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Current Pharmaceutical Design, 2020, 26, 1-8 1
REVIEW ARTICLE

Bench-to-Bedside Theranostics in Nuclear Medicine

Narges Jokar1 , Majid Assadi1, Anna Yordanova2 and Hojjat Ahmadzadehfar2,3,*

1
The Persian Gulf Nuclear Medicine Research Center, Department of Molecular Imaging and Radionuclide Therapy (MIRT),
Bushehr Medical University Hospital, School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran; 2Department of
Nuclear Medicine, University Hospital Bonn, Bonn, Germany; 3Department of Nuclear Medicine, Klinikum Westfalen, Knappschaft
Hospital, Dortmund

Abstract: The optimum selection of the appropriate radiolabelled probe for the right target and the right patient is
the foundation of theranostics in personalised medicine. In nuclear medicine, this process is realised through the
appropriate choice of radiopharmaceuticals based on molecular biomarkers regarding molecular imaging. Ther-
anostics is developing a strategy that can be used to implement accepted tools for individual molecular targeting,
ARTICLE HISTORY
including diagnostics, and advances in genomic molecular knowledge, which has led to identifying theranostics
biomaterials that have the potency to diagnose and treat malignancies. Today, numerous studies have reported on
Received: November 02, 2019
Accepted: December 11, 2019 the discovery and execution of these radiotracers in personalised medicine. In this review, we presented our point
of view of the most important theranostics agents that can be used to treat several types of malignancies. Molecu-
DOI: lar targeted radionuclide treatment methods based on theranostics are excellent paradigms of the relationship
10.2174/1381612826666200218104313   between molecular imaging and therapy that has been used to provide individualised or personalised patient care.
Toward that end, a precise planned prospective examination of theranostics must be done to compare this ap-
proach to more standard therapies.
Keywords: Theranostics, precision medicine, MIBG, FAPI, PRRT, PSMA, Radioiodine.

1. INTRODUCTION Treatment based on theranostics helps increase tumour dose

The term, personalised medicine, was introduced during the
same period in which the human genome project began. Personal-
ised medicine offers significant benefits in the management of dis-
eases, including treatment approaches tailored to the individual
characteristics of patients, risk assessment, safety, accuracy, effi-
cacy and enhancing patients’ quality of life. Since the introduction
of personalised medicine, many studies have reported on drug dis-
coveries based on the use of biomarkers, including molecular imag-
ing in personalised or precision medicine. Similar terms that are
used to describe personalised medicine include: pharmacodiagnos-
tics, integrated medicine, and theranostics. All of these concepts use
detailed, precise information about gene expression and an individ-
ual’s clinical data to choose the drugs, treatment method or preven-
tive plans that are especially suited to each patient [1]. Theranostics
include a combination of diagnostic and subsequent therapeutic
applications introduced by John Funkhouser in August 1998. He
defined this term as single compounds that are implemented for
diagnostic imaging and therapeutic purposes [2]. Nevertheless, the
use of radioactive iodine isotopes in both diagnostic and therapeutic
proceedings in thyroid abnormalities is an example that this concept
was applied in nuclear medicine long before the term theranostics
was defined [3]. In the tumour biology era, ongoing research has
resulted in a major understanding of the molecular pathology of
carcinogenesis. This information has led to the expansion of imag-
ing methods and the evolution of treatments targeting tumour
masses and specific biological molecules [4,5]. The theranostics
approach in nuclear medicine couples diagnostic imaging and ther-
apy with the same, but differently radiolabeled, molecule, or the
same agent in different dosages [6] (Table 1).
*Address correspondence to this author at the Department of Nuclear Medi-
cine, Klinikum Westfalen, Knappschaft Hospital, Dortmund;
E-mail: nuclearmedicine@gmail.com
absorbance versus sparing non-targeted tissues with rapid absor-
bance and high specific value in the target lesions. For many years,
functional imaging methods, including single-photon emission
computed tomography (SPECT), positron emission tomography
(PET), PET-computed tomography (PET/CT), and recently PET-
magnetic resonance imaging (PET/MRI), have been used in oncol-
ogy for tumour cell assessment. These kinds of imaging are very
useful for in vivo tissue specification, target identification, prognos-
tication, patient monitoring, and, consequently, personalised treat-
ment planning [7]. Advances in genomic molecular knowledge
have led to identifying theranostics biomaterials that have the po-
tency to diagnose and treat malignancies based on molecular imag-
ing. Consequently, many different theranostics probes have been
developed. This review examined the development of theranostics
agents that are being utilised in a clinical setting or have been used
in current preclinical and clinical for various malignancies, includ-
ing thyroid, neuroendocrine and prostate cancers, bone metastases,
melanoma and neuroblastoma. In an attempt to provide an overview
of this topic, only the routine theranostics approaches in nuclear
medicine are discussed.
2. THERANOSTICS IN NUCLEAR MEDICINE
2.1. Radioiodine in Thyroid Cancer
For many years, iodine radioactive has commonly been used to
evaluate physiologic metabolism and thyroid disorders, including
benign and malignant conditions. In the late 1930s, Hertz et al.
described the first investigation of radioiodine uptake in the thyroid;
in the early 1940s, they reported the first treatment of Graves’ dis-
ease with radioiodine [8,9]. While there are various iodine isotopes,
the ones that are most frequently used are 131I, 123I and 124I. 131I
emits beta (β−) and gamma (γ) radiation that is used for imaging
and therapy [6]. The quality and sensitivity of this imaging are high,
especially for detecting thyroid microlesions and determining the

1381-6128/20 $65.00+.00 © 2020 Bentham Science Publishers

2 Current Pharmaceutical Design, 2020, Vol. 26, No. 00 Yadav et al.

Table 1. Common and Under-investigated Theranostics Radiopharmaceuticals in Nuclear Medicine.

Cancer Type Theranostic Agent Theranostic Agent

Thyroid Iodine 123,124I for imaging

131I for imaging and therapy
Neuroblastoma, Pheochromocytomas, Paraganglio- Metaiodobenzylguanidine (MIBG) 123I-mIBG for imaging
mas, Medullary thyroid Carcinomas, and other neu- 131I-mIBG for imaging and therapy
roendocrine neoplasia

advanced and metastatic neuroendocrine tumours
, especially gastroenterpancreatic
Somatostatin Analog Receptors
(SSR) ligands, especially SSTR 2
68Ga labelled somatostatin analogues (DOTA-
NOC-DOTATOC -DOTATATE), 99mTc-Hynic-
toc and 111In labelled octreotide for diagnostic
imaging
90Y labelled DOTATATE/TOC for therapy
177Lu labelled DOTATATE/TOC for imaging
and therapy
64Cu-TETA-octreotide/ 64Cu-DOTATATE

Prostate Cancer PSMA-ligands 68Ga or 99mTc labelled-PSMA-617 for imaging,

177Lu and 225Ac-PSMA-617 for therapy
64Cu-PSMA-617 for imaging and therapy

Metastatic Melanoma Benzamide/ arylcarboxamide 123I-BZA2 for imaging

131I-BZA2 for therapy
Bone Metastases Ethylene Diamine Tetraethylene Phospho- 153Sm, 177Lu, labelled EDTMP
nate (EDTMP)

Pancreatic, Ductal Adenocarcinoma, Colorectal Can- Neurotensin Receptors ligands 111In/177Lu-3B-227

cer, Gastric Cancer, Squamous Cell Carcinoma of the
Head and Neck, Bone Cancer, Advanced Cancer,
Recurrent Disease, and Metastatic Tumors

Several Epithelial Carcinoma’s Cells, especially Co- Fibroblast Activation Protein (FAP) 68Ga-FAPI-04 for imaging
lon, Breast and Pancreatic Carcinomas 90Y-FAPI-04 for therapy

localisation of recurrent or metastatic disease. The radiation emis-
sion of 131I includes 90% β− and 10% γ, with a mean and maxi-
mum energy of 192 keV and 610 keV, respectively, and mean tis-
sue penetration of 0.4 mm. The appropriate 8-day half-life of 131I
makes it a valuable radionuclide for treatment approaches. Iodine is
an essential element for the synthesis of thyroid hormones, such as
thyroxine and triiodothyronine. The iodide transporter of the thy-
roid absorbs radioactive iodine in a process that is similar to that of
natural iodine. The β− emission destroys the abnormal cells; simul-
taneously, γ radiation enables the post-therapeutic imaging. In
1997, de Vathaire et al. examined the risk of leukaemia and cancer
following administration of 131I in 1771 patients treated for thyroid
cancer with a mean cumulative activity of 7.2 GBq; they followed-
up the patients for 10 years. They reported a slightly elevated risk
for colon cancer, but the risk for the second type of cancer or leu-
kaemia was not significantly increased. Today, 131I is a theranos-
tics radionuclide that is considered to be one of the main therapeutic
options for hyperthyroidism and differentiated thyroid cancer (Fig.
1) [10].
2.2. Somatostatin Analogue Receptors in Neuroendocrine
Tumours
Neuroendocrine tumours (NETs) arise from cells in the endo-
crine system; in most cases, they are derived from the gastroentero-
pancreatic (GEP) (60–70%) and pulmonary systems (almost 30%).
Depending on the site from which they originate or the site to
which they spread, they can show different clinical presentations
[11]. Overexpression of somatostatin receptors (SSTR) is character-
istic of these tumours. Targeting these receptors with radiopharma-
ceuticals enables the imaging and treatment of NETs [12]. Of the
five types of SSTRs, SSTR 2 is the most important for peptide re-
ceptor imaging and therapy using a radiolabelled analogue com-
plex. The expression of SSTR can be imaged using radiopharma-
ceuticals with either SPECT or PET techniques. SSTR imaging
provides information about the receptor status of the tumour, which
is important for evaluating the eligibility of patients for treatment
with somatostatin analogues as well as peptide-receptor radionu-
clide therapy (PRRT). The classic theranostics radiopharmaceuti-
cals for NETs are 68Ga-labeled somatostatin analogues for diag-
nostic methods using PET or 111In-Octreotide and 99mTc-Hynic-
toc using SPECT and beta-emitter therapeutic radionuclides, in-
cluding 177Lu- and 90Y-labeled somatostatin analogues [12,13].
One of the most important facets of 68Ga-labelled SSTR PET-CT
is its potential for molecular quantification of NETs. The three
tracer peptides are routinely labelled to 68Ga are DOTA-1-Nal3-
octreotide (DOTANOC), DOTA-D-Phe1-Tyr3-octreotide (DOTA-
TOC) and DOTA-D-Phe1-Tyr3-Thr8-octreotide (DOTATATE).
Hofmann et al. showed that 68Ga-DOTATOC PET/CT is superior
to 111In-octreotide SPECT for detecting upper abdominal metasta-
ses [14]. Moreover, this radiopharmaceutical can be used for patient
follow-up and assessment of molecular response to treatment by
Current Scenario in Computational Drug Designing for Malaria
Fig. (1). Post radioiodine therapy scan of a patient with follicular thyroid
cancer with diffuse lung metastases as well as lymph node metastasis left
retro-clavicular. A: whole-body radioiodine scan. B: transversal SPECT/CT
fused image in soft tissue window. C: transversal SPECT/CT fused image in
lung window.
evaluating the dimensions of the tumour and quantifying the recep-
tor density prior to and after PRRT (Fig. 2). The sensitivity and
specificity of these tracers are 82%–97% and 80%–92%, respec-
tively, for detecting small lesions or metastases of GEP neuroendo-
crine malignancies [15-17].
Furthermore, 90Y-DOTATATE/TOC and 177Lu-
DOTATATE/TOC are used for the systematic treatment of patients
with advanced and metastatic NETs (in G1-G3 NETs) [12]. In
many centres, 177Lu-DOTATATE and DOTATOC are preferred
because they result in less renal toxicity. The renal excretions of
these tracers could induce renal function impairment; therefore, the
short penetration range of 177Lu (max 2 mm) makes it more suit-
able for PRRT than 90Y, which has a mean and max tissue penetra-
tion rate of 2.5 mm and 11 mm, respectively. In addition, 177Lu
emits both γ and β− radiation, which makes it a bi-functional diag-
nostic and therapeutic radionuclide. Different studies have demon-
strated the efficacy and safety of PRRT [12,18-22]. Since 2018,
PRRT using 177Lu-DOTATATE has been an approved therapy by
the FDA for the treatment of NETs with GEP-NETs [23].
Fig. (2). Pretreatment 68Ga-DOTATATE PET scan of a 50-year-old female showed multiple somatostatin receptor positive lesions in the liver, around the intra
vena cava (IVC) in the right side, and also a focus in the left side of the vermis. After successful treatment with three cycles PRRT using 177Lu-DOTATATE,
follow-up 68Ga-DOTATATE PET showed partial response.
Current Pharmaceutical Design, 2020, Vol. 26, No. 00 3
2.3. PSMA-based Radioligand Diagnostics and Therapy
Prostate-specific membrane antigen (PSMA) is a transmem-
brane glutamate carboxypeptidase that can be expressed in a variety
of tissues, including the prostate, salivary glands, kidney, brain and
small intestine. PSMA is overexpressed in prostate cancer (PC)
cells. This antigen augments an opportunity for targeting tumours
through PSMA radiolabelled targeting based on a precision medi-
cine approach [24]. PSMA ligands consist of a binding motif, a
radiolabel bearing moiety and a linker molecule [25]. Modifications
in the linker molecule or chelator result in significant variations in
the specifications of the PSMA ligand [26]. At first, the humanised
monoclonal antibody, J591, is labelled to radionuclides, such as
177Lu, and it has been reported to be effective for PSMA targeting.
These radioimmunoconjugates showed proper sensitivity and speci-
ficity for targeting metastatic PC lesions in both soft and osseous
tissues; however, they have a high toxicity profile [24,27-33].
Later, small molecule inhibitors have been developed and used
to target PSMA enzyme through labelling with different radionu-
clides for PET and SPECT imaging and radioligand therapy [25]
(Fig. 3). Theranostics approaches, achieved by implementing a
single agent through PSMA low molecule inhibitor ligands, have
been conjugated with 68Ga or 99mTc for diagnostic applications
and with 177Lu or 225Ac for therapeutic applications [24].
In recent years, PSMA-based PET imaging has revolutionised
the diagnostic and therapeutic approach for PC patients [24,34].
Several studies have reported detection rates for lesions based on
different PSA values. For patients with a PSA value <0.5 ng/ml,
0.5–<1.0 and 1.0–<2.0, detection rates ranging between 47% and
57%, up to 70% and up to nearly 90%, respectively, have been
reported [35-38]. A PET scan with PSMA ligands is very effective
for detecting metastatic spread or cancer recurrence; it is also the
best treatment approach for patient management, assessment of
treatment response and targeted biopsy. Numerous studies have
reported that a PSMA PET/CT is superior to bone scans, CT, MRI
and 18F-choline PET/CT for the detection of metastases in initial
staging [39-43].
According to the results reported in different retrospective and
prospective studies, PSMA-based radioligand therapy is an effec-
tive treatment for patients with metastatic CRPC (mCRPC) [ 44-
48]. At the time this paper was written, this therapy was still an
experimental treatment approach; in the majority of cases, it is per-
formed as the last possible therapeutic option. However, even if the
disease has progressed or if patients are intolerant of prior therapies,
PSMA therapy seems to be an effective and tolerable therapy with a
very low-toxicity profile [48-55].
4 Current Pharmaceutical Design, 2020, Vol. 26, No. 00
Fig. (3). A 70-year-old patient with prostate cancer and multiple bone me-
tastases lesions. Pre-therapeutic Ga-PSMA PET/CT and an initial cycle of
the Lu-PSMA-617 whole-body scan showed similar pattern tracer uptake
through the body.
2.4. 131I-Metaiodobenzylguanidine Theranostics in Neuroblas-
toma, Pheochromocytomas and Paragangliomas
The most frequent, heterogeneous extracranial solid tumour in
infancy is neuroblastoma, which originates from the sympathetic
system, a branch of the autonomic nervous system. Overall survival
(OS) in neuroblastoma is <40%, despite implementing multimodal-
ity treatment methods. However, it is associated with one of the
highest proportions of spontaneous and complete regression of all
human cancers [56-57]. Diagnosis of neuroblastoma is based on
pathologic information and imaging modalities, including CT, MRI
and nuclear imaging, including bone scintigraphy, 123I-
metaiodobenzylguanidine (MIBG) scanning, fluorodeoxyglucose
(18F-FDG)-PET and SSTR-PET. Depending on the stage of the
neuroblastoma, treatment can include surgery, chemotherapy, bone
marrow transplantation and systematic internal radiation treatment
through MIBG or PRRT [58-60].
MIBG is a norepinephrine analogue that targets tumour cells in
the sympathetic nervous system; it has been administrated since
1984. The labelling of MIBG with radioactive iodine enables
evaluation of the staging and treatment response in neuroblastoma
[61]. 123I-MIBG has low gamma energy and a short half-life (159
keV and 13 hours), which make it an optimal agent for diagnostic
imaging. In patients with MIBG-positive tumours and metastases,
therapy with 131I-MIBG seems to be very promising, especially in
combination with chemotherapy [62-64]. Many clinical studies
have verified the effectiveness and 30%–40% response rate for
131I-IMBG as a systemic delivery dose to tumour cells, especially
in high-risk neuroblastoma with refractory, relapsed or resistant
conditions [65-66]. Radiolabelled MIBG is a valuable theranostics
compound, which has resulted in the evolution and improvement of
new strategies as well as reasonable hopes for prolonged survival
and complete response to cancer (Fig. 4).
Pheochromocytomas and paragangliomas are catecholamine-
secreting (epinephrine and norepinephrine) tumours that originate
from the adrenal medulla and outside the adrenal gland, respec-
tively. Management of these tumours is challenging, both diagnos-
Yadav et al.
tically and therapeutically [67-68]. Catecholamines, similar to 90%
of other neuroblastomas, together with adrenergic innervation, are
the principle 123I/131I-MIBG radiopharmaceutical agents used in
theranostics [57]. Functional 123I-MIBG scintigraphy is being used
to characterise whether patients with pheochromocytomas and
paragangliomas are appropriate for targeted radiotherapy with 131I-
MIBG [69-70]. Apart from MIBG based diagnostic and therapy,
SSTR imaging and therapy has also an important utility in the man-
agement and therapy of these tumours [71].
Fig. (4). An 8-year-old boy affected by neuroblastoma. 131I-MIBG whole-
body scintigraphy showed intense tracer uptake through the body.
2.5. Bone Palliation
Radiolabelled phosphonates have a high bone affinity, and they
can be used for imaging and palliation of painful bone metastases.
Depending on the degree of osseous metabolism, the tracer accu-
mulates via adhesion to bones, and, preferably, to osteoblastic bone
metastases [72]. The use of bone-seeking radiopharmaceuticals is
one of the approaches that is implemented in patients with various
skeletal lesions. It is used alone or in combination with other mo-
dalities to increase survival rate, relieve pain and minimise skeletal
morbidity. Some of the benefits of this treatment option include
efficiency, low cost and relatively low toxicity in comparison to
other modalities [6]. In this method, the radioactive matter links to
the bone-seeking agent and targets the osseous malignant cells
[72,73]. Different therapeutic radioactive agents are available, in-
cluding 186Re (β− emission, T1/2=89 hours, maximum range=4.6
mm, maximum energy=1.1 MeV), 188Re (β− and γ emitters [85%
and 15%; 2.1 MeV and 155 keV energy, respectively], half-
life=16.8 hours, maximal range=10 mm) 32P, and 89Sr labelled
with hydroxyethylidene diphosphonate (HDEP) and 153Sm (half-
life=1.9 days, mean β−energy =233 keV, γ−energy=103 keV) and
177Lu (half-life, 6.7 day, maximum β−energy=497 keV,
γ−energy=208 keV) labelled with ethylene diamine tetramethylene
phosphonate (EDTMP) [74,75]. When determining which therapy
to use, a bone scan is required to estimate the metabolism and the
extent to which the metastases are involved. However, it has been
reported that there is no significant difference between different beta
emitters regarding pain palliation [72]. Moreover, alpha particle ther-
apy with 223RaCl2 (Dichrolide) was approved by the Food and Drug
Administration (FDA) in 2013 for osteoblastic metastatic lesions in
CRPC [76]. Ra223 is the first, and currently the only FDA-approved
alpha emitter for the treatment of symptomatic bone metastases of
CRPC patients with a positive impact on OS [77]. It has a half-life of
11.4 days, with a total emitted energy of approximately 28 MeV.
2.6. Theranostics Approach for Metastatic Pigmented Mela-
noma
For decades, high stage melanoma has been considered to be
the most aggressive form of skin malignancy, with a 10% 5-year
Current Scenario in Computational Drug Designing for Malaria
survival rate and median OS of 8 to 18 months. Interleukin 2 (HD
IL-2) and dacarbazine are two FDA-approved agents; however,
patients treated with these agents show low response rates and poor
OS [78]. One of the intrinsic features of melanoma in 20–30% of
metastases is the presence of melanin pigment, which makes it a
promising target. Several studies have evaluated the use of radioio-
dinated N-(dialkylaminoalkyl) benzamides for SPECT imaging of
melanoma metastases. The high absorbance and slow clearance of
131I are two characteristics of this radiotracer that have been
proven to be beneficial in the imaging and radionuclide therapy of
melanoma [79]. SPECT imaging in melanoma has been conducted
with N-(2-diethylaminoethyl)-4-iodobenzamide and N-(2-
diethylaminoethyl)-2-iodobenzamide (BZA2) labelled with 123I in
phase II and multicentre phase III clinical studies, respectively.
These radiotracers have been applied in selected patients with pig-
mented metastases, which facilitate melanin-targeted therapies
[80,81].
3. NOVEL THERANOSTIC AGENTS AND FUTURE DE-
VELOPMENTS
New advances in preclinical oncology with a primary focus on
immunology have resulted in the discovery of new molecular tar-
gets with potentially significant applications in theranostics. Among
the many medical disciplines, nuclear medicine based on molecular
imaging may be the most suitable field for implementing theranos-
tics approaches. Thus, new, rapid development in radiopharmaceu-
ticals, which have been implemented in nuclear medicine and in the
molecular imaging era, facilitate the evolution of targeted drug
delivery for patient-friendly treatment, especially in oncology.
3.1. Neurotensin/177Lu-3BP-227
The peptide Neurotensin is present in the gastrointestinal tract,
the adult central nervous system (e.g., the brain) and the myocar-
dium. Neurotensin, as well as three distinct neurotensin receptors
(NTSRs), are found in different tissues during embryogenesis, and
they are overexpressed in different malignancies, such as colorectal
carcinomas, small cell and non–small cell bronchial, carcinomas,
pancreatic carcinomas and breast carcinomas. Recently, the NTSR-
ligand 111In/177Lu-3B-227 has been reported to have potential
applications in diagnostic imaging and therapy for these malignan-
cies [82]. It has been confirmed that the density of NTSR1 on pan-
creatic adenocarcinoma may be as great as the expression of SSRTs
in NETs [83]. Thus, radiolabelled NTSR1 ligands were considered
to be an absorbent choice for radioligand targeted therapy of pan-
creatic carcinomas. Today, phase I and phase II clinical trials
(NCT03525392) are being carried out with 177Lu-3BP-227 radio-
pharmaceutical for advanced NTSR1-positive tumours, including
pancreatic, ductal adenocarcinoma, colorectal cancer, gastric can-
cer, squamous cell carcinoma of the head and neck, bone cancer,
advanced cancer, recurrent disease and metastatic tumours.
3.2. Copper Radioligands
The diagnostic and therapeutic potential of various radioiso-
topes of copper has been investigated in different tracers; it seems
to be promising for the personalised treatment of various diseases.
Copper (Cu) ions are necessary for a large number of biological
processes; they are essential as catalytic cofactors for many en-
zymes and they play substantial roles in living cells [84]. As the
radioisotope with the longest half-life, 67Cu (half-life=62h) is used
to deliver a favourable dose to the target cells. Furthermore, its β−
and γ decay (Ee, max=577 keV and 185 keV (48.7%), 93 keV
(16%), respectively) makes 67Cu appropriate for SPECT imaging
and radioimmunotherapy. In comparison to another prevalent ra-
dioisotope, 131I, 67Cu has a shorter half-life and it emits low en-
ergy γ rays, which may help to avoid unnecessary radiation expo-
sure for patients and medical staff. Other radioisotopes of Cu, such
as 64Cu and 61Cu (half-life=3.3 h), have also been investigated in
preclinical and clinical studies for theranostics applications. A pre-
Current Pharmaceutical Design, 2020, Vol. 26, No. 00 5
liminary study by Anderson et al. evaluated the diagnostic charac-
teristics of the radiotracer 64Cu-TETA-octreotide in comparison to
the usual SPECT agent 111In-DTPA-octreotide in a small group of
patients with NETs [77]. They reported that radiopharmaceutical
64Cu-TETA-octreotide had high sensitivity, excellent lesion detec-
tion and desired dosimetry and pharmacokinetics, indicating that it
is a promising radiotracer for PET imaging in patients with NETs
[85]. The first human prospective study confirmed that Cu-
DOTATATE has better image quality than 111In-DTPA-octreotide
[86]. Another study demonstrated that the diagnostic sensitivity and
accuracy of 64Cu-DOTATATE (97%) is superior to 111In-DTPA-
octreotide for NET patients, and it recommends implementation of
these new radiopharmaceuticals as a substitution for 111In-DTPA-
octreotide [87]. Recently, 64Cu-labeled ligand DOTA-PSMA-617
has been widely investigated as a diagnostic potential agent of PET
imaging for PC. The best resolution PET images of the malignant
lesions were detected with high target-to-nontargeted contrast.
64Cu-PSMA-617 PET/CT could be a suitable replacement for PET
imaging in PC, even though it is a potent radioligand therapy due to
the β− radiation of 67Cu as the “theranostics pair” [88,89].
3.3. Fibroblast Activation Protein Imaging
The fibroblast activation protein (FAP) is another impressive
novel tracer in nuclear medicine. FAP is overexpressed in several
epithelial carcinoma cells, especially colon, breast and pancreatic
carcinomas. The tumour masses in the malignant cells and stromal
cells contain inflammatory cells, vascular cells and fibroblasts. This
cancer-associated fibroblast extra-cellular fibrosis constitutes more
than 90% of the gross tumour volume. Therefore, recently, FAP-
specific inhibitors have been developed as anti-cancer agents and
tumour-targeting radiopharmaceuticals. FAP imaging (FAPI) has
been conducted with inhibitor molecules and antibodies, such as
28H1 labelled with 99mTc, 111In and 89Zr. For therapeutic appli-
cations, this would be labelled with α and β emitters, such as
153Sm, 188Re, 213Bi or 212Pb [90,91]. Promising pre-clinical and
clinical results of some of the labelled tracers have been reported.
Kratochwil demonstrated that several cancers showed high uptake
and image contrast with 68Ga-FAP-PET/CT. This high absorbance
could lead to tumour-characterisation and radioligand therapy in sev-
eral tumours in the future [92]. In comparison with FDG-PET/CT,
there is no need for diet/fasting restrictions before PET imaging, and
the tumour-to-nontarget ratio was similar or even better than FDG
[93]. FAPI-04 was reported to be a promising tracer for both imaging
and potency targeted treatment in breast cancer. 68Ga-FAPI-04 PET-
CT scans present high absorbance in lesions associated with metasta-
ses of breast cancer; moreover, pain symptoms were found to de-
crease when using a low dose of 90Y-FAPI-04 [94].
CONCLUSION
The biological characterisation of each patient is unique. This
important property leads to significant differences in pharmacoki-
netics and drug distribution. In theranostics, the goal is to identify
potential targets that can help predict if a patient would benefit from
a specific treatment. Molecular-targeted radionuclide treatment
methods based on theranostics are excellent paradigms of the rela-
tionship between molecular imaging and therapy that have been
used to individualise or personalise patient care.
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
None.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or other-
wise.
6 Current Pharmaceutical Design, 2020, Vol. 26, No. 00
ACKNOWLEDGEMENTS
Declared none.
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