
DOI: 10.2967/jnumed.123.266978
S
ince the beginning of the 20th century, the field of drug dis-
covery and development has undergone continuous evolution in
the pursuit of finding the zauberkugel (magic bullet) (1) that speci-
fically interacts with the molecular and cellular targets associated
with diseases. As a realization of this concept, radiopharmaceuti-
cals have been engaged in molecular imaging, radioisotope ther-
apy, and related theranostic strategies.
The development of radiopharmaceuticals is a complex and
time-consuming process. Compared with regular drugs, additional
challenges relate to their special requirements, such as dosage
dependence, radiation safety, and short shelf-life (2). Because PET
and SPECT imaging play a crucial role in the application of radio-
pharmaceuticals, advancements in imaging technologies can thus
expedite drug development in both preclinical and clinical study
stages.
PET imaging visualizes the administration and biodistribution
of labeled molecules in living organisms, accurately quantifying
the metabolism of positron emitters. Through PET images, the
pharmacologic characteristic of the drug can be noninvasively
Received Oct. 31, 2023; revision accepted Jan. 23, 2024.
For correspondence or reprints, contact Zhi Yang (pekyz@163.com).
COPYRIGHT ! 2024 by the Society of Nuclear Medicine and Molecular Imaging.
46S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65 ! No. 5 (Suppl. 1)
assessed in living animals and human subjects. In the development
and evaluation of positron-emitting radiopharmaceuticals, PET
imaging inevitably assumes the central role. Beyond PET tracer
development, PET imaging is used to assess the effects in clinical
trials of other therapeutic products. In general, PET imaging pro-
vides insights into the pharmacokinetics, pharmacodynamics,
safety, efficacy, toxicity, dosage regimen, and response monitoring
in the clinical trials (3).
Facing uncertainties and unknown properties, the use of PET
imaging in drug development is more challenging than in clinical
routines. Clinical trials often demand unconventional scanning
conditions, such as ultrashort duration, ultralow dose, and ultra-
long uptake time, and these special requirements challenge con-
ventional PET scanners. Equipment developers strive to pursue
higher performance to meet these demands.
Several technologies mark the paradigm shift in PET imaging,
and among them, total-body PET is especially intriguing. After the
successful introduction of the world’s first total-body PET/CT
scanner, the United Imaging uEXPLORER PET/CT scanner (4),
several other models with the long-axial-field-of-view feature have
emerged (5), including PennPET EXPLORER (6) and Siemens
Biograph Quadra (7). Other long-axial-field-of-view or total-body
scanners are being developed, but uEXPLORER is the only clini-
cally available total-body scanner (5). Despite its high investment
cost, the unparalleled image quality and enhanced detection ability
of total-body PET indicate particular advantages in clinical scenar-
ios (8). Clinical evidence is being accumulated, and the compara-
tive value of total-body PET scanners versus conventional PET
scanners with a shorter axial field of view has been manifested.
Therefore, it is not surprising that total-body PET technology is
poised to have substantial influence on drug development, particu-
larly in the field of radiopharmaceuticals. This review commences
by introducing possibilities brought by total-body PET and asses-
sing their potential impact on drug development. Next, we review
the current research experience of using total-body PET to study
novel tracers. In the end, we discuss the challenges and the oppor-
tunities of total-body PET in drug development and evaluation.
NEW POSSIBILITIES IN DRUG DEVELOPMENT WITH
TOTAL-BODY PET
The physical attributes and imaging characteristics of total-body
PET have been elaborated upon extensively in previous review
articles (9–11). This new technology dramatically improves sensi-
tivity and system performance, enabling a series of applications.
! May 2024
Some of these applications are likely to profoundly affect drug
development and evaluations.
High-Quality Whole-Body Dynamic Imaging and
Kinetic Studies
PET imaging has been used in the study of physiologic mathe-
matic models of tracer kinetics since its early days (12). Conven-
tional PET acquisition comes from the time-weighted distribution of
tracers within a given duration. To study the kinetic behavior, a
sequence of frames can be reconstructed to obtain tracer distribution
at multiple time points. However, in vivo transport phenomena and
various physiologic processes often occur at rates faster than most
PET scanners could capture. Processes such as blood circulation,
respiration, and heartbeat require subsecond-temporal-resolution
image reconstruction, which is challenging to achieve with conven-
tional PET scanners. Therefore, state-of-the-art technologies are
indispensable when conducting kinetic studies using PET.
Total-body PET brings time resolution to another level. Using
the kernel expectation maximization method, a temporal resolution
of 0.1 s was achieved for dynamic PET reconstruction of the initial
stage after tracer injection with total-body PET (13). This unprece-
dentedly high frame rate is sufficient for the study of blood flow
and cardiac cycles, visualizing the circulation of a drug molecule
in the distribution stage.
Dynamic PET images represent tracer distribution across a
period, facilitating the application of mathematic modeling in the
study of tracer kinetics. The most widely used model in kinetic
modeling is the compartment model, followed by spectral analysis.
In studies with [18F]FDG, the kinetic parameter Ki is important,
because it correlates with the glucose metabolic rate (14). How-
ever, for some more sophisticated applications, parameters such as
the distribution volume, binding potential, and microparameters
(K1, k2, k3, … ) should be used to elucidate the pharmacokinetic
properties. Kinetic parameters reflect multiple facets of pharmaco-
logic effects, such as influx, drug–receptor interaction, and elimi-
nation. For drug development in particular, correlating kinetic
parameters with biologic processes at the molecular and cellular
levels provides a functional interpretation of tissue activity. These
parameters can be calculated voxel by voxel, and the parameter
map thus obtained may provide information about metabolism and
disease progression. Total-body PET enables simultaneous acqui-
sition of dynamic images of the entire body, allowing the calcula-
tion of parameter maps that cover all organs and tissues of
interest. This capability proves especially beneficial when compre-
hending the physiologic characteristics of the entire body (15) and
studying systematic diseases, as well as brain–body interactions.
Studying Multiple Tracers with a Lower Radiation Dose
Molecular imaging provides tools for molecular medicine by
visualizing and quantifying in vivo processes, as well as interac-
tions, among various molecular and cellular entities, enabling pre-
cise and personalized disease identification. PET tracers can be
used to study metabolic pathways involving glucose, glutamine,
and nucleotides (16,17); signaling pathways such as ErbB, VEGF,
and PARP (18–20); and immune mechanisms involving
CD4/CD8, PD1/PD-L1 (21,22), and more. However, because of
the complexity of the physiologic system, the combination of multi-
ple PET tracers is often required in the development of drugs or to
diversify the application strategy of these drugs. For example, for
certain neuroendocrine cancer patients, a [68Ga]Ga-DOTATATE and
[18F]FDG dual-scan protocol has been proven to achieve favorable
TOTAL-BODY PET IN DRUG DEVELOPMENT
prognostic performance by evaluating somatostatin receptor expres-
sion and glycolysis level, respectively (23).
However, clinical applications and clinical trials involving a
protocol of repeated PET scans raise concerns related to radiation
protection and medical ethics, because patients or volunteers are
exposed to an extra radiation dose from the tracer and the CT
scans compared with scenarios in which only 1 tracer is used. The
higher sensitivity of total-body PET presents a potential solution
to obtain satisfactory diagnostic images with a fraction of the dose
level required by conventional PET (24). Ultra-low-dose (0.37
MBq/kg for [18F]FDG) acquisition is even feasible in dynamic
PET acquisitions (25).
Traditionally, in PET imaging, a CT scan often has been neces-
sary to obtain the attenuation map for implementing physical cor-
rections, such as attenuation and scattering corrections. However,
in drug development studies that involve multiple tracers and
repeated scans, the cumulative x-ray exposure from these CT
scans can be a concern. In total-body PET scanners, the prompt
g-photons accompanied by the b2 decay of 176Lu from the
lutetium–yttrium oxyorthosilicate crystals are sufficient to provide
a transmission scan of the subjects. Through algorithms such as
maximum-likelihood transmission reconstruction, the background
radiation acquired around 307 keV can be reconstructed to attenua-
tion maps without introducing extra radiation to the patients
receiving total-body PET scans (26,27).
Continual efforts have been undertaken to achieve simultaneous
PET images of multiple tracers through several proposed signal-
unmixing methods (28). Total-body PET technology may bring
new solutions to this long-sought objective.
Tracer-Specific Image Enhancement with Total-Body PET
Supervised learning, as well as weakly or semisupervised learn-
ing, in medical image enhancement requires high-quality images
as labels. With its unprecedented image quality, total-body PET
provides an excellent platform for such scenarios (29,30). In this
way, the image quality of short-axis PET can be improved, as
shown in Figure 1.
Several learning strategies based on this concept have been pro-
posed. The deep progressive learning reconstruction algorithm
constructs 2 neural networks to perform image denoising and
image enhancement, respectively, and to incorporate them into the
Training
Total body PET scan
Down-sampling
OSEM reconstruction
OSEM reconstruction
Low quality image High quality image
Image enhancement model
Predicting
Short-axis PET scan Enhanced image
FIGURE 1. Representation of image enhancement model trained with
total-body PET scans and its application with short-axis PET. OSEM 5
ordered-subset expectation maximization.
! Meng et al. 47S
reconstruction process (31,32). The deep progressive learning
reconstruction algorithm has shown nice performance in clinically
oriented scenarios, but it has been tested only on [18F]FDG scans.
However, discrepancies among images of different tracers are
likely to deteriorate the generalization ability of such models,
given the inherent differences in their noise distribution and other
statistical characteristics. There is a need to accumulate images of
different tracers for the models to adapt to different tracer-specific
applications (33).
TRACERS DEVELOPED WITH TOTAL-BODY PET
Total-body PET scanners in top medical centers have already
been involved in the clinical trials of tracers. Table 1 summarizes
some registered clinical trials. Initial experiences can be learned
from these trials, which can be roughly categorized into trials that
further develop the clinically available tracers and those involving
innovative, often first-in-humans tracers.
Extending the Scope of Clinically Available Tracers and
Classic Targets
In recent years, positron-emitting tracers have been emerging.
Among them, several types of tracers have received extra research
interest, namely, prostate cancer imaging probes targeting the
prostate-specific membrane antigen (PSMA) receptor or prostate-
specific antigen (34), neuroendocrine tumor imaging probes target-
ing the somatostatin receptor (35), radiolabeled fibroblast active
protein (FAP) inhibitors (FAPIs) focusing on FAP and cancer-
associated fibroblasts (36), and metabolite positron tracers involv-
ing biomolecules, such as amino acid, nucleotide, and other small
molecules (37). Although a handful of these tracers have already
been approved for clinical use in at least 1 country or region, trials
after approval or investigator-initiated trials using total-body PET
are continuously updating our knowledge on their pharmaceutical
aspect. Moreover, a “me-better” version of drug innovation can be
derived from these targets.
Recently, PSMA-targeted compounds for diagnostic and thera-
peutic uses have been the focus of the radiopharmaceutical devel-
opment, and clinical trials involving PSMA tracers have been
TABLE 1
Selected Registered Clinical Trials Related to New Tracers
Register no. Public or brief title
ChiCTR2200059004 New technology in clinical
trials targeting fibroblast
activated protein PET/CT
imaging
NCT04678440 [18F]F-AraG/total-body PET
imaging and healthy
subjects and lung cancer
patients
NCT04941248 Total-body 13N-NH3 PET/CT
to study blood perfusion in
whole body
18
NCT05269446 F-PBR06/total-body PET
imaging in patients with
STEMI
*Retrieved January 1, 2024.
STEMI 5 ST-segment elevation myocardial infarction.
48S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65
conducted with total-body PET. When [68Ga]Ga-PSMA-11 is
used, the image quality of total-body PET has been demonstrated
to be superior to that of conventional scanners, bringing a higher
detection rate of lesions (38). A half-dose [68Ga]Ga-PSMA-11 scan
was found to provide noninferior diagnostic ability in patients with
biochemical recurrent prostate cancer (39), whereas a single-center
retrospective study with total-body PET found that the SUVmax of
the prostate can be an independent predictor for prostate cancer
diagnosis (40). With dynamic imaging using total-body PET, the
optimal imaging time window of [68Ga]Ga-PSMA-11 has been
revealed to be 35–59 min after injection (41). A study on another
long-axial-field-of-view scanner also proposed late-stage imaging
with the same tracer (42). Dynamic imaging was performed with
[68Ga]Ga-PSMA-11 and fitted with 2-tissue- and reversible 2-tissue-
compartment models. Further diagnostic analysis showed that
microparameters are capable of distinguishing normal organs from
lesions (43). Using the irreversible 2-tissue-compartment model, the
parametric images of this tracer were prepared and showed better
lesion detectability than static images (44). Kinetic analysis of the
18
F-labeled [18F]AlF-PSMA-11 was also performed, assuming a
reversible 2-tissue model (45). In PSMA radioligand therapy, the
salivary glands are among the dose-limiting organs. Total-body
dynamic PET verified the effectiveness of oral vitamin C adminis-
tration in radiation protection of the salivary glands with [68Ga]Ga-
PSMA-11 (46). Besides PSMA, [18F]fluciclovine has been imaged
with a total-body scanner in a center (47).
Among the somatostatin receptor probes, DOTATATE is the
best-studied one because of its merits in diagnosis and peptide
receptor radionuclide therapy. In combination with [18F]FDG,
[68Ga]Ga-DOTATATE can fully exploit the comprehensive diag-
nostic capability of total-body PET, and low-dose acquisition is
sufficient in such scenarios (48). To optimize the acquisition
scheme, a time regimen adjusted with patient body weight was
proposed and validated on total-body PET (49). Taking advantage
of the dynamic imaging ability, the kinetic behavior of [68Ga]Ga-
DOTATATE in normal organs has also been studied (50).
FAPI PET is an emerging diagnostic tool in oncology and other
fields, such as cardiology and immunology. As with other tracers,
Institution Status*
Nanfang Hospital, Southern Prospective registration
Medical University, China
University of California, Davis, Enrolling by invitation
California
Renji Hospital, China Recruiting
Renji Hospital, China Recruiting
! No. 5 (Suppl. 1) ! May 2024

[18F]FDG injection
1/10 dose
Static acquisition
10 min
[68Ga]Ga-FAPI injection Dynamic acquisition
Half dose
Uptake time
PETFDG PETD30-40
FIGURE 2. Schematic of 1-stop [18F]FDG and [68Ga]Ga-FAPI-04 imag-
ing protocol. D30–40 5 static reconstruction of dual-tracer acquisition
between 30 and 40 min after [68Ga]Ga-FAPI injection; D50–60 5 static
reconstruction of dual-tracer acquisition between 50 and 60 min after
[68Ga]Ga-FAPI injection.
the low-dose acquisition of FAPI has also been studied. [68Ga]Ga-
FAPI-04 PET images can be acquired at half-dose (#0.1 MBq/kg)
and a 120-s duration after 35–75 min of uptake time with total-
body PET and maintain diagnostic efficiency (51). The earliest
optimal time window, 34–60 min after half-dose [68Ga]Ga-FAPI-
04 injection, was validated using dynamic imaging with total-body
PET (52). Alternatively, a full-dose injection of [68Ga]Ga-FAPI-
04 with an acquisition of 30 s at 5 min after injection was con-
ducted. This ultraearly and fast acquisition scheme was found to
meet the clinical requirement and thus can be used in patients with
poor tolerance (53). As shown in Figure 2, a 1-stop dual-tracer
imaging protocol was devised to provide information about the
tumor and the stroma simultaneously, using low-dose [18F]FDG
and [68Ga]Ga-FAPI-04 (54). The kinetic behavior of [68Ga]Ga-
FAPI-04 has also been studied using total-body PET, and with the
reversible 2-tissue compartment model, parametric maps for pan-
creatic and gastric cancer patients were obtained (55). Another
study established the correlation between the tumor-to-blood ratio
and the distribution volume Vt of pancreatic cancer lesions (56).
Clinical applications of FAPI imaging beyond oncology were
explored using a total-body PET scanner, including a case
of MDA5 dermatomyositis showing high muscle uptake of
[68Ga]Ga-FAPI-04 (57) and a comparative study using [18F]AlF-
FAPI-42 and [18F]FDG to evaluate acute kidney injury in cancer
patients (58). [18F]AlF-FAPI-42 has also been systematically stud-
ied using total-body PET (59).
Metabolite PET tracers are usually small molecules that are often
labeled with low-atomic-number positron emitters with a short radio-
active half-life. Using total-body PET, these tracers can be visualized
in an extended time window. Metabolite tracers with a short-half-life
positron emitter that have been studied with total-body PET include
[13N]ammonia (60), 1-[11C]butanol (61), and
[11C]methionine (62). Their kinetic behavior,
pathologic correlations, and accurate dosime-
try have been studied using this technique.
Studies have also been conducted using
multiple tracers on total-body PET. A case
was reported in which [18F]FDG, [68Ga]Ga-
PSMA, and [68Ga]Ga-DOTATATE PET
images were acquired separately on a patient
who had metastatic prostate adenocarcinoma
with neuroendocrine differentiation, taking
advantage of ultra-low-dose imaging (63).
Dynamic PET images of [18F]FDG,
[68Ga]Ga-PSMA-11, and [68Ga]Ga-FAPI-
FIGURE 3. (A) [68Ga]Ga-N188 PET image of healthy volunteer 30–35 s after injection. (B) SUVmax in
04 were acquired using total-body PET on organs (kidney, aorta, liver, spleen, lung, and brain) obtained from dynamic total-body PET images of
different cohorts, and the biodistribution patients injected with 1.23 MBq/kg [68Ga]Ga-N188. (C) Organ uptake in all 16 healthy volunteers and
and radiation dosimetry of these tracers patients at 40 min after injection, as shown by static [68Ga]Ga-N188 PET imaging and indicated by
were analyzed (64). SUVmax. (Reprinted from (67).)
Early-Stage Trials of Innovative Tracers
60 min
An investigator may initiate a clinical trial with an innovative
positron tracer once the institutional review board and other
administrative entities have granted permission. At this stage, it is
PETD50-60 most likely to be a first-in-humans study of a pharmaceutical
entity. Several trials in the early stage are using total-body PET to
develop innovative tracers.
With understanding of the structure–activity relationship of the
tracer molecules, the tracer [18F]AlF-FAPITG was designed on
the basis of the FAPI pharmacophore. A glucosamine-conjugated
Asp2Glu peptide with a di(ethylene glycerol) linker moiety was
inserted into the molecular structure of NOTA-FAPI-42. This
modification significantly altered the hydrophilicity of the mole-
cule and the tracer biodistribution and reduced the gallbladder and
bile duct concentration (65). A slightly modified molecule,
[18F]AlF-FAPIT, showed similar performance. Using total-body
PET, the biodistribution of the tracer was compared with that of
[18F]AlF-FAPI-42 in a healthy volunteer, validating the lowered
gallbladder uptake (66).
The use of radiolabeled molecules for noninvasive visualization
and targeting of specific biomarkers, such as nectin-4 in various
malignancies, may lead to significant advancement in diagnostic
imaging and potential therapeutic applications. In this context, a bicy-
clic peptide, BT8009 (Bicycle Therapeutics), targeting nectin-4 was
radiolabeled with 68Ga, and the resulting tracer, [68Ga]Ga-N188, was
validated in animal models, as well as a cohort of healthy volunteers
and patients with advanced urothelial carcinoma. Total-body PET
imaging was conducted to evaluate the dynamic characteristics and
organ distribution of the tracer (67), as shown in Figure 3
Total-body PET imaging, combined with physiologically based
pharmacokinetic modeling, offers insights into the kinetic behavior
of pharmaceuticals across multiple organs and tissues. Aptamer is
a class of oligonucleotides with targeting ability, and their pharma-
ceutical applications recently have been recognized. Among
aptamers, SGC8 is a promising one that targets protein tyrosine
kinase 7, a key member of cancer-related signaling pathways.
With total-body PET, radiolabeled [68Ga]Ga-NOTA-SGC8 was
studied in cancer patients. Dynamic images over durations of 15,
30, and 60 min were acquired, and a physiologically based phar-
macokinetic model was developed using dynamic PET data (68).
Antibody derivatives include the fragments of monoclonal antibo-
dies and other engineered peptides with similar properties. Minibo-
dies, single-domain antibodies, Affibody molecules (Affibody AB),
TOTAL-BODY PET IN DRUG DEVELOPMENT ! Meng et al. 49S
 TABLE 2
Selected Current Regulatory Guidelines Concerning Pharmacokinetic Study of New Drugs in China, European Union, and
United States

Nation or region Regulatory body Name of file, effective year

China National Medical Products Technical Guidelines for Clinical Pharmacokinetic Studies
Administration of Chemical Drugs, 2005
Technical Guidelines for Clinical Pharmacology Research
of Innovative Drugs, 2021
European Union European Medicines Agency Pharmacokinetic Studies in Man, 2015
United States Food and Drug Administration Population Pharmacokinetics Guidance for Industry, 2022
Physiologically Based Pharmacokinetic Analyses: Format
and Content Guidance for Industry, 2018

and other antibody derivatives constitute a set of versatile tools for
designing molecular probes, and they demonstrate diverse biologic
behaviors. In a recent study (69), a minibody targeting human CD8
(#80 kDa) was radiolabeled with 89Zr (78.4-h half-life) to obtain the
tracer [89Zr]Zr-Df-crefmirlimab. This tracer was used to reveal the
distribution of CD81 cells. Total-body PET images at different time
points, ranging from 30–90 min to 48–49 h, were acquired in a
cohort of healthy individuals and coronavirus disease 2019 patients.
Various compartment models were used to evaluate the tracer
kinetics in different organs, and it was found that the influx rate Ki,
as well as the tissue-to-blood ratios of the bone marrow, showed a
significant difference between healthy volunteers and coronavirus dis-
ease 2019 patients. A Nanobody (Ablynx)-based tracer, [68Ga]Ga-
HNI01, was developed to visualized the in vivo distribution of carci-
noembryonic antigen. Colorectal carcinoma patients were recruited
and underwent total-body PET scans using [68Ga]Ga-HNI01. The
dynamic images were acquired and reconstructed, showing the bio-
distribution of the tracer (70). In another study (71), 2 Affibody-
based tracers were compared, namely, [18F]AlF-RESCA-HER2-BCH
and [18F]AlF-NOTA-HER2-BCH. Although the only difference
between them is the chelator, the RESCA tracer showed significantly
lower renal accumulation than the NOTA tracer, as demonstrated by
total-body PET imaging at 2 and 4 h after injection. In those pharma-
cologic evaluations, total-body PET played a central role.
CHALLENGES AND OPPORTUNITIES
coverage simultaneously. Total-body PET has the potential to expe-
dite the drug development process by offering detailed insights into
drug behavior at various stages of development.
Regulatory bodies around the world have established a series of
guidelines for pharmacokinetic studies of new drugs. Table 2
shows current guidelines in China, the European Union, and the
United States. In these guidelines, the blood clearance characteris-
tics are often directly measured by repeated blood sampling, which
is associated with risks and discomfort, and often only the periph-
eral blood can be obtained easily. The activity concentration in the
arterial or cardiac regions obtained from the reconstructed dynamic
PET images has been considered a good representation of the pres-
ence of the drug in the arterial blood, which is called the image-
derived input function (72). However, using the image-derived
input function from PET imaging for pharmacokinetic studies has
its own set of challenges, including equilibrium establishment, stan-
dardization and reliability of the PET measurement, PET image
resolution, and quantification precision (73). With the state-of-
the-art dynamic imaging of total-body PET, the quality of the
image-derived input function and other blood time–activity curves
in central and peripheral blood vessels has been dramatically
improved. This can be illustrated by the demonstrative experiment
in Figure 4. Although the reliability of the image-derived method
in the blood clearance study still requires validation, total-body
PET could offer a promising, noninvasive way to investigate the

Total-body PET/CT scanners have shown

promise in advancing drug development and
clinical evaluations, but there is considerable
potential for further use of this technology.
In the future, we expect to witness the
increased influence of total-body PET on
drug development and clinical evaluations.
In drug development, elucidating phar-
macokinetic behavior not only is required
by regulatory bodies during the investiga-
tional new drug phase but also constitutes
a crucial factor in pharmacologic evaluation.
Since its inception, total-body PET has
shown significant promise in optimizing FIGURE 4. (A) Maximum-intensity projections of representative frames in dynamic PET image of
healthy volunteer who received intravenous injection of 113.3 MBq of [18F]FDG on right hand. (B)
kinetic studies of positron-emitting drugs,
Blood time–activity curves of aorta, carotid artery, and cephalic vein as measured on image without
offering several advantages over conven- applying partial-volume correction, and time–activity curve of venous blood collected from left
tional PET scans, because total-body PET median cubital vein during PET acquisition. All activity concentrations were decay-corrected to start
achieves better image quality and total-body of acquisition. Conc. 5 concentration.

50S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65 ! No. 5 (Suppl. 1) ! May 2024
spatiotemporal distribution of tracers within central venous and
arterial blood and potentially reduce the need for the vascular punc-
ture procedure. Moreover, as already demonstrated (68), the whole-
body dynamic PET images with total-body PET may provide a
shortcut for physiologically based pharmacokinetic studies.
As shown earlier, total-body body PET can also provide infor-
mation on clinical pharmacodynamics, including determination of
the optimal imaging time window and mapping of organ uptake. It
may also be feasible to use total-body PET to study the interaction
between the drug and the immune system. In this way, the pro-
posed mechanism of action of the drug can be validated by the
sophistication of total-body PET. Regulatory bodies require robust
evidence of the accuracy, precision, and consistency of these
imaging techniques before considering their integration into drug
development guidelines. Continued research efforts aimed at vali-
dating total-body PET imaging for pharmacologic studies will be
crucial in establishing its role as a reliable tool in understanding
drug distribution, pharmacokinetics, and pharmacodynamics in a
noninvasive manner.
Total-body PET has stimulated research in kinetic modeling,
and with the plethora of data generated, more sophisticated model-
ing techniques have been proposed or validated, providing more
opportunities in the validation of drug kinetics. For example, time
delay and dispersion corrections have been applied in dynamic
total-body PET imaging with high temporal resolution of the lung
to obtain high-quality kinetic parameters (74). Statistical inference
methods are also being developed to improve parametric imaging
of total-body PET. Despite these advancements, challenges persist
(75), especially in the context of drug development. These include
determining the input function and deviation from the ideal com-
partment model because of transport phenomena and nonuniform
mixing within tissues.
Total-body PET may provide important information for tailor-
ing treatment regimens to individual patients, personalizing
dosages and treatment planning, and minimizing potential side
effects in radionuclide therapy and theranostics, including previ-
ously mentioned peptide receptor radionuclide therapy and PSMA
radioligand therapy. However, unsolved problems in these fields
related to radiopharmaceuticals necessitate further research and
development. Personalized dosimetry and treatment planning with
PET, prognosis and patient selection, treatment monitoring, and
evaluation all require further research and development. One spe-
cific case is the direct imaging of 90Y, which generates only 32
positrons per million decays. In radioembolization with 90Y micro-
spheres, total-body PET can capture the sparse signal and perform
voxelwise dosimetry based on the Monte Carlo simulation (76). In
general, the theranostic application of total-body PET is worthy of
more investigation.
Several additional research topics, although not extensively
exploited at the current time, are likely to achieve expectations in
the intersection between total-body PET and drug development.
The first idea is about using total-body PET to develop drugs for
immunotherapy. One of the key challenges in immunotherapy
involves finding potent biomarkers (77), and the toolbox of
immuno-PET (78) may provide a strategy for engineering key
molecules into PET tracers. This strategy has already been used
with total-body PET in some preliminary applications (69,70,79).
Besides, because of the extended axial field of view, total-body
PET provides an opportunity to study systematic metabolic charac-
teristics across different organs, especially brain–body interactions.
Several studies have been conducted with [18F]FDG (80), and
TOTAL-BODY PET IN DRUG DEVELOPMENT
• Total-body dynamic imaging for comprehensive drug
First-in-human metabolism characterization, especially in the early stage.
Phase 0/I
• Study drug biodistribution over longer time scales.
• The high sensitivity of total-body PET/CT enables more
Safety evaluation flexible exploration of dose effects.
Phase I • A paradigm change in whole-body radiation dosimetry
calculations to assess radiopharmaceutical safety.
• Fully reveal the absorption, distribution, metabolism and
Pharmacokinetics excretion (ADME) processes.
Phase I • Analyze drug distribution and clearance through quantitative
parametric imaging.
• Enabling high-throughput imaging with short acquisition time,
accelerating the study process.
Randomized study
Phase II/III • Improved image quality to reveal subtle manifestations,
allowing for accurate analysis.
FIGURE 5. Potential role of total-body PET in different aspects of clinical
investigation and different phases of clinical trials of new drugs.
using new drugs will expand the matrix of combination to another
dimension.
In this review, we have gone through the impacts of total-body
PET on drug development. Total-body PET imaging has substan-
tially affected the spectrum of drug development, including the
initial phases 0 and I, which focus on establishing the basic valid-
ity of the pharmaceuticals, and the latter phases II and III, which
involve a larger, often randomized cohort. Figure 5 provides a
summary of these impacts in different aspects of the clinical inves-
tigation of new drugs. With the active involvement of all stake-
holders, including the PET imaging community, pharmaceutical
scientists, and the pharmaceutical industry, the potential of total-
body PET is expected to be gradually unlocked, and we will wit-
ness more exciting new applications in the near future.
CONCLUSION
Total-body PET is pushing the limits of PET imaging and offers
immense potential in tracer development, innovative drug develop-
ment or enhancement, and clinical evaluation of pharmaceuticals.
It brings possibilities in clinical research and translation accelera-
tion. Such potential has been validated in studies of several new
tracers. We believe this technology may continue to flourish and
benefit the pharmaceutical and medical imaging communities in
the era of theranostics.
DISCLOSURE
No potential conflict of interest relevant to this article was
reported.
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! Meng et al. 53S
Advantages and Challenges of Total-Body PET/CT at a
Tertiary Cancer Center: Insights from Sun Yat-sen
University Cancer Center
Wanqi Chen1,2, Yinghe Li1,2, Zhijian Li1,2, Yongluo Jiang1,2, Yingpu Cui1,2, Jiling Zeng1,2, Yiwen Mo1,2, Si Tang1,2,
Shatong Li1,2, Lei Liu1,2, Yumo Zhao3, Yingying Hu*1,2, and Wei Fan*1,2
1
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China;
2
Department of Nuclear Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China; and 3United Imaging Healthcare Co.
Ltd., Shanghai, China
In recent decades, researchers worldwide have directed their efforts
toward enhancing the quality of PET imaging. The detection sensitivity
and image resolution of conventional PET scanners with a short axial
field of view have been constrained, leading to a suboptimal signal-
to-noise ratio. The advent of long-axial-field-of-view PET scanners,
exemplified by the uEXPLORER system, marked a significant adv-
ancement. Total-body PET imaging possesses an extensive scan
range of 194 cm and an ultrahigh detection sensitivity, and it has
emerged as a promising avenue for improving image quality while
reducing the administered radioactivity dose and shortening acquisition
times. In this review, we elucidate the application of the uEXPLORER
system at the Sun Yat-sen University Cancer Center, including the dis-
ease distribution, patient selection workflow, scanning protocol, and
several enhanced clinical applications, along with encountered chal-
lenges. We anticipate that this review will provide insights into routine
clinical practice and ultimately improve patient care.
Key Words: total-body PET/CT; oncology; application; imaging proto-
col; pediatric
J Nucl Med 2024; 65:54S–63S
DOI: 10.2967/jnumed.123.266948
P ET/CT is a noninvasive examination that plays a crucial role
in the visual assessment of tumor staging, restaging, and therapy
response monitoring (1). Researchers worldwide have been focused
on improving the sensitivity and resolution of PET imaging. In the
case of the short axial field of view (SAFOV), PET detectors capture
approximately only 1% of emitted coincidence photons. Because of
the limitation posed by the length of the AFOV, whole-body scan-
ning has traditionally entailed shifting the bed (typically from head
to thigh in about 5 bed positions). Each bed position requires about
1–3 min, resulting in whole-body scans taking 10–30 min.
Extending the AFOV length could increase the number of
detectors and allow the simultaneous capture of more emitted
photons. The image quality could be improved through enhanced
counting statistics achieved by broader solid angle coverage. The
Received Oct. 25, 2023; revision accepted Jan. 31, 2024.
For correspondence or reprints, contact Wei Fan (fanwei@sysucc.org.cn)
or Yingying Hu (huyy@sysucc.org.cn).
*Contributed equally to this work.
COPYRIGHT ! 2024 by the Society of Nuclear Medicine and Molecular Imaging.
54S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65
194-cm long-AFOV (LAFOV) PET scanner, uEXPLORER
(United Imaging Healthcare), became operational in 2018 (2).
Given its substantially higher sensitivity (3–5) and a long scan
range in a single bed position, total-body PET can provide ultra-
high system sensitivity, coupled with high spatial resolution. There
are several enhanced clinical applications using total-body PET/
CT: full-body coverage, short acquisition time, low injection dose,
high image quality, and simultaneous total-body dynamic imaging.
Despite these advantages, the high detection of both anatomic and
pathologic uptake could still lead to challenging and equivocal
interpretations in clinical practice (6). Therefore, experimental
experience is crucial for understanding and use.
In this review, we provide an overview of the application of the
uEXPLORER system in Sun Yat-sen University Cancer Center
(SYSUCC), including the patient characteristics, selection work-
flow, scanning protocol, several enhanced clinical applications,
and challenges encountered in routine clinical practice. Future per-
spectives on the opportunities offered by total-body PET scanners
are also presented.
APPLICATION OF TOTAL-BODY PET/CT IN SYSUCC
From May 1, 2020, to June 30, 2023, 30,786 examinations were
conducted in our center using the uEXPLORER PET/CT scanner.
The top 3 cancers were nasopharyngeal carcinoma (NPC), lym-
phoma, and lung cancer (Fig. 1A). Among these, NPC and lung
cancer accounted for a significant proportion of initial diagnoses;
other diseases were more prevalent in follow-up examinations
(Fig. 1C). Most patients were in the age range of 45–65 y
(Fig. 1B). Numerous pediatric patients were younger than 15 y, pri-
marily diagnosed with lymphoma, sarcoma, neuroblastoma, and
NPC (Fig. 1D). In clinical practice, there was also a small propor-
tion of nononcologic patients, such as patients with unexplained
elevated tumor markers but no malignant imaging signs or those
with suspected lesions of malignancy that were finally pathologi-
cally diagnosed as benign diseases.
SCANNING PROTOCOLS OF TOTAL-BODY PET/CT
IN SYSUCC
Compared with SAFOV PET/CT, a LAFOV PET/CT scanner
faces new challenges in acquisition workflow. Attenuation correc-
tion in PET/CT hybrid imaging typically relies on CT transmission
data. Although there have been studies focused on using lutetium
background radiation for attenuation correction (7,8), no precedent
! No. 5 (Suppl. 1) ! May 2024
FIGURE 1. Application of total-body PET/CT at SYSUCC. (A) Disease distribution. (B) Age distribution. (C) Disease stage distribution. (D) Disease distri-
bution in pediatric patients younger than 15 y. Others 5 nononcologic patients or patients who have not yet been followed up.
has been established in clinical practice. This means that CT acqui-
sition must fully cover the range of the 194-cm PET detectors.
PET/CT examinations include different types of CT scans depend-
ing on their purpose, such as a low-dose CT scan solely for attenua-
tion correction and/or a diagnostic CT scan with a higher x-ray dose
(1). Therefore, 2 routines of CT scans can be used in the workflow
of the uEXPLORER scanner: total-body diagnostic CT scan with a
higher x-ray dose (TB routine) and total-body, low-dose CT scan
for attenuation correction plus a torso (from skull to mid thigh) diag-
nostic CT scan with a higher x-ray dose (torso routine).
By considering different ages and diseases, we have designed var-
ious acquisition protocols. For adults older than 20 y, TB routine or
torso routine was selected on the basis of doctors’ recommendations
and depending on the risk of systemic metastasis. Furthermore, cer-
tain parameter modifications or optimizations were based on the TB
and torso routine (Table 1; Supplemental Table 1 [supplemental
materials are available at http://jnm.snmjournals.org]) to create spe-
cific disease protocols. For example, high-resolution PET recon-
struction of the head was added for patients with lung cancer; fast,
deep inspiration breath-hold PET acquisition was performed for
patients with poor alignment of thoracoabdominal lesions; and a
short acquisition time was performed for NPC patients while meet-
ing the diagnostic requirements for the high throughput of patients
in our center.
To enhance the number of lines of response for pairs of annihi-
lation photons by increasing the axial acceptance angle (9), it
becomes necessary for the CT acquisition range to extend beyond
the PET reconstruction range if a limited-area tumor imaging is
TOTAL-BODY PET/CT IN SYSUCC
required. With regard to dose accumulation, we performed a diag-
nostic CT scan with a higher x-ray dose in the limited area and
included an additional 10 cm of low-dose CT scan for attenuation
correction above and below.
For children, adolescents, and young adults (#20 y), the dose of
the TB routine is notably lower than that of the torso routine, lead-
ing us to use the TB routine exclusively. The pixel size for PET
reconstruction decreases in descending order according to age.
With regard to CT scanning and reconstruction parameters, the
acquisition protocols for each age group are divided into 3 catego-
ries: nonlymphoma, lymphoma, and lymphoma follow-up, with
decreasing CT doses. For children aged 7 y and younger with
smaller body sizes, we use a tube voltage of 100 kV, whereas for
those older than 7 y, we use 120 kV, both with automatic tube cur-
rent modulation. In addition, in pediatric patients younger than
15 y, we use a rotation time of 0.3 s and reduce the CT acquisition
time from 25 to 15 s to minimize the risk of body motion. Besides,
for youths with larger body sizes (weight . 45 kg), we appropri-
ately reduce the reference milliampere$seconds because of the
higher dose administrated when using tube current modulation.
Moreover, all protocols for youths have incorporated thin-slice CT
reconstructed with the artificial intelligence iterative reconstruction
algorithm.
SELECTION OF PET/CT SCANNERS ACCORDING TO
PATIENTS’ MEDICAL CONDITIONS
The selection among various PET/CT devices is a critical aspect
of the daily operations at SYSUCC. The facility uses a total-body
! Chen et al. 55S
56S
TABLE 1
Key Parameters of Total-Body PET/CT Acquisition Protocols at SYSUCC

CT-AC parameters CT-Dx parameters Reconstruction parameters of PET

Tube Fixed Tube Ref.mAs

Dose Time voltage tube voltage of TCM Rotation FOV
Age Protocol (MBq/kg) (min) (kV) (mAs) (kV) (mAs) time (s) Iterations Subsets Matrix (mm)

.20 y, torso or Torso routine 3.70 5 120 10 120 80 0.5 3 20 256 3 256 600
TB routine
Torso NPC 3.70 3 120 5 120 80 0.5 2 20 256 3 256 600
TB routine 1.85 8 NA NA 120 120 0.5 3 20 256 3 256 600
TB NPC 1.85 6 NA NA 120 120 0.5 3 20 256 3 256 600
#20 y, TB routine 0- to 4-y nonlymphoma 1.85 10 NA NA 100 75 0.3 3 20 512 3 512 600

THE JOURNAL OF NUCLEAR MEDICINE

only

!
0- to 4-y lymphoma 1.85 10 NA NA 100 70 0.3 3 20 512 3 512 600
0- to 4-y lymphoma 1.85 10 NA NA 100 55 0.3 3 20 512 3 512 600
follow-up

Vol. 65
4- to 7-y nonlymphoma 1.85 10 NA NA 100 80 0.3 3 20 512 3 512 600

!
4- to 7-y lymphoma 1.85 10 NA NA 100 70 0.3 3 20 512 3 512 600
4- to 7-y lymphoma 1.85 10 NA NA 100 60 0.3 3 20 512 3 512 600
follow-up
7- to 15-y nonlymphoma 1.85 10 NA NA 120 60 0.3 3 20 512 3 512 600
7- to 15-y lymphoma 1.85 10 NA NA 120 55 0.3 3 20 512 3 512 600

No. 5 (Suppl. 1)
7- to 15-y lymphoma 1.85 10 NA NA 120 50 0.3 3 20 512 3 512 600

!
follow-up
15- to 20-y nonlymphoma 3.70 6 NA NA 120 65 0.5 3 20 360 3 360 600
15- to 20-y lymphoma 3.70 6 NA NA 120 60 0.5 3 20 360 3 360 600
15- to 20-y lymphoma 3.70 6 NA NA 120 55 0.5 3 20 360 3 360 600

May 2024
follow-up
.45-kg nonlymphoma 3.70/1.85 6/10 NA NA 120 60 0.5 3 20 256 3 256 600
.45-kg lymphoma 3.70/1.85 6/10 NA NA 120 50 0.5 3 20 256 3 256 600
.45-kg lymphoma 3.70/1.85 6/10 NA NA 120 40 0.5 3 20 256 3 256 600
follow-up

CT-AC 5 low-dose CT scan for attenuation correction; CT-Dx 5 diagnostic CT scan with higher x-ray dose; Ref.mAs 5 reference milliampere$seconds; TCM 5 tube current
modulation; FOV 5 field of view; TB 5 total body; NA 5 not applicable.
For patients >45 kg, injection dose is based on age (1.85 MBq/kg applied for pediatric patients younger than 15 y and 3.70 MBq/kg for patients from 15- to 20-y old).
PET/CT scanner (uEXPLORER) alongside 2 SAFOV PET/CT
scanners: uMI 780 (United Imaging Healthcare) and Biograph
mCT.X (Siemens Healthineers). To ensure patient interests are pri-
oritized, medical considerations are accurate, and scanning pro-
cesses are efficient, physicians are tasked with making numerous
decisions to determine which patients are suitable for total-body
PET/CT examinations. The workflow is detailed in Figure 2.
For newly diagnosed patients, total-body PET/CT is given prior-
ity for the following conditions: pediatric patients, for whom total-
body PET/CT aided in reducing the PET imaging agent dosage
(10–12) and potentially shortening acquisition time; patients who
required whole-body scanning, such as those with systemic dis-
eases, malignances affecting multiple organs or extremities, and
advanced tumors with distant metastases beyond the scanning
range of SAFOV PET/CT; patients with complex diseases or
occult lesions, for whom total-body PET/CT might enhance diag-
nosis sensitivity (13,14) and assist in recognizing the tumor’s ori-
gin (15); patients experiencing untenable body position induced by
cancer-related pain or involuntary movement (16); and patients
expected to undergo multiple PET/CT examinations as part of reg-
ular surveillance, for whom total-body PET/CT also aided in
reducing cumulative radiation exposure.
For patients undergoing dynamic PET/CT examinations or par-
ticipating in the pharmacokinetics studies involving radiopharma-
ceuticals, total-body PET/CT is the primary choice. In the case of
patients returning for reevaluation of therapeutic efficacy by com-
paring current and previous PET/CT images, it is important to
ensure that the same device is used for the current scanning as for
the previous scan. This consistency is necessary to maintain com-
parable detection sensitivity and SUV. For patients with claustro-
phobia exhibiting as fear of enclosed spaces, SAFOV scanners are
the primary recommendation.
ADVANTAGES AND APPLICATIONS OF TOTAL-BODY
PET SCANNING
Low-Dose Injection of PET Imaging Agents
The high sensitivity, along with a dramatically improved signal- to reduce the CT dose in a total-body PET/CT examination to an
to-noise ratio, of the total-body PET/CT scanner allows a substantial average of approximately 4 mSv, representing a 66.1% reduction
FIGURE 2. Selection of PET/CT devices according to patients’ medical conditions at SYSUCC.
TOTAL-BODY PET/CT IN SYSUCC
reduction in the injected radiopharmaceutical activity. There have
been several studies exploring total-body PET/CT with low-dose
injection activity (as summarized in Table 2). Most of these studies
have focused on adult populations. However, children and young
adults are more sensitive to the stochastic effects of ionizing radia-
tion, because their bodies are undergoing rapid cell division. In
addition, children and adolescents have a relatively longer life span
and more time to manifest potential radiation effects than adults
(17,18). Concerns about additional radiation have arisen as a result
of multiple PET/CT scans performed before and during treatment.
To minimize unnecessary ionizing radiation exposure, the injec-
tion dose of 18F-FDG for pediatric patients younger than 15 y at
our center is 1.85 MBq/kg, with a standard scanning time of
10 min. Our research (12) has found that total-body PET/CT with
a one-half dose of 18F-FDG (1.85 MBq/kg; estimated whole-body
effective dose, 1.76–2.57 mSv) demonstrates excellent perfor-
mance in pediatric patients, providing adequate image quality
and lesion conspicuity. Theoretically, image quality could be
maintained at ultralow doses, going as low as a one-tenth dose
(0.37 MBq/kg) of the standard dose when using a total-body PET
scanner (11). A study of 18F-FDG dose deescalation and shortened
acquisition duration using total-body PET/CT is under implementa-
tion at our center, and we aim to formulate a standardized working
protocol of pediatric tumor imaging. An example of a pediatric
patient scanned with a one-fifth dose (0.74 MBq/kg) of the standard
dose of 18F-FDG using total-body PET/CT with an acquisition time
of 10 min is shown in Figure 3.
Low-Dose CT in Total-Body PET/CT
Dosimetric studies related to total-body PET/CT have mainly
focused on reducing the 18F-FDG injection dose, with fewer stud-
ies dedicated to the CT dose. The CT dose constitutes a significant
portion of the total effective dose, especially when low or ultralow
18
F-FDG injection doses are achieved (11,19,20). In our previous
study, the potential of total-body PET/CT to reduce the CT dose
in pretreatment pediatric patients with lymphoma was validated
(21). Through optimization of scanning parameters, it was possible
in the CT dose compared with SAFOV
PET/CT. This study primarily focused on the
diagnosis and staging of pretreatment pediat-
ric patients. Exploring lower CT doses for
various clinical applications, such as treat-
ment evaluation, is a worthwhile endeavor.
Pediatric lymphoma of various subtypes is
almost always 18F-FDG-avid and relies more
on PET than CT for diagnosis and staging,
so further investigation is needed to under-
stand the universal potential of total-body
PET/CT in reducing the CT dose across vari-
ous tumors. In addition, the CT component
dose in PET/CT scans should be institution-
specific and determined according to its local
preferences, scanner hardware, technologist
experience, and available reconstruction
methods (22). Besides, an ongoing study at
our center exploring the diagnostic efficacy
of low-dose CT combined with low-dose
18
F-FDG activity is being implemented
(Fig. 4). Preliminary results suggest that the
! Chen et al. 57S
 TABLE 2
Clinical Studies Exploring Low-Dose Injection Activity of 18F-FDG Using Total-Body PET/CT

Year Author Patients (n) Population Disease Injection dose Conclusion

2022 Chen et al. (12) 100 Pediatric patients Oncology Half dose Sufficient image quality
(1.85 MBq/kg) and lesion conspicuity
could be maintained at
fast acquisition time of
1 min with half-dose
activity of 18F-FDG
2022 He et al. (17) 46 Adults Oncology Half dose Half dose of 18F-FDG
(1.85 MBq/kg) with acquisition times
$ 5 min could be
applied in clinical
practice
2021 Tan et al. (13) 56 Adults Lung cancer Half dose Total-body PET/CT with
(1.85 MBq/kg) half dose of 18F-FDG in
2 and 4 min achieved
comparable image
quality to conventional
PET/CT
2022 Hu et al. (18) 30 Adults Oncology Ultralow dose Ultralow 18F-FDG activity
(0.37 MBq/kg) with 8-min acquisition in
total-body PET/CT can
achieve acceptable
image quality equivalent
to that in full-activity
group after 2-min
acquisition
2022 Abdelhafez 30 Adults AIA Ultralow dose Systemic joint evaluation in
et al. (54) (78.1 6 4.7 AIA (and non-AIA) is
MBq) feasible with total-body
PET/CT and ultra-low-
dose 18F-FDG protocol
2022 Tan et al. (55) 62 Adults CRC Ultralow dose Total-body PET/CT with
(0.37 MBq/kg) ultralow dose of
18
F-FDG can maintain
satisfactory image
quality and lesion
detectability in CRC
2023 Tan et al. (56) 30 Adults Oncology Ultralow dose Total-body PET/CT
(0.37 MBq/kg) with ultra-low-dose
vs. half dose activity of 18F-FDG,
(1.85 MBq/kg) corresponding acquisi-
tion time of 8 min,
provides acceptable
image quality and lesion
detection

AIA 5 autoimmune inflammatory arthritis; CRC 5 colorectal cancer.

total effective dose of a total-body PET/CT scan can be reduced to a
minimum of 3.75 mSv.
Rapid Scanning
The ultrahigh system sensitivity and spatial resolution of the total-
body PET scanner offer an opportunity to reduce acquisition time
while preserving image quality. In certain scenarios, shorter scan
durations can serve as a salvage method to mitigate or eliminate the
requirement for sedation or repeat scanning, which is particularly
advantageous in the context of pediatric imaging among children
from 3 to 5 y old (23). However, for infants and toddlers, involuntary
movement might occur during the initial phase of the scan, resulting
in imperceptible mismatch at the beginning. Therefore, younger
pediatric patients still require sedation or must remain asleep during
the scan. In addition, a shorter imaging duration can benefit patients
with advanced tumors who may encounter respiratory difficulties
or discomfort while reclining on the scanner bed (16). For patients
with brain metastases who exhibit compulsive movements, the
total-body PET scanner can provide relief during the examination
or potentially shorten the duration of constraints. Although it is
rare, the necessity for PET imaging in such circumstances should
not be underestimated.
How fast could the total-body PET scan be? Prior investigations
have demonstrated that the acquisition times can be reduced to
30 s when using the uEXPLORER scanner for total-body PET/CT
(20,24). The rapid PET protocol, with acquisition durations of

58S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65 ! No. 5 (Suppl. 1) ! May 2024

FIGURE 3. Example of total-body PET scan with one-fifth dose of 18F-
FDG (0.79 MBq/kg) activity. Thirteen-year-old boy diagnosed with relapsed
anaplastic lymphoma kinase-positive anaplastic large cell lymphoma under-
went ninth PET/CT examination for follow-up after chemotherapy. Slight
radiotracer uptake of inflammatory lymph node in right neck (arrow) is shown.
Axial PET image of liver displays good background quality.
FIGURE 4. Comparison of image quality between CT-Dx and LDCT combined with different 18F-
FDG injection doses. Five-year-old boy diagnosed with B-cell lymphoblastic leukemia underwent
complete remission after systemic chemotherapy. Total-body PET/CT examinations were performed
during 2-y follow-up. One-half dose of 18F-FDG (1.85 MBq/kg) combined with reduced CT dose was
used for latter examination (right) to minimize radiation exposure. Representative CT images, axial
PET images, and fused PET/CT images of liver show diagnostic and staging efficacy is not compro-
mised. CT-Dx 5 diagnostic CT scan with higher x-ray dose; LDCT 5 low-dose CT.
30–45 s, can deliver image quality equivalent to that of SAFOV
digital uMI 780 PET/CT, which typically necessitates 2–3 min per
bed position. The 30-s total-body PET/CT achieved similar sensi-
tivities and accuracy in a cohort of 88 oncology patients, thus ade-
quately meeting clinical diagnostic requirements, to those
achieved with the standard 300-s acquisition time (25). Similar
results were supported by another LAFOV scanner, the Biograph
Vision Quadra PET/CT (Siemens Healthineers). Shorter LAFOV
acquisitions of 30 s were sufficient for target lesion identification,
suggesting that ultrafast or low-dose acquisitions can be consid-
ered acceptable (26).
Full-Body Coverage
SAFOV PET imaging protocols recommend scanning from the
base of the skull to the upper-mid-thigh region, considering that
most bone metastases tend to migrate to the red bone marrow, pre-
dominantly located in axial and appendicular skeletons (27).
Besides, a comprehensive scan of the lower extremities using the
SAFOV modality increases the number of bed positions required,
thus extending the scan time. Unfortunately, this protocol over-
looks the presence of widespread musculoskeletal metastases.
Pediatric and adult-onset malignancies such as cutaneous lym-
phoma, renal cancer, lung cancer, and melanoma have a higher
propensity of developing distant metastases in the extremities
(28). Moreover, several cancers are characterized by biologic het-
erogeneity, with substantial variations observed both within the
primary site and among metastatic sites. This inevitably leads to
diagnostic and classification inaccuracies when based on a limited
number of biopsy samples, resulting in deviations in therapeutic
selection and response to treatment. Although SAFOV PET/CT
may not fully reflect overall disease activity, total-body PET offers
the potential to detect cancers at multiple sites, with full-body cov-
erage achievable in a single bed position (Fig. 5). This greatly
enhances the sensitivity for detecting various cancers and holds
the potential for a groundbreaking impact
on comprehensive disease management.
Despite limited experience, total-body
PET allows the assessment of nononcolo-
gic systematic diseases, including degener-
ative atherosclerosis (29,30), rheumatoid
arthritis, and deep venous thrombosis (31).
High Sensitivity and Improved
Lesion Detection
Increased sensitivity broadens the appli-
cability of total-body PET scans across
various clinical scenarios, especially those
that were unattainable with SAFOV
PET/CT scanners (Fig. 6). A cohort study
featuring a head-to-head intraindividual
comparison between 2 PET scans demon-
strated that total-body PET/CT exhibited
greater sensitivity in detecting small
lesions (4.3 mm; SUVmax, 1.0) or those
with low uptake (tumor-to-liver ratio, 1.6;
SUVmax, 4.1) (32). This heightened sensi-
tivity yields a superior signal-to-noise
ratio, enabling the identification of small,
low-contrast tumor deposits and microme-
tastases (33). Another study illustrated that
total-body PET achieves enhanced contrast
TOTAL-BODY PET/CT IN SYSUCC ! Chen et al. 59S
 parametric images from dynamic PET/CT,
which improves the accuracy of cancer seg-
mentation (36). For lung cancer, we have
shown that the kinetic parameter of Ki
obtained from whole-body dynamic PET/CT
provides a more precise characterization of
the metabolic heterogeneity of non–small
cell lung cancer. This metric correlates with
levels of immune cell infiltration and the
response to immune-chemotherapies (37).
However, parametric imaging does en-
counter challenges related to extended scan-
ning times. Encouragingly, several studies
have explored shorter acquisition protocols
to enhance clinical efficiency (38–40).
Another study demonstrated the feasibility
of performing accurate 18F-FDG Patlak
analysis using a scaled population-based
input function with only 20 min of PET data
from a LAFOV PET scanner (41).

CHALLENGES OF TOTAL-BODY PET/CT

False Positives Arising from High

Sensitivity
The enhanced image quality also intro-
duces challenges in terms of image inter-
pretation and differentiation. In clinical
practice, the primary challenge associated
with total-body PET/CT scanners lies in
FIGURE 5. Advantages of full-body coverage using 18F-FDG (3.7 MBq/kg) total-body PET/CT. (A) distinguishing between benign and malig-
PET images of 32-y-old man diagnosed with right pelvic melanoma and lymph nodal metastases. nant lesions. Unlike the mild-to-moderate
18
Arrowheads indicate venous thrombosis within right leg veins. (B) 65-y-old man with malignant mela- F-FDG uptake observed in the spinal
noma. Diagnostic accuracy of total-body PET was confirmed by extensive detection of cutaneous cord in SAFOV PET/CT scans, total-body
primary lesion and lymph node metastases throughout entire body. (C) 9-y-old girl with lymphoma PET/CT scans have shown intense 18F-
revealed by biopsy of left orbital mass. Total-body PET image shows lymph, cutaneous, and bone
FDG uptake in the distal spinal cord, which
involvement. (D) 3-y-old child diagnosed with B lymphoblastic lymphoma. Multiple masses in liver,
spleen, and kidney with multisystem invasion, including lymph nodes and focal distal bones, were
is considered a physiologic phenomenon
detected. (42). Structures previously deemed non–18F-
FDG-avid in SAFOV PET/CT scans, such
as the gallbladder, may exhibit FDG uptake
recovery through the use of small voxels, coupled with low back- (43). This necessitates careful consideration when distinguishing these
ground variability. This enhancement aids in the detection and findings from inflammatory or neoplastic diseases. The emerging pat-
quantification of uptake in smaller lesions (5). Furthermore, arti- tern observed in total-body PET/CT scans warrants further exploration
facts stemming from respiratory, cardiac, intestinal motion, and and summarization.
overall body movement can greatly affect the image quality. How- Because of improved spatial resolution, total-body PET/CT
ever, the elevated sensitivity affords the opportunity for total- images reveal a greater number of small lesions and lymph nodes.
body scans to be conducted in a single breath-hold, as well as However, we should not automatically assume that all of these are
for motion-frozen scans of the heart, lungs, and gastrointestinal malignant. Radiologists face challenges in determining the nature
tract (4). of these findings (Fig. 7). Taking biopsy samples for every lesion
or lymph node in most patients is impractical. Therefore, it is cru-
Whole-Body Dynamic Studies cial to approach the interpretation of these small lesions and lymph
In conjunction with tracer kinetic modeling, whole-body dynamic nodes with great caution to avoid false-positive diagnoses. Limited
18
F-FDG PET enables a multiparametric quantification approach studies specifically address false-positive rates in total-body
that holds the potential to unveil clinical insights into the metabolic PET/CT scans, and this issue has been recognized as a potential
properties of tissues. In turn, these derived-image metrics offer the challenge associated with total-body PET/CT scanners (44,45).
possibility to facilitate tumor characterization and assess therapy
responses (34,35). Our current emphasis is on patients with NPC or Claustrophobia and Other Psychologic Disorders
lung cancer, both prevalent diseases in our center. We initiate a Claustrophobia, anxiety, and other unanticipated psychologic
60-min dynamic scan after the injection of 3.0 MBq/kg 18F-FDG. To disorders during imaging examinations not only result in excessive
ensure a seamless workflow, patients scheduled for dynamic scans motion, which precludes diagnostic-quality imaging, but also can
undergo their initial examination each day. The intricate tumor struc- negatively affect the patient experience. The LAFOV scanner,
ture of NPC led us to develop a segmentation method based on with larger body coverage, tends to induce more stress in patients

60S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65 ! No. 5 (Suppl. 1) ! May 2024
 claustrophobia. Most patients with mild or
moderate anxiety or claustrophobia can
complete the scan with the aid of psycho-
logic support and audiovisual intervention
performed before and during imaging by
the referred physicians and technicians.
However, PET imaging remains chal-
lenging for patients with severe claustro-
phobia. Several interventions and efforts,
such as open PET geometry (46), quieter
machines, guided imagery, fragrance
administration, and patient positioning
devices (47), should be developed to mini-
mize these psychologic disorders. This not
only improves patient satisfaction but also
enhances operational efficiency and diag-
nostic capacity.

Differences Between Total-Body and

SAFOV PET/CT Systems Introduce
Challenges in Harmonization
The obvious differences among devices
18 pose hurdles for the quantitative assess-
FIGURE 6. Example of intraindividual comparison of F-FDG (3.7 MBq/kg) total-body PET (left) and
conventional PET (right) images in lung cancer patient with liver and bone metastases. Axial PET images ment of PET parameters in therapeutic
of total-body PET scans revealed 4 lesions in liver (arrows) that were barely recognizable in conventional evaluation and disease monitoring, because
PET/CT scans, because radiotracer uptake of liver lesions was similar to physiologic liver background. these parameters are substantially influ-
enced by the specific PET scanners in use.
than SAFOV scanners. Patients with claustrophobia at our center Furthermore, the employment of different filtering and reconstruc-
found SAFOV scanners to be more acceptable in practice, even tion methods across various PET scanners can exacerbate the
if they required a longer acquisition time. Therefore, SAFOV variability among PET parameters (48). In the clinical setting
scanners were the primary recommendation for patients with of SYSUCC, which is equipped with multiple PET devices,
the major strategy for ensuring parameter
comparability involves using the same
devices for both baseline and follow-up
scans, as described in an earlier section.
An additional crucial strategy involves
standardizing patient preparation, image
acquisition and reconstruction, and image
interpretation, aligning these with recom-
mendations from the European Association
of Nuclear Medicine (1) and the Uniform
Protocols in Clinical Trials (49). The third
strategy entails conducting annual quality
control experiments using a set of phan-
toms for adherence to the European
Association Research Ltd. accreditation
program (50). Furthermore, comparable
PET parameters can be achieved through
the application of advanced reconstruction
algorithms, such as the point spread
function (51), Bayesian penalized likeli-
hood reconstruction (52), and EQ.PET
software (Siemens) (53). Nevertheless,
when multiple centers are involved, harmo-
nization becomes a more complicated
endeavor because of the challenges of
ensuring standardized patient preparation
and scan procedures. In addition, the feasi-
FIGURE 7. Example of retroperitoneal small lymph nodes posing challenges for diagnosis. Fifty-
18
five-year-old woman with surgically removed cervical cancer was referred for F-FDG (3.7 MBq/kg) bility of advanced reconstructions may
total-body PET/CT scan. Axial PET images and fused PET/CT images display paraaortic small lymph be limited by the absence or lack of
nodes (arrowheads) with higher 18F-FDG uptake (SUVmax, 6.5) than physiologic background. raw data. It is imperative to promote

TOTAL-BODY PET/CT IN SYSUCC ! Chen et al. 61S

harmonization strategies in the routine operations of multiple medi-
cal institutions.
SUMMARY
Total-body PET/CT scanners have demonstrated their superior-
ity over SAFOV systems in terms of sensitivity and lesion detec-
tion. They offer the advantages of requiring less administered
radioactivity and shorter acquisition times. This increase in signal
collection efficiency has enabled the optimization of clinical rou-
tines and the enhancement of several applications in disease diag-
nosis, staging, treatment response evaluation, and prognosis.
Nevertheless, concerns inevitably arise about the ultimate benefits
of total-body PET imaging. Many challenges, including false posi-
tives, psychologic disorders, and harmonizing results among dif-
ferent devices, must be addressed. In our center, we have reviewed
the advantages and clinical applications of the total-body PET
scanner, highlighting the substantial advancements made in vari-
ous fields. Our aim is that this article will provide insights into
routine clinical practices and ultimately improve patient care. We
believe that there are still many impactful applications to be devel-
oped, and further demonstrations of the capabilities of the uEX-
PLORER scanner are warranted.
DISCLOSURE
Yumo Zhao is an employee of United Imaging Healthcare Co.
Ltd. No other potential conflict of interest relevant to this article
was reported.
ACKNOWLEDGMENTS
We thank our industry advisors at United Imaging Healthcare Co.
Ltd. for their expertise and assistance.
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TOTAL-BODY PET/CT IN SYSUCC ! Chen et al. 63S
Clinical Implementation of Total-Body PET in China
Yaping Wu1–3, Tao Sun4, Yee Ling Ng5, Jianjun Liu6, Xiaohua Zhu7, Zhaoping Cheng8, Baixuan Xu9, Nan Meng1–3,
Yun Zhou5, and Meiyun Wang1–3
1
Department of Medical Imaging, Henan Provincial People’s Hospital, Zhengzhou, China; 2People’s Hospital of Zhengzhou University,
Zhengzhou, China; 3Institute for Integrated Medical Science and Engineering, Henan Academy of Sciences, Zhengzhou, China;
4
Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China; 5Central Research Institute,
United Imaging Healthcare Group Co., Ltd., Shanghai, China; 6Department of Nuclear Medicine, RenJi Hospital, School of Medicine,
Shanghai Jiao Tong University, Shanghai, China; 7Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, China; 8Department of Nuclear Medicine, First Affiliated Hospital of
Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China; and 9Department of Nuclear
Medicine, Chinese PLA General Hospital, Beijing, China

Imaging Healthcare), pioneered this concept in 2018 (1). Another

Total-body (TB) PET/CT is a groundbreaking tool that has brought
about a revolution in both clinical application and scientific research.
The transformative impact of TB PET/CT in the realms of clinical prac-
tice and scientific exploration has been steadily unfolding since its
introduction in 2018, with implications for its implementation within
the health care landscape of China. TB PET/CT’s exceptional sensitiv-
ity enables the acquisition of high-quality images in significantly
reduced time frames. Clinical applications have underscored its effec-
tiveness across various scenarios, emphasizing the capacity to per-
sonalize dosage, scan duration, and image quality to optimize patient
outcomes. TB PET/CT’s ability to perform dynamic scans with high
temporal and spatial resolution and to perform parametric imaging
facilitates the exploration of radiotracer biodistribution and kinetic
parameters throughout the body. The comprehensive TB coverage
offers opportunities to study interconnections among organs, enhanc-
ing our understanding of human physiology and pathology. These
insights have the potential to benefit applications requiring holistic
TB assessments. The standard topics outlined in The Journal of
Nuclear Medicine were used to categorized the reviewed articles
into 3 sections: current clinical applications, scan protocol design,
and advanced topics. This article delves into the bottleneck that
impedes the full use of TB PET in China, accompanied by suggested
solutions.
Key Words: PET; total-body PET/CT; high-quality imaging; ultrafast
scan; low dose; parametric imaging
J Nucl Med 2024; 65:64S–71S
DOI: 10.2967/jnumed.123.266977
commercially available system, the Siemens Biograph Vision
Quadra, offers a 104-cm length (2). A prototype with scalable
length is under development (3).
TB PET/CT has revolutionized molecular imaging in clinical
and scientific domains. Long-axial-field-of-view PET systems
have exhibited 40-fold enhancement in sensitivity, image quality,
and the capabilities of molecular imaging compared with conven-
tional PET/CT (4). The first human TB PET/CT images were
reported in 2019, marking the inception of widespread clinical
use. In China, the uEXPLORER PET/CT system found initial
application at Zhongshan Hospital and was rapidly adopted by
numerous hospitals across the country, totaling 16 installations as
of September 2023. uEXPLORER use is expected to increase at a
rate of 6–7 units per year in China.
TB PET/CT systems offer greatly improved sensitivity, detect-
ing micrometastases, reducing injection dose, and shortening scan
durations, all of which have substantial clinical implications.
Moreover, a TB PET/CT system enables dynamic PET imaging
of metabolic processes and tracer biodistribution throughout
the body, promising advancements in drug development and
clinical translation. However, TB PET/CT imaging presents chal-
lenges, including radiation exposure, acquisition and maintenance
costs, the complexity of implementing dynamic scans, and the
necessity for standardized protocols across various sites and
settings.
With 16 TB PET scanners installed in China, this review
explores clinical implementation studies of TB PET/CT in China

C
linical PET/CT scanners typically have an axial field of
view of 15–30 cm, primarily determined by the need to encompass
a single region. Short-axial-field-of-view scanners are character-
ized by suboptimal signal collection efficiency, because they col-
lect less than 1% of the available signal (1). This issue can be
addressed by extending the detector rings to cover the entire body,
which is called total-body (TB) PET. The inaugural human TB
PET system, with a remarkable 2-m length (uEXPLORER; United
Received Nov. 4, 2023; revision accepted Feb. 13, 2024.
For correspondence or reprints, contact Meiyun Wang (mywang@zzu.edu.cn).
COPYRIGHT ! 2024 by the Society of Nuclear Medicine and Molecular Imaging.
and provides an overview of key findings. This review addresses
the challenges encountered and offers perspectives into the future
directions of TB PET research and its impact on health care.
CURRENT CLINICAL APPLICATIONS
18
F-FDG Oncologic Imaging
18
F-FDG is a well-established radiopharmaceutical agent that is
widely used in TB PET/CT examinations for oncologic diseases
and yields encouraging results (Fig. 1) (5). A consensus on onco-
logic 18F-FDG TB PET/CT imaging that used extensive clinical
expertise has been published (6). In the realm of early tumor diag-
nosis, TB PET/CT demonstrates heightened sensitivity, particu-
larly in detecting small or low-uptake lesions (7). This superiority
is evident in colorectal cancer (8). In addition, TB PET/CT is used

64S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65 ! No. 5 (Suppl. 1) ! May 2024

FIGURE 1. Subjective overall image quality at various acquisition
times using full dose, with ringlike 18F-FDG uptake lesion in liver shown in
maximum intensity projection (A–F) and axial view (G–L) for 900- to 18-s
groups. Overall image scores of 5, 4, 3, 2, and 1 were assigned to 180-,
120-, 60-, 30-, and 18-s groups, respectively. (Reprinted with permission
of (5).)
the potential of 11C-methionine–based TB PET/CT for monitoring
multiple myeloma and stratifying risk. Parametric imaging proved
to have superior quantification and enhanced lesion contrast com-
pared with standard SUV images (16). In addition, using a half-
dose of 68Ga-FAPI-04 in TB PET/CT imaging reduced acquisition
time to 120 s while maintaining acceptable image quality and
achieving a 100% tumor detection rate (17).68Ga-FAPI PET/CT
may outperform 18F-FDG PET/CT in staging lung cancer (18).
Evaluation of 18F-AlF-P-FAPI demonstrated specific uptake, rapid
internalization, and low cellular efflux, showing results for primary
tumors and lymph node metastases comparable to those of 18F-FDG
(19). Recent studies have illustrated that the TB PET/CT, when cou-
pled with 68Ga-prostate-specific membrane antigen (PSMA)-11,
offers advanced insights into metabolic heterogeneity (20) and
enhanced lesion detection in prostate cancer patients using TB
parametric imaging (21), as well as highlighting the improved
detection rate compared with conventional PET (22).
A HER2 molecular probe based on Affibody molecules (Affi-
body AB), 18F-AlF-RESCA-HER2-BCH, exhibits improved
tumor uptake and renal clearance, reducing the renal absorbed dose
and enhancing its clinical value for targeted radionuclide therapy
(23). 18F-FAPI-42, a newly developed FAP-specific cancer imaging
tracer, demonstrates optimal imaging 1 h after injection, displaying
high uptake and clear lesion visualization (Fig. 2) (24). 68Ga-
HNI01 has high specificity for carcinoembryonic antigen in vivo,
which can effectively detect colorectal cancer lesions and identify
small metastases, making it an ideal tool for selecting patients for
anti–carcinoembryonic antigen therapy (Fig. 3) (25).

to assess neuroendocrine tumors, distin-

guish benign from malignant lymph nodes,
and address issues of tumor recurrence and
metastasis (9). Xie et al. (10) found that TB
PET/CT aids in exploring potential correla-
tions between lung cancer and brain metasta-
ses. TB PET/CT also aids in treatment
planning by identifying immunotherapy-
responsive patients (11) and evaluating pleu-
ral involvement in lung cancer, especially
solid nodules (12). TB PET/CT detects and
locates primary ectopic pheochromocytomas,
facilitating early diagnosis and treatment (13).

Non–18F-FDG Oncologic Imaging

The clinical application of non–18F-
FDG tracers in oncology is an active focus
of TB PET/CT research in China. The radi-
oligand 68Ga-N188 offers a noninvasive
quantification of nectin-4 expression in
advanced urothelial carcinoma. TB
PET/CT may aid in selecting patients
likely to respond to enfortumab vedotin
and in predicting their response, optimizing
targeted nectin-4 therapy (14). Dynamic
68
Ga-fibroblast activation protein inhibitor
FIGURE 2. TB PET monitoring of biodistribution and optimization of acquisition time. (A)
(FAPI)-04 TB PET/CT imaging in pancre-
Maximum-intensity projection images of 18F-FAPI-42 at 5, 10, 15, 20, 65, and 120 min after injection
atic and gastric cancer enabled the study of in patient 21 (female). (B) Time–activity curves of 18F-FAPI-42 at various time points after injection.
68
Ga-FAPI-04 kinetics in normal organs and (C) Tumor SUVmax–to–organ SUVmean ratios at various time points after 18F-FAPI-42 injection,
lesions. Research by Li et al. (15) suggests excluding tumor SUVmax–to–brain SUVmean ratio. (Reprinted with permission of (24).)

TOTAL-BODY PET IN CHINA ! Wu et al. 65S

 pose challenges. TB PET/CT dynamic imag-
ing confirms excellent systemic distribution,
minimal internal radiation exposure, and high
imaging quality for 11C-2ß-carbomethoxy-
3ß-(4-fluorophenyl)tropane, making it suit-
able for PD diagnosis in patients requiring
multiple follow-up examinations (32). Simi-
larly, uEXPLORER PET/CT can simulta-
neously measure the time–activity curve of
13
N-ammonia in all body organs, providing
more precise information about biologic dis-
tribution and radiation dose estimation (33).

SCAN PROTOCOL DESIGN

Short Scan Time

The high sensitivity of TB PET/CT
allows data acquisition time to be curtailed
without compromising image quality, thus
optimizing clinical practice and benefiting
patients (34). Reduced scan times enhance
throughput and patient comfort even as
they effectively minimize motion-induced
artifacts. For full-dose (3.7 MBq/kg) TB
PET/CT, a 2-min scan in oncologic patients
yields satisfactory image quality (Fig. 1) (5)
and matches conventional PET/CT in diag-
nostic performance (35). Even a 30- to 40-s
TB PET/CT scan suffices for intolerant
patients and provides image quality that riv-
FIGURE 3. 68Ga-HNI01 PET images in patients with colorectal cancer primary tumors. (A) Recon- als conventional PET/CT (36,37). Research
structed dynamic whole-body PET/CT maximum-intensity projection (MIP) images of 68Ga-HNI01 in
confirms good image quality and diagnostic
patient 10 (10 frames). (B) MIP images from 68Ga-HNI01 PET/CT (left) and 18F-FDG PET/CT (right) in
68
patient 10 with abnormal intestinal activity uptake. (C) MIP images from Ga-HNI01 PET/CT (left) efficacy even at lower doses. In oncology
and 18F-FDG PET/CT (right) in patient 4 with normal intestinal activity uptake. (D) Time courses and patients, a 2-min TB PET/CT with half-
fitting curves (fit spline or locally weighted scatterplot smoothing) of 68Ga-HNI01 uptake in normal dose (1.85 MBq/kg) 18F-FDG offers accept-
tissues and tumors for 3 patients in terms of SUVmax. (E) Immunohistochemical staining for carcino- able performance, whereas a 5- to 8-min
embryonic antigen in tumor samples from patients 1 and 4. A.U. 5 abnormal uptake; C 5 cecum; scan aligns well with clinical practice
G.E.J. 5 gastroesophageal junction; K 5 kidney; p.i. 5 postinjection; T 5 tumor. (Reprinted with
needs (22,38–40). Ultralow (one tenth,
permission of (25).)
0.37 MBq/kg) 18F-FDG activity with an
8-min acquisition is clinically feasible (41),
Nononcologic Imaging and a 2-min acquisition can achieve acceptable image quality (42).
In nononcologic fields, TB PET/CT demonstrates high diagnostic Image quality is contingent on factors such as tracer activity, acquisi-
potential, with heightened sensitivity in detecting early inflammation, tion time, and body mass. Research underscores the quadratic relation-
particularly in vasculitis cases (26,27). It aids in gauging infection ship between body mass index and injected activity (43) for oncology
severity and assisting treatment strategy development. With its exten- patients undergoing TB PET/CT imaging.
sive detector coverage and sensitivity, TB PET/CT enables compre- Reducing scan times helps minimize the impact of patient move-
hensive assessments of TB glucose uptake and vascular wall lesions, ment, especially during chest scans, where respiratory motion can
yielding promising outcomes (28). Increased 18F-FDG uptake in the cause image blurring. Respiration-gated imaging with a reduced
distal spinal cord has been identified in young individuals without dia- scan time on TB PET/CT outperforms ungated imaging in terms
betes or those with low fasting blood sugar levels (29). Yu et al. (30) of lesion detectability, offering promising clinical applications (44).
used TB PET/CT to evaluate radiation accumulation within salivary If TB PET/CT’s ultrafast imaging capabilities are leveraged, a
glands, revealing that oral vitamin C effectively mitigates radiation- 20-s breath-hold acquisition will prove practical for reducing motion
related adverse effects. A growing number of studies reveal the skele- artifacts and shows potential for enhancing lesion detection, parti-
ton’s endocrine role in influencing glucose metabolism and human cularly in stage IA pulmonary adenocarcinoma (Fig. 4) (45).
glucose homeostasis. Scientists used state-of-the-art TB PET/CT to TB PET/CT’s potential for shorter scan times applies to explor-
investigate in vivo glucose uptake and distribution across the human ing alternative radiotracers, such as 68Ga-PSMA and 68Ga-FAPI.
skeleton, reinforcing its significance in regulating glucose metabolism Combining early dynamic 68Ga-PSMA PET (75–360 s) with static
and providing insights into age- and obesity-related factors (31). imaging at 60 min after injection can circumvent interference from
Although 11 C-2ß-carbomethoxy-3ß-(4-fluorophenyl)tropane urinary bladder activity, facilitating the detection of pathologic
PET/CT is widely used for early Parkinson disease (PD) diagnosis, lesions with low PSMA uptake (46). Research indicates that TB
its short half-life and limited understanding of its biologic distribution 68Ga-FAPI-04 PET/CT images, obtained within a 30-s acquisition

66S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65 ! No. 5 (Suppl. 1) ! May 2024
 standard dose, require only 150 s of raw data to generate clear
PET images displaying lesions.

Dual Tracer Single Scan

Various radiotracers provide complementary insights into lesion
characteristics, contributing to precise diagnosis. For instance,
combining 68Ga-DOTATATE PET/CT with 18F-FDG PET/CT
effectively diagnoses and evaluates neuroendocrine neoplasm het-
erogeneity (54). A streamlined approach proposes a single CT scan
paired with a dual-tracer (18F-FDG and 68Ga-DOTA-FAPI-04)
imaging protocol. This protocol effectively amalgamates the benefits
of both tracers, ultimately enhancing diagnostic precision. It also
significantly reduces both scan time and radiation exposure, making
FIGURE 4. Breath-hold (BH) acquisition in TB PET. Images of 59-y-old it clinically applicable (55). This protocol may serve as a supple-
man with lung adenocarcinoma show solitary solid lung nodule in right mentary approach to 18F-FDG PET/CT for suitable patients, broad-
lower lobe in axial, coronal, and sagittal chest CT (top row), PET (middle ening the scope of oncologic imaging using 68Ga-DOTA-FAPI-04
row), and PET/CT (bottom row). (A) Free-breathing (FB) PET/CT. (B) BH
PET/CT.
PET/CT. Blurred uptake area results from breathing artifacts in FB PET
image. (Reprinted with permission of (45).)
OTHER ADVANCED TOPICS
at 5 min after injection, yield diagnostic results similar to those of Dynamic Imaging
traditional scans conducted 60 min after injection with a 300-s TB PET/CT’s sensitivity and TB coverage provide unprece-
acquisition. This reduction in waiting and acquisition times dented advantages for dynamic scanning. Its impressive temporal
enhances patient throughput and comfort (47). and spatial resolution forms a robust foundation for dynamic data
Low Injection Dose analysis, essential for TB exploration of radiotracer biodistribution
The attractiveness of minimal TB PET doses lies in their reduc- and kinetic parameters, whether using a full or reduced dose (48).
tion of radiation exposure (48). Studies demonstrated that half For instance, dynamic scanning reveals variation in uptake and
(22,38), one-tenth (8,48,49), or even one-thirtieth (50) doses poten- clearance among normal organ types, aiding assessment of tracer
tially reduced the internal radiation effective dose in PET/CT exami- kinetics (41,56,57). Using dynamic frame reconstruction at 0.5-s
nations to 0.6–0.9 mSv. During the scanning process, CT plays a intervals can demonstrate a pediatric patient’s movements during
pivotal role in 3 stages: localization, attenuation correction, and sleep (58). Dynamic scanning usually necessitates data collection
diagnosis. A study on TB PET/CT for pediatric lymphoma reveals a exceeding 60 min; by leveraging the superior image quality provided
66.1% reduction in effective dose using low-dose CT, without by TB PET, acquisition times to 45 min may still obtain kinetic
compromising diagnostic accuracy and staging efficacy (51). metrics for 18F-FDG (59). The clinical feasibility of ultra-low-dose
18
Combining attenuation-corrected CT with artificial intelligence (AI) F-FDG TB PET/CT imaging has been validated by dynamic imag-
techniques empowers the reconstruction of ultra-low-dose CT scans ing through both quantitative and qualitative analyses (41). Dynamic
as an alternative to diagnostic CT in specific scenarios (52). When TB PET imaging also enables the attainment of comparable kinetic
the rich anatomic data from long-axial-field-of-view TB PET images metrics (49) and tumor-to-background ratios in lung adenocarcinoma
are used as input, an AI application that
uses a deep learning reconstruction algo-
rithm can potentially enable the image
reconstruction process without additional
CT images for attenuation and scattering
corrections (53). However, a drawback was
the loss in converting 3-dimensional sino-
grams to 2 dimensions, which introduced
noise, lost spatial information, and resulted
in an incomplete recovery of details in the
ground truth images. These low-dose meth-
ods hold promise for more efficient execu-
tion of multiple TB PET/CT scans.
Enhanced TB PET sensitivity offers sig-
nificant advantages for pediatric patients,
who are more susceptible to risk of radia-
tion exposure from PET and CT scans. TB
PET/CT can reduce the administered 18F-
FDG dose to one-thirtieth while preserving
FIGURE 5. Subjective overall image quality at different doses. 18F-FDG PET image of 1.9-y-old
image quality and lesion detectability.
male patient, weighing 10 kg with Langerhans cell histiocytosis, is reconstructed at 600, 300, 60, 40,
Optimal image quality is attainable with a and 20 s and depicted in maximum-intensity projection and axial views (A–E), representing full, half,
one-tenth dose and a 10-min scan (Fig. 5) one-tenth, one-fifteenth, and one-thirtieth dose, respectively. Effective doses are shown in parenthe-
(50). Pediatric patients, receiving half the ses. (Reprinted with permission of (50).)

TOTAL-BODY PET IN CHINA ! Wu et al. 67S

patients (48), which demonstrates that equivalency extends between
normal and low-dose dynamic imaging.
For precise early activity measurement, shorter frame durations
are essential, albeit at the cost of a reduced signal-to-noise ratio.
Conventional denoising methods, such as the nonlocal mean method,
often address individual frames or slices (60). Adjacent frames
exhibit an anticipated pattern in voxel activity, allowing the use of
interframe information to enhance image quality through pixel-level
time–activity curve correction (61). Motion correction is also vital in
maintaining image quality in dynamic TB PET imaging. It effec-
tively reduces the impact of random body movements on dynamic
images and may prove beneficial for comprehensive TB assessment,
such as brain–gut axis and systemic disease imaging (62).
A closely related topic to dynamic imaging is dosimetry, which
is vital for radiation protection, dose optimization, image quality
enhancement, and workflow simplification. Traditional PET strug-
gles with precise internal dose assessment because of limited axial
coverage. TB PET/CT’s dynamic scanning enables detailed voxel-
based radiation dose calculations, ensuring accurate total internal
dosimetry (63). This approach applies to tracers such as 68Ga-
PSMA-11 (64), 68Ga-FAPI-04 (64), 11C-2ß-carbomethoxy-3ß-
(4-fluorophenyl)tropane (32), and 13N-ammonia (33), offering insights
for optimizing dose and workflow in future clinical settings (64).
Kinetic Modeling
The widely adopted SUV from a single time frame suffices for
many clinical purposes. Nevertheless, dynamic scans using multiple
time frames offer more comprehensive metabolic insights. Paramet-
ric imaging, facilitated by appropriate kinetic models, generates
quantitative images and parameters with diverse applications in
advanced diagnosis, treatment assessment, therapy management,
and drug or tracer development (65). A study of healthy volunteers
revealed significant variations in kinetic and metabolic rates of 18F-
FDG across organs (66). TB dynamic PET imaging using ultralow
injected activity achieved pertinent kinetic metrics for 18F-FDG and
maintained image contrast comparable to that of full-activity imaging
(49). Wu et al. (67) performed qualitative and quantitative compari-
sons between metabolic rate images from dynamic 18F-FDG imaging
FIGURE 6. Ki images with various settings. These 16 schemes use different durations (40, 30, 20,
and 16 min), input functions (image-derived input function [IDIF] and population-based input function
[PBIF]), and application with or without nonlocal means (NLM) filter. Arrow indicates lesion. (Rep-
rinted from (60).)
68S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65
and delayed images. The clinical values in improved lesion detection
and differential diagnosis were evaluated for the same group of
patients. The Patlak model is increasingly favored for 18F-FDG TB
PET dynamic imaging because of its simplicity (60) and predictive
value in immunochemotherapy response (68).
Scanning protocols have emerged to shorten the total imaging
time (Fig. 6) (59,60,69). The derived Ki and K1 values from a pro-
tocol with dual time windows, comprising a 10-min early scan and
a 5-min late scan, showed strong agreement with the results from
a full 60-min dynamic scan (69). An dual-injection protocol,
involving an initial scan 50–60 min after injection followed by a
second injection at 56 min, reduces TB Ki imaging time to 10 min
with a single CT scan, enabling the incorporation of parametric
imaging into clinical practice (70). In addition, K1 images can be
estimated using only data from the first 90 s after injection with a
1-tissue compartment model (71). When it comes to non–18F-FDG
tracers, researchers are also interested in their kinetic information and
effect in clinics. Analyzing dynamic data for 68Ga-PSMA-11 (20)
and 68Ga-FAPI-04 (72) establishes a strong correlation between the
mean tumor-to-blood ratio and the total distribution volume, which
would be the preferred measurement tool for semiquantitative assess-
ment of tumor uptake and treatment response evaluation. In addition,
11
C-methionine TB PET scans capture dynamic changes in myeloma
metabolism by tracking radiotracer distribution in vivo. This
approach unveils the metabolic process of 11C-methionine in multi-
ple myeloma through kinetic modeling and found that risk stratifica-
tion in multiple myeloma based on the k4 value holds promise (15).
Connectome Analysis
TB PET’s exceptional sensitivity enables high-temporal-resolution
TB dynamic imaging, facilitating the study of organ connectomes to
comprehend human physiology and pathology. This capability
allows measurement of simultaneous or delayed signal changes in
different organs, paving the way for causal relationships that hold
promise for medical interventions (73). Maintaining health relies on
the stability of interorgan interactions for homeostasis. Metabolic
abnormalities in certain organs can disrupt this equilibrium, poten-
tially causing diseases. Consequently, using organ networks as diag-
nostic tools offers a systemic perspective
to identify individual metabolic abnormali-
ties (Fig. 7) (74). When investigating the
brain–gastrointestinal relationships in PD
through dynamic 11C-2ß-carbomethoxy-3ß-
(4-fluorophenyl)tropane TB PET/CT imag-
ing of dopamine transporters, the results
suggest a loss of interactions between gas-
trointestinal organs and PD-related brain
nuclei in PD patients (75). Moreover, study-
ing metabolic interactions between organs
in overweight and obese patients using TB
PET underscores the significance of under-
standing organ connectivity for a compre-
hensive assessment of health and disease
(76). Exploiting the advantages of TB PET
low-dose imaging expands its application to
health assessments and treatment efficacy
evaluations.
AI Application
AI is an effective tool that enhances image
quality in TB PET studies. High-quality TB
! No. 5 (Suppl. 1) ! May 2024

FIGURE 7. Abnormal metabolic connectivity between organs. (A–C) Metabolic connectivity plots
show 2 abnormal subjects and control, with middle images displaying coronal SUV slices and side
plots showing network connections between organs. Abnormal subjects demonstrated denser con-
nectivity and higher strength at relevant nodes than did control network, marked with red arrows for
SUV uptake. CER 5 cerebellum; Covid-19 5 coronavirus disease 2019; CSF 5 cerebrospinal fluid;
GI 5 gastrointestinal; LV 5 left ventricle; SF 5 frontal cortex; WM 5 white matter. (Reprinted from (74).)
PET images can serve as training labels when training deep learning
models for denoise (77) and enhance contrast (78) in PET images
from conventional devices, as well as improving the quality of low-
dose (79) or ultrafast acquisition (80) TB PET images. AI methods
also facilitate the reconstruction and synthesis of parametric images
(81). A deep learning–driven approach has demonstrated its capacity
to create superior direct Patlak Ki images without necessitating an
input function (82), which may mitigate the challenge posed by
protracted scan times of dynamic PET. AI-based image quality
control enables automated generation of comprehensive and intri-
cate image quality assessment reports (83). Lesion segmentation is
time-consuming, and automatic segmentation performance is often
unsatisfactory. By harnessing the high contrast provided by TB
PET parametric images, the accuracy of automatic lesion segmenta-
tion can be significantly improved, integrating Ki parametric images
with PET and CT images (84).
SUMMARY
Over the years, TB PET/CT has achieved sensitivity and capabili-
ties that advanced the realm of molecular imaging. This article encap-
sulates the key findings of TB PET in China, covering both oncologic
and nononcologic applications and delving into advanced topics such
as dynamic parametric imaging, component analysis, and AI. It is evi-
dent that TB PET is making significant strides in clinical applications
in China, promising to enhance clinical efficiency.
Despite the achievements, the application of TB PET in China
encounters challenges. From an economic standpoint, the purchase
and maintenance costs of TB PET are higher than those of conven-
tional PET. In China, the price of a TB scan is about ¥6,000–¥9,000
(#$832.72–$1,250.57), which is the same or slightly higher than that
of a conventional full-body scan from eye to thigh. Many hospitals in
China have a large patient population and
limited space for equipment installation. The
high throughput of TB PET can effectively
alleviate this problem. Furthermore, beyond
its clinical value, TB PET may be more
important as a scientific platform to enhance
research capabilities, potentially outweighing
economic concerns. The legal and regulatory
frameworks are incomplete, and non–18F-
FDG radiotracers lack approval. Meanwhile,
the discipline of PET started relatively late in
China, resulting in a shortage of expertise. In
addition, limited familiarity with PET tech-
nology and its applications in other disci-
plines hinders multidisciplinary collaboration
in clinical applications. For example, applica-
tion and research in nononcologic disease are
relatively limited compared with oncologic
disease. However, efforts have been initiated
to formulate a long-term plan that encourages
the development of nuclear medicine, and
we believe that TB PET will play an impor-
tant role in Chinese clinical practice.
DISCLOSURE
This work was partially supported by the
National Key R&D Program of China
(2023YFC2414200), National Natural Sci-
ence Foundation of China (82371934), and Joint Fund of Henan Prov-
ince Science and Technology R&D Program (225200810062). Yee
Ling Ng and Yun Zhou are employed by United Imaging Healthcare.
No other potential conflict of interest relevant to this article was reported.
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TOTAL-BODY PET IN CHINA ! Wu et al. 71S
Pathway to Approval of Innovative Radiopharmaceuticals
in China
Shuxian An*1, Lu Wang*2, Fang Xie3, Dawei Jiang4–6, Gang Huang1, Jianjun Liu1, Xiaowei Ma7, Weijun Wei1
1
Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong
University, Shanghai, China; 2Center of Cyclotron and PET Radiopharmaceuticals, Department of Nuclear Medicine and PET/CT-MRI
Center, First Affiliated Hospital of Jinan University, Guangzhou, China; 3Department of Nuclear Medicine & PET Center, Huashan
Hospital, Fudan University, Shanghai, China; 4Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong
University of Science and Technology, Wuhan, China; 5Hubei Key Laboratory of Molecular Imaging, Wuhan, China; 6Key Laboratory
of Biological Targeted Therapy, Ministry of Education, Wuhan, China; and 7Department of Nuclear Medicine, Second Xiangya
Hospital of Central South University, Changsha, China

radiopharmaceuticals was $5.9 billion, with radioactive diagnostic

Since the late 1950s, radiopharmaceuticals have been used for diag-
nosis and treatment in clinical nuclear medicine in China. Over the
decades, China has successfully established a relatively sophisticated
system for radiopharmaceutical production and management, sup-
ported by state-of-the-art facilities. With the rapid growth of the national
economy, the radiopharmaceutical market in China is expanding at
a remarkable pace. This burgeoning market has led to an escalating
demand for clinical-stage radiopharmaceuticals, either produced
domestically or imported. Despite this positive trajectory, the develop-
ment and application of radiopharmaceuticals in China have been hin-
dered by several challenges that persist, such as inadequate research,
insufficient investment, limited availability of radionuclides, shortage of
trained personnel in related fields, and imperfections in policies and
regulations. In an exciting development, the regulation reforms imple-
mented since 2015 have positively affected China’s drug regulatory
system. The introduction of the “Mid- and Long-Term Development
Plan (2021–2035) for Medical Isotopes” created concurrently an oppor-
tune environment for the advancement of innovative radiopharmaceuti-
cals. In this review, we aim to provide an overview of the approval
process for novel radiopharmaceuticals by the National Medical Pro-
ducts Administration and the status of radiopharmaceuticals in research
and development in China. Preclinical development and clinical transla-
tion of radiopharmaceuticals are undergoing rapid evolution in China. As
practitioners in the field in China, we provide several practical sugges-
tions to stimulate open discussions and thoughtful consideration.
Key Words: radiopharmaceuticals; NMPA; drug approval; diagnosis;
therapy
J Nucl Med 2024; 65:72S–76S
DOI: 10.2967/jnumed.123.267127
drugs accounting for 90% of the market. The corresponding mar-
ket size in China was approximately ¥4.456 billion (#$624 mil-
lion), accounting for about 8% of the global radiopharmaceutical
market (1). With the popularization of SPECT, PET, and PET/CT,
research and development of diagnostic radiopharmaceuticals
represented by 99mTc-, 18F-, or 68Ga-labeled agents have advanced
rapidly, especially of positron-emitting radiopharmaceuticals. Almost
10 y after the discovery of [68Ga]Ga-PSMA-11, it was approved by
the U.S. Food and Drug Administration as the first 68Ga-labeled
radiopharmaceutical for PET imaging of prostate-specific membrane
antigen (PSMA)–positive prostate cancer in the United States in
2020 (2). This means that the clinical potential of targeted radiophar-
maceuticals is rapidly transforming into a clinical practicality. In
recent years, with the rapid development of targeted ligands and the
widespread application of new medical radionuclides, therapeutic
radiopharmaceuticals have attracted more attention. 153Sm, 89Sr,
223
Ra, 90Y, 131I, 177Lu, 225Ac, and other radionuclides are com-
monly used to treat cancer bone metastases, liver cancer, thyroid
cancer, and other malignant conditions, and they have shown enor-
mous therapeutic potential. In March 2022, [177Lu]Lu-PSMA-617
was approved for the treatment of metastatic castration-resistant
prostate cancer (3), which demonstrated good clinical therapeutic
efficacy and tolerance (4,5).
Radiopharmaceuticals were developed in China in the late
1950s, with industries mainly distributed in Beijing, Chengdu, and
Shanghai. After more than 60 y of development, a relatively com-
plete system for the research and development, production, supply,
and clinical application of radiopharmaceuticals has been estab-
lished. Nevertheless, the radiopharmaceutical industry in China

R
adiopharmaceuticals are compounds that contain radionu-
clides or their labeled ligands, and they are widely used in tumor
diagnosis and treatment, myocardial imaging, early detection of
neurodegenerative diseases, and imaging of inflammatory diseases,
among other uses. In 2020, the global market size of
Received Nov. 27, 2023; revision accepted Jan. 29, 2024.
For correspondence or reprints, contact Weijun Wei (wwei@shsmu.edu.cn)
or Xiaowei Ma (maxiaowei@csu.edu.cn).
*Contributed equally to this work.
COPYRIGHT ! 2024 by the Society of Nuclear Medicine and Molecular Imaging.
started late and is still in a rapid development stage, with gaps
remaining in several aspects in China compared with developed
countries. In recent years, the development and supply of radionu-
clides and radiopharmaceuticals have progressed rapidly. China
has successively formulated and introduced multiple policies to
promote the healthy development of the radiopharmaceutical
industry, with an overall tone of strict supervision. In China, most
radiopharmaceuticals used in clinical practice are generic drugs,
with diagnostic radiopharmaceuticals as the mainstays of clinical
use and research. The number of innovative therapeutic radiophar-
maceuticals is limited, and radiopharmaceuticals with global intel-
lectual property rights are countable. Although the development of
radiopharmaceuticals has similarities to drug discovery, significant

72S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65 ! No. 5 (Suppl. 1) ! May 2024
differences allow a faster, safer, and more cost-effective route for
progressing radiolabeled molecules into human studies (6–8). This
review aims to provide an overview of the process for acquiring
National Medical Products Administration (NMPA) approval for an
innovative radiopharmaceutical in China and discuss the current sta-
tus of research and development of radiopharmaceuticals in China.
INTRODUCTION TO RADIOPHARMACEUTICAL
ADMINISTRATION IN CHINA
China’s nuclear medicine has undergone a development process
of more than 60 y, completing the transformation of drugs and
equipment heavily relying on importation to domestic substitution
and, more recently, to the stage of independent innovation and
translation (9). The 2020 edition of the Pharmacopoeia of the People’s
Republic of China includes 24 types of radiopharmaceuticals labeled
with 11 radionuclides: 99mTc, 18F, 131I, 153Sm, 89Sr, 125I, 32P, 67Ga,
201
Tl, 51Cr, and 133Xe (10). For a long time, China’s radiopharma-
ceuticals, especially the medical radionuclides, heavily depended
on importation. This dependence hindered the development of
radiopharmaceuticals and nuclear medicine in China. In 2021, 8
state departments, including the China Atomic Energy Authority,
the Ministry of Science and Technology, and the NMPA, jointly
issued the “Mid- and Long-Term Development Plan (2021–2035)
for Medical Isotopes” (11), aiming to establish a stable and inde-
pendent medical isotope supply and security system, accelerate the
research and development of innovative radiopharmaceuticals and
medical equipment, and expand the popularity of nuclear medicine
in China. The plan holds significant importance and presents a road
map for promoting the development of China’s radiopharmaceuti-
cal industry (12).
Radiopharmaceuticals were included as pharmaceuticals by the
Drug Administration of the Ministry of Health of China in 1974.
The 1977 edition of the Pharmacopoeia of the People’s Republic
of China accommodated radiopharmaceuticals for the first time
(13). On January 13, 1989, the “Provisions for the Administration
of Radioactive Pharmaceuticals” was officially implemented and
the radiopharmaceutical administration entered the era of supervi-
sion (14). In 2006, the NMPA issued the “Regulations on the
Administration of the Preparation of Positron Radiopharmaceuti-
cals by Medical Institutions,” which stipulated the licensing condi-
tions for the use and preparation of radiopharmaceuticals at
medical institutions (15). This regulation has been in use to this
day. The license is divided into 4 levels: to use radioimmunoassay
kits for in vitro diagnosis, a class I or higher-level license should
be held; to use radiopharmaceuticals, a class II or higher-level
license should be granted; to prepare radiopharmaceuticals, a class
III or higher-level license should be obtained; and for the develop-
ment of and related clinical research into a new type of radiophar-
maceutical, a class IV license should be obtained. The
introduction and use of new radiopharmaceuticals without market
authorization in medical institutions are mainly through clinical
investigator–initiated trials. Investigators should submit complete
preclinical study data to the Clinical Research Management Com-
mittee and the Ethics Committee for approval of clinical studies
(recruiting a limited number of patients) that are not intended to
seek marketing approval and are used for internal research pur-
poses (12,16). Some examples of such radiopharmaceuticals
include [18F]FES, 68Ga-labeled PSMA-targeting tracers, [68Ga]Ga-
DOTATATE, and 68Ga-labeled fibroblast activation protein inhibi-
tors (12). Investigator-initiated trials have accelerated preliminary
INNOVATIVE RADIOPHARMACEUTICAL APPROVAL
clinical translation and evaluation of various radiopharmaceuticals in
China. The bonus policy will continuously benefit the development
of radiopharmaceuticals in China.
According to the old version of the Drug Administration Law
and the Provisions for Drug Registration, the approval number of
radiopharmaceuticals can be issued only to the enterprise holding
the production license of radiopharmaceuticals, which restricts the
rapid development of the industry to a certain extent. Enterprises
have low enthusiasm for and a slow pace in the research and
development of radiopharmaceuticals, and no innovative radio-
pharmaceutical has been approved for marketing for a long time in
China. In 2019, the newly revised Drug Administration Law
implemented the market permit holder system. This system sepa-
rates the drug marketing license and production license, optimizes
the resource allocation of the radiopharmaceutical industry, and
greatly promotes the research and innovation of radiopharmaceuti-
cals in China. With the promotion of the policy, some companies
focusing on the research and development of radiopharmaceuticals
have joined the field of radiopharmaceuticals to become market
permit holders. This has improved the research and development
capacity of radiopharmaceuticals and enabled them to meet more
clinical needs. The market permit holder system promotes the
transformation of the existing production model of radiopharma-
ceuticals, encourages the emergence of enterprises specializing in
the entrusted production of radiopharmaceuticals, reduces produc-
tion costs, and saves social resources. Subsequently, on March 29,
2022, the “Provisions for the Administration of Radioactive
Pharmaceuticals” was revised for the third time (17). Provisions
have been made for the establishment of enterprises engaged in
the production or the operation of radiopharmaceuticals. Since
then, the production and business licenses for radiopharmaceuti-
cals have been officially separated, and a market-oriented radio-
pharmaceuticals business market is gradually taking shape.
Since August 2021, the NMPA has made adjustments and provisions
in 3 aspects for the production license of radiopharmaceuticals and the
filing of positron radiopharmaceuticals prepared by medical institutions
(18,19). The approval of radiopharmaceutical production and operation
enterprises will be delegated by the NMPA to the provincial drug super-
vision and management department. The testing of 3 consecutive
batches of radiopharmaceuticals has been adjusted to be undertaken after
a manufacturer has obtained the production license for radiopharmaceu-
ticals, and it may be performed simultaneously with the dynamic pro-
duction batch for inspection of conformity to good manufacturing
practices. The samples should be tested by drug testing institutions
that meet the requirements in the “Provisions for the Administration
of Radioactive Pharmaceuticals.” For the filing of a medical institu-
tion for the preparation of positron radiopharmaceuticals, the 3 con-
secutive batches of samples of the variety to be manufactured should
be tested and the quality standard should be reviewed by drug testing
institutions that meet the requirements in the “Provisions for the
Administration of Radioactive Pharmaceuticals.”
NMPA APPROVAL PROCEDURES FOR
RADIOPHARMACEUTICALS
In China, the development, production, and sales of novel drugs,
devices, and cosmetics, including radiopharmaceuticals, were overseen
by the China Food and Drug Administration (the predecessor of the
NMPA), which was administered by the State Administration for
Market Regulation (20). The China drug regulatory system has
undergone substantial changes in the past 10 y. On August 18,
! An et al. 73S
2015, the State Council of China released a policy document titled
“Opinions on the Reform Review and Approval Process for Drugs
and Medical Devices,” (21) marking the beginning of regulatory
reform (22–25), including establishment of an expedited program,
streamlining of investigational new drug (IND) applications, and
improvement of the drug priority review system (26,27). Joining
the International Council for Harmonisation of Technical Require-
ments for Pharmaceuticals for Human Use in 2017 was another
important milestone (28). This indicates that the agency is prepared
to adopt the technical requirements of the International Council for
Harmonisation for drug registration and become an active partici-
pant in global drug approval and regulation (29). On January 22,
2020, the State Administration for Market Regulation published the
Provisions for Drug Registration (30) and the Provisions for the
Supervision and Administration of Drug Production (31), which are
the core supporting regulations in the field of drug supervision.
These regulations will lay the foundation for the rule of law to
strengthen drug quality and safety risk control, standardize and
strengthen drug supervision, and ensure drug safety, effectiveness,
and quality control. All efforts are aimed at achieving a more scien-
tific and efficient drug regulatory process (Fig. 1).
Drug research and development are divided into 3 stages: pre-
clinical research, clinical research, and marketing registration. The
preclinical phase is fundamental in the progression to clinical-
stage trials and subsequent NMPA approval. After the completion
of the preclinical study, the drug sponsor applies for a commercial
IND application with the NMPA. The U.S. Food and Drug
Administration has a time limit of 30 d from IND application to
license (32), whereas the NMPA has a time limit of 60 d. IND
applications for phase I clinical trials with the NMPA are similar
to the U.S. Food and Drug Administration guidance in overall con-
tent (33–35). The NMPA guidance has chapters that cover biolo-
gics and overseas data, and it states that the format and content of
INDs can be prepared by direct reference to the International
Council for Harmonisation’s common technical document (36).
Ethnic sensitivity analysis is a China-specific requirement that
needs to be implemented early in drug development plans (37,38).
The International Council for Harmonisation published Ethnic
Factors in the Acceptability of Foreign Clinical Data in 1998 (39).
It also described the factors that need to be considered when
extrapolating and facilitating the acceptance of foreign clinical
FIGURE 1. Overview of NMPA process for new drug approval. NDA 5
new drug application.
74S THE JOURNAL OF NUCLEAR MEDICINE ! Vol. 65 ! No. 5 (Suppl. 1)
data in new regions. Sponsors are encouraged to conduct early
clinical trials in China or include China early in multiregional clin-
ical trials to obtain safety, efficacy, and pharmacokinetic data for
ethnic sensitivity analysis (36). These are called phase 0 clinical
trials to support clinical trial conduct and registration (40,41). On
completion of the phase III trial, the new drug application may be
submitted to the NMPA. The expedited pathways instituted in
2021, such as breakthrough therapy drug procedures, conditional
approval procedures, priority review approval procedures, and spe-
cial approval procedures, have significantly reduced the time
needed for new drug application approval compared with standard
review. The median approval time of new drug applications was
15.4 mo in 2017–2021, which was significantly shorter than the
time during the prereform period (22.1 mo in 2011–2013 and
31.5 mo in 2014–2016) (25).
Because of the particularity of radiopharmaceuticals in develop-
ment and use, the implementation process of nonclinical and clini-
cal studies of radiopharmaceuticals cannot refer to the technical
requirements of conventional drugs. To facilitate innovation in
radiopharmaceuticals in enterprises, as well as to promote and
standardize the research and development and clinical application of
radiopharmaceuticals in China, the Center for Drug Evaluation of
the NMPA issued the “Guidance on Clinical Studies of Diagnostic
Radiopharmaceuticals” (42) in October 2020, the “Guidance on
Non-clinical Studies of Diagnostic Radiopharmaceuticals” (43) in
February 2021, and the “Guidance on Clinical Studies of Therapeu-
tic Radiopharmaceuticals” (44) in February 2023. In addition, to
strengthen the quality control of 99mTc and positron radiopharmaceu-
ticals, the NMPA issued “Guidelines for Technetium [99mTc] Radio-
pharmaceutical Quality Control” (45) and “Guidelines for Positron
Radiopharmaceutical Quality Control” (46) in 2004. Further improve-
ment of the technical guidance principle system, as well as guidance
of the development and research of innovative or generic radio-
pharmaceuticals that are urgently needed in clinical practice, is an
important task of high industry concern.
COMMERCIAL AND CLINICAL USE OF RADIOPHARMACEUTICALS
IN CHINA
To date, more than 40 radiopharmaceuticals have been approved
for commercial use by the NMPA. The radiopharmaceuticals
approved for marketing are similar to those in Western countries. In
terms of diagnosis, [18F]FDG and [99mTc]Tc-methylene diphospho-
nate are the most widely used radiopharmaceuticals in China. However,
there are relatively few clinically approved therapeutic radiophar-
maceuticals in China. Clinically available therapeutic radiopharma-
ceuticals include [131I]NaI oral solution (or capsules), [89Sr]SrCl2
injection, 125I brachytherapy source, [153Sm]Sm-ethylenediaminete-
tramethylene phosphonate, and 32P (12). In recent years, many
domestic and foreign radiopharmaceutical companies have intensi-
fied their application for radiopharmaceutical registration in China
as a result of the technologic progress of radiopharmaceutical
research and development, as well as the introduction of NMPA
policies to encourage the innovation of new drugs. [99mTc]Tc-
3PRGD2 is a SPECT imaging agent developed by Professor Fan
Wang from Peking University (47,48). As the first independently
developed class I diagnostic radiopharmaceutical to obtain clinical
trial approval in China, it completed a phase III clinical trial at
11 hospitals in 2022 (http://www.cde.org.cn). There is no signifi-
cant difference between [99mTc]Tc-3PRGD2 SPECT/CT and
[18F]FDG PET/CT in the differentiation of benign and malignant
! May 2024
lung lesions. However, in the diagnosis of lymph node metastasis
of lung tumors, [99mTc]Tc-3PRGD2 SPECT/CT outperformed
[18F]FDG PET/CT in specificity and accuracy, and the clinical
trial reached both primary and secondary endpoints. Moreover,
[99mTc]Tc-3PRGD2 can be prepared via kit formulation, making it
easily available for routine clinical use. It has spent more than 20 y
moving from chemical modification to radionuclide labeling and
from preclinical research to clinical translation. The success of
[99mTc]Tc-3PRGD2 indicates that we have experiences to learn
from in developing diagnostic radiopharmaceuticals in China.
As stated previously, with the development of the national econ-
omy, the market for radiopharmaceuticals in China has expanded
rapidly. More than 70 research pipelines in China involve multiple
domestic pharmaceutical companies. Several new radiopharma-
ceuticals have entered the approval process, clinical trials, or the
marketing approval stage, and some of them are expected to be
approved and provide clinical services to patients soon (Supple-
mental Table 1 [supplemental materials are available at http://jnm.
snmjournals.org]). Since the Center for Drug Evaluation of the
NMPA began implementing the priority evaluation system in
2016, many innovative drugs from multinational pharmaceutical
companies have entered the priority evaluation process, and the
speed at which imported drugs reach market in China has been
greatly improved. In August 2020, Xofigo (223Ra injection; Bayer
Healthcare) was approved by the NMPA for treating patients
with castration-resistant prostate cancer with symptomatic bone
metastases and no known visceral metastases. Subsequently, SIR-
Spheres resin microsphere (Sirtex Medical) was approved for
marketing for the treatment of unresectable colorectal cancer liver
metastases that failed standard treatment. The “Opinions on
Reforming and Improving the Review and Approval System for
Radioactive Pharmaceuticals” (49), issued by the NMPA in April
2023, will further promote the innovation of radiopharmaceuticals
and encourage the importation and registration in China of original
radiopharmaceuticals that have been listed overseas. The release
of this policy document clarified the clinical use value of radio-
pharmaceuticals, gave direction for the reform of regulations and
policies, and encouraged the training of professionals in the field
of radiopharmaceuticals. It will play an important guiding role in
promoting the research, development, and application of radio-
pharmaceuticals in China.
REFLECTIONS ON THE DEVELOPMENT OF
RADIOPHARMACEUTICALS IN CHINA
After a series of significant events and the introduction of perti-
nent regulations and policies, China’s radiopharmaceutical indus-
try is embarking on a historic new stage. It is undeniable that
China faces a challenge in developing independent and original
radiopharmaceuticals, with a reliance on imported medical radio-
nuclides so far. Concerted efforts are required to address this,
including the continuous training of young professionals in related
fields, such as radiochemistry, nuclear medicine, and molecular
imaging. Further critical steps include fostering domestic and
international collaboration for the cultivation of nuclear medicine
practitioners, encouraging sustained investment in basic research
and translational studies, optimizing sincere cooperation among
disciplines and departments, increasing deployment of imaging
equipment and cyclotrons (some capable of producing radiometals
on a small scale), integrating contract research organizations for
the production of radiopharmaceuticals, improving the logistics
INNOVATIVE RADIOPHARMACEUTICAL APPROVAL
system for transporting radiopharmaceuticals, and refining the approval
and supervision processes for radiopharmaceuticals. These steps
will collectively expedite the healthy development, approval, and
use of innovative radiopharmaceuticals in China. Ultimately, only
radiopharmaceuticals that effectively tackle unmet clinical chal-
lenges will successfully integrate into routine clinical practices.
Given the unique properties of radiopharmaceuticals, careful con-
sideration and reassessment before their commercialization are
imperative.
CONCLUSION
In the past decade, China has improved its drug regulatory land-
scape to accelerate the acquisition of new drugs that address unmet
medical needs, leading to the rapid development of radiopharma-
ceuticals in China. With the joint efforts of radiopharmaceutical
research and development institutions, enterprises, commercial
investors, and the nuclear medicine community, the development
and approval of radiopharmaceuticals in China will steadily
increase under the guidance and supervision of national regulatory
authorities. The development and use of radiopharmaceuticals in
China will contribute to the growth of nuclear medicine worldwide
and improve the management of human diseases in the era of pre-
cision medicine.
DISCLOSURE
This work was supported in part by the National Key Research
and Development Program of China (grant 2020YFA0909000), the
National Natural Science Foundation of China (grants 82372014 and
82302236), and the Shen Kang–United Imaging Joint Research and
Development Plan (grant SKLY2022CRT301). Weijun Wei is a con-
sultant of a-Nuclide (Ningbo) Medical Technology Co., Ltd. No
other potential conflict of interest relevant to this article was reported.
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The editors of The Journal of Nuclear Medicine and
SNMMI gratefully acknowledge the following companies
for their generous support of this supplement:
 The Journal of Nuclear Medicine May 2024 Vol. 65 Suppl. 1 Pages 1S–76S

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