Molecular Imaging and Targeted Therapy: Radiopharmaceuticals and Clinical Applications, 2nd 2nd Edition Shankar Vallabhajosula

Molecular Imaging and Targeted
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Shankar Vallabhajosula
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Molecular
Imaging and
Targeted Therapy
Radiopharmaceuticals and
Clinical Applications
Second Edition
123
Molecular Imaging and Targeted Therapy
Molecular Imaging
and Targeted Therapy
Radiopharmaceuticals and Clinical
Applications
Second Edition
Editorial Assistance
By
Brigitte Vallabhajosula, Ph.D.
Emeritus of Radiochemistry and Radiopharmacy in Radiology
Weill Cornell Medicine, Cornell University
New York, NY, USA
ISBN 978-3-031-23203-9 ISBN 978-3-031-23205-3 (eBook)

https://doi.org/10.1007/978-3-031-23205-3
© Springer Nature Switzerland AG 2023

This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or
part of the material is concerned, specifically the rights of translation, reprinting, reuse of
illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way,
and transmission or information storage and retrieval, electronic adaptation, computer software,
or by similar or dissimilar methodology now known or hereafter developed.
The publisher, the authors and the editors are safe to assume that the advice and information in
this book are believed to be true and accurate at the date of publication. Neither the publisher nor
the authors or the editors give a warranty, express or implied, with respect to the material
contained herein or for any errors or omissions that may have been made.
This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
To my precious wife Shanthi,
For her belief and trust in me.
Foreword to the First Edition
Molecular imaging is a term that is now used frequently to describe much

of what nuclear medicine has been involved in for almost 50 years. Since
the early attempts to produce images representing the spatial distribution
of specific tissue and organ functions such as the use of radioiodine to
identify (and also to quantify) thyroid tissue function or the use radioio-
dine labeled human serum albumin (HSA) to identify the increased extra-
cellular fluid in a brain tumor, nuclear medicine scientists and physicians
have used the powerful tools, radioactive emission and decay and the tracer
principle, for this purpose.
In the case of thyroid imaging with radioiodine, the radionuclide itself is
the tracer that specifically recognizes (and is recognized by) the iodide trans-
porter and the subsequent trapping and organification mechanism results in
thyroid hormone synthesis. In the early efforts to localize brain tumors, the
radioiodine was chemically bound to HSA, and as a result of its molecular
size, radioiodinated HSA was useful to identify the increased extracellular
fluid content of various brain tumors in contrast to normal cerebral cortex.
The number of applications of molecular imaging therefore depends upon
the radionuclides available, their inherent biochemistry whereby the radionu-
clide itself might be a useful tracer [such as 131I, 124I, or 123I as an iodide for
assessment of thyroid function and imaging or 18F as the fluoride to measure
bone kinetics and skeletal imaging]. In addition, depending upon the chemis-
try of a particular element, the radiotracer may be useful to evaluate and
image other molecular and physiologic processes if the radionuclide can
either be incorporated into the native molecular structure of a compound
[such as 197Hg in a mercurial diuretic for renal imaging in the pre-99mTc era or
57
Co within the cyanocobalamin molecule to evaluate the intestinal absorp-
tion of vitamin B12] or bound to a messenger molecule without significantly
interfering with recognition by the specific receptor [such as 111In-DTPA-
pentetreotide or 68Ga-DOTATOC to somatostatin receptor subtypes].
To fully utilize these various radiotracers and radiolabeled molecules, the
medical scientist and physician needs also to appreciate issues related to pro-
duction and availability, type of radioactive decay and dosimetry, and the
interaction of radiation and matter in order to efficiently detect the distributed
signal or at least understand the inherent limitations and source of potential
errors. Furthermore, by understanding existing instruments and radiotracers
one may better design the next generation of strategies to help drive the field
of molecular imaging.
vii
viii Foreword to the First Edition
Molecular Imaging: Radiopharmaceuticals for PET and SPECT is not a

mere text on radiopharmaceuticals. In this volume, Shankar Vallabhajosula,
Ph.D., has provided the reader with a single volume that describes and
explains all of these components of radionuclide-based molecular imaging.
Dr. Vallabhajosula shares his insight that molecular imaging is based on an
understanding of the continuum of science from atomic structure and rela-
tionships, through chemistry and physiology, the physics of instrumentation,
and the relationship of radiation and matter as well as the specific details of
the radiopharmaceuticals themselves and the pharmaceutical principles
including the practice of pharmacy. His description of his insight is further
enriched by over 35 years of experience in nuclear medicine and all of its
applications and his affection for the history and philosophy of science.
Molecular Imaging: Radiopharmaceuticals for PET and SPECT is a
remarkable volume in that it comprehensively covers the entire scope of the
basic sciences of nuclear medicine—and it does so in a highly readable style.
It is further remarkable in that the entire text has been written by a single
author, perhaps necessary to communicate, in addition to all of the scientific
details, this over-riding view that all of the details are part of a continuum and
that it is necessary to “see the forest as well as the trees” [to paraphrase an
expression].
This is both a textbook on the subject and a history of the subject. It should
be read by students and practitioners, medical doctors and scientists, radio-
chemists, physicists, radiopharmacists, technologists, and research person-
nel. In addition, for those learning about molecular imaging using
non-radionuclide (e.g., optical, MRI) based strategies, this book is an excel-
lent introduction to important issues, lessons, and unifying principles for the
entire field. The volume consists of 20 chapters and many excellent figures
and tables. In addition to the science, it includes some brief history of the
discoveries, the insights and developments that hopefully will sustain our
memory of the science as well as of the scientists. Each chapter begins with a
quote from a senior scientist. These quotes set a tone; recognition of, and
respect for, the complexity of the physical and biological world—and man’s
ability to understand it.
Dr. Vallabhajosula has performed a highly important service for nuclear
medicine and the medical imaging community by creating this volume that
brings together the scientific foundation of our field and by sharing his pas-
sion for the subject. Hopefully, the material and this stimulating presentation
will motivate some of the readers to contribute to further evolution of this
adventure.
New York Presbyterian Hospital Stanley J. Goldsmith, MD

and Weill Cornell Medical College
Cornell University,
New York, NY, USA
Stanford University Medical Center Sanjiv Sam Gambhir, MD, PhD
Stanford, CA, USA
Foreword to the Second Edition
I am delighted to provide a “foreword” to this second edition of Molecular

Imaging and Targeted Therapy: Radiopharmaceuticals and Clinical
Applications by Dr. Shankar Vallabhajosula. The foreword to the highly suc-
cessful first edition was contributed by Drs. Goldsmith and Gambhir, two
giants in clinical nuclear medicine and molecular imaging. Sadly, Dr.
Gambhir passed away far too early and was not able to contribute to the fore-
word to this new and updated edition, hence my authorship.
This is a remarkable effort by Dr. Vallabhajosula to cover, in a consistent
manner, the entire spectrum of the field of nuclear medicine. So often, text-
books are written by multiple authors and the presentations, though expert,
are not always well integrated. This book has the clear fingerprints of a true
expert who has nearly five decades of experience in the field with relevant
experiences in virtually all aspects of the discipline.
While the author is well known and respected in the fields of radiophar-
macy and radiopharmaceuticals, he carefully covers the remarkable spectrum
of technologies needed to deliver successful nuclear medicine imaging and
treatments. From “A” toms to high “Z” materials to detect photons, Dr.
Vallabhajosula has it covered. This is a great read for anyone interested in a
comprehensive, but not exhaustive, review of nuclear medicines breadth with
sufficient depth and referencing to guide further study. It is obvious that Dr.
Vallabhajosula loves the field of nuclear medicine, and the manuscript reflects
this love, and continued curiosity for the field. It should serve to bring new
scientists into the field. The author’s enthusiasm is apparent on each page and
chapter.
It is an incredibly exciting time for nuclear medicine. While nuclear imag-
ing and radiopharmaceutical therapy have been around for well over half a
century, in my long experience in nuclear medicine, this is the most exciting
time ever. There have been many patients, from newborns to seniors, posi-
tively impacted through nuclear medicine imaging. FDG PET/CT is now the
preferred diagnostic and follow-up test in many patients with cancer; addi-
tionally it is now widely used to detect infection and inflammation. The
explosion in PSMA targeting for diagnosis and therapy with newly approved
diagnostic and therapeutic agents has brought renewed excitement to the
field. There has also been substantial investment given the favorable results
from targeted radiopharmaceutical therapies. The excitement with the newer
alpha emitters is palpable and I am confident we are now moving from
“improving survival” to “curing cancer.” Expanding these methods more
ix
x Foreword to the Second Edition
broadly will be the future of our field with major investments from increas-
ingly large, as well as small, innovative pharmaceutical companies. I believe
radiopharmaceutical therapy is now the fifth arm of cancer therapy along with
surgery, chemotherapy, external beam irradiation, and immunotherapy.
It is also a great time to use nuclear medicine techniques to interrogate
brain health. With the recent approval of two antibody drugs to remove amy-
loid plaques from the brain and preserve cognition, the exciting opportunities
in nuclear neurology are highlighted. The opportunities in brain imaging are
massive. The projected growth in nuclear imaging of the brain, to guide treat-
ments, will impact a huge population who could benefit from the procedures.
In addition, fundamental studies of brain health with PET are pivotal for our
understanding of the function of the brain, especially in aging, dementia,
movement disorders, and psychiatric conditions.
An excellent review of cardiac imaging is provided as well. This is an area
of great opportunity as we can now precisely measure cardiac blood flow and
flow reserve, especially with PET. Similarly with nuclear methods we can
now detect and guide treatment of amyloid cardiomyopathies, and detect pre-
viously undetectable inflammatory processes, and infections among other
interrogations.
Dr. Vallabhajosula describes this book, in effect, as a “labor of love.”
Having been introduced to the field personally over four decades ago, falling
in “love” with nuclear medicine is not a unique experience. I’m sure readers
of this comprehensive yet approachable text will gain an increasing affection,
possibly blossoming into a long-term relationship, or even “love” with
nuclear medicine.
Department of Radiology Richard L. Wahl, MD, FACR

Mallinckrodt Institute of Radiology,
Professor of Radiology and Radiation
Oncology, Washington University in
St Louis School of Medicine
St. Louis, MO, USA
Preface to the First Edition
Everything is determined, the beginning as well as the end, by forces over which we
have no control. It is determined for the insect, as well as for the star. Human
beings, vegetables, or cosmic dust, we all dance to a mysterious tune, intoned in the
distance by an invisible piper.
Albert Einstein
In my life, the invisible piper has long been and will continue to be “science.”
Indeed, in 1967, during my second year in pharmacy school, while reading
general books on science, I first learned that an unstable atom emits radiation,
which might be used as a beacon or a signal for detecting the exact location
of that atom. This initial introduction to atomic physics had a significant
impact on my view of the universe and all that is within and has shaped my
academic and scientific career in a way I could not have foreseen, then.
The discipline of nuclear medicine has tremendously enriched my profes-
sional and personal life and several people have been instrumental in shaping
my destiny. Professor Walter Wolf, who ignited my research interests in the
development of radiopharmaceuticals, Professor Henry Wagner, Jr., the
ambassador of nuclear medicine, Professor Michael Phelps, the pioneer, and
visionary of PET, in particular, have been my inspirational and intellectual
gurus. Also, Professor Sanjiv Sam Gambhir, one of the founders of molecular
imaging as a scientific discipline in diagnostic radiology, has been a continu-
ous source of inspiration not only to me but to a whole new generation of
young investigators. Words cannot express my gratitude to Professor Stanley
J. Goldsmith, who for almost three decades has instigated many challenging
discussions, supported me in all my scientific endeavors, and is now a part of
my family.
Molecular imaging is a fascinating and important technology in radiology
that grows more diverse every day. Imaging based on radioisotopes is the
major theme of this book and emphasizes both the basic and clinical science
of nuclear medicine, based exclusively on radiopharmaceuticals for PET and
SPECT. This book grew out of many lectures and my own struggles to more
fully understand this subject. My goal in writing this book was not to discuss,
in depth, the chemistry of radiopharmaceuticals. Instead it was my intention
to provide a broad view of clinical applications in molecular imaging and,
thereby, make the readers better understand and appreciate the importance of
radiopharmaceutical design and development in the optimization of molecu-
lar imaging technology. Finally, although Chapter 2, which provides a history
of the atom, is not necessarily relevant to the practical and clinical applica-
xi
xii Preface to the First Edition
tions of molecular imaging, it is my way of paying tribute to those extraordi-

nary scientists who have systematically studied “nature” and demonstrated
the reality of atoms.
It is impossible to acknowledge every technologist, scientist, and student,
who has contributed to my understanding of nuclear medicine. However, I
especially thank Ms. Helena Lipszyc not only for working with me on count-
less research projects, but most of all for her friendship. I also express my
gratitude to Dr. Harry M. Lander, Associate Dean for Research at Weill
Cornell Medical College, for encouraging me to write this book.
Also, I greatly appreciate the support of the editorial staff of Springer-
Verlag and, especially, thank Ms. Dörthe Mencke-Bühler, Ms. Wilma
McHugh, and Mr. Saravanan Thavamani. Finally, this book could not have
been completed without the love, support and encouragement of my wife,
Brigitte (affectionately called Shanthi), who has read every word of the man-
uscript and made countless corrections.
New York, NY, USA Shankar Vallabhajosula, PhD

May 2009
Preface to the Second Edition
Look deep into nature, and then you will understand everything better.
Albert Einstein
The primary goal of targeted radionuclide therapy (TRT) is to fight cancer

cells with more precision and with less side effects. TRT is based on thera-
peutic radiopharmaceuticals that are radiolabeled molecules consisting of a
target-specific moiety, such as peptides, low molecular weight ligands, or
monoclonal antibodies labeled with an appropriate alpha or beta emitting
radionuclide designed to deliver therapeutic doses of ionizing radiation to
specific disease sites. The continuing progress in biotechnologies over the
last couple of decades opened avenues to a new management of many dis-
eases, switching from a population treatment approach to the concept of per-
sonalized medicine or precision medicine. Theranostics in nuclear medicine
is a molecular precision medicine approach to treating cancer, using similar
(or same) molecules for both molecular imaging (based on PET or SPECT)
and TRT.
The first edition of this book, published in 2009, focused primarily on the
initial development of molecular imaging (MI) based on PET and SPECT
radiopharmaceuticals. Since that time there has been tremendous interest and
progress in the development of target-specific radiopharmaceuticals (TSRP)
for radionuclide molecular imaging (RMI) and TRT.
The second edition was, specifically, designed to revise and update several
chapters related to the development of FDA-approved PET and SPECT radio-
pharmaceuticals. In addition, six new chapters (Chaps. 17–22) were added to
provide an extensive review of the basic concepts and clinical applications of
therapeutic radiopharmaceuticals for TRT. While it is beyond the scope of
this book to cover the entire field of radiopharmaceutical research and devel-
opment in the last 15 years, the focus of this book is primarily to provide a
broad overview of RMI and TRT, and to specifically describe the chemistry
of radiopharmaceuticals in clinical use.
I want to thank all the nuclear medicine physicians, oncologists, scientists,
and technologists at Weill Cornell Medicine and New York Presbyterian
Hospital. Special thanks to Professor Stanley J. Goldsmith who, for almost
four decades, has been my major research collaborator. I also want to give
special thanks to several oncologists (Profs. Neil H. Bander, Scott T. Tagawa,
John P. Leonard, and Morton Coleman) who believed in TRT, supported me,
and collaborated with me for the last 25 years. I have no words to express my
xiii
xiv Preface to the Second Edition
gratitude to my research staff, specifically, Drs. Paresh Kothari, Anastasia

Nikolopoulou, and Ms. Irina Lipai.
I, also, greatly appreciate the support of the editorial staff of Springer
Nature and want to, especially, thank Ms. Smitha Diveshan, Ms. Antonella
Seri, and G. Rajesh. Finally, this book could not have been completed without
the love, support, and encouragement of my wife, Dr. Brigitte Vallabhajosula,
who kindly took the responsibility for editing the manuscript and made
countless corrections.
New York, NY, USA Shankar Vallabhajosula, PhD

February 2023
Contents
1 Molecular Imaging and Targeted Radionuclide

Therapy: Introduction�� 1
1.1 Nuclear Medicine�� 1
1.2 Molecular Medicine�� 2
1.3 Molecular Imaging�� 3
1.3.1 Definitions�� 4
1.3.2 Molecular Imaging Technologies�� 5
1.4 Radiation Therapy�� 12
1.4.1 Targeted Radionuclide Therapy (TRT) �� 13
1.4.2 Personalized Medicine and Theranostics�� 14
1.5 Summary �� 18
References�� 18
2
Science of Atomism: A Brief History�� 21
2.1 Atomism�� 21
2.2 Chemical Elements �� 22
2.2.1 Chemical Laws�� 22
2.2.2 Atomic Theory�� 23
2.3 Electricity and Magnetism�� 23
2.3.1 Electrolysis�� 24
2.3.2 Electromagnetism �� 25
2.4 Thermodynamics�� 26
2.4.1 Heat, Energy, and Temperature�� 26
2.4.2 Emission of Light�� 27
2.5 Major Discoveries �� 27
2.5.1 Cathode Rays�� 27
2.5.2 X-Rays�� 28
2.5.3 Electron �� 28
2.5.4 Radioactivity �� 29
2.5.5 Light Quantum�� 30
2.6 Reality of Atoms �� 31
2.6.1 Avogadro’s Number�� 31
2.6.2 Brownian Motion�� 31
2.7 Atomic Structure�� 32
2.7.1 Nuclear Atom�� 32
2.7.2 Bohr’s Model of Atom�� 32
2.7.3 Isotopes �� 33
xv
xvi Contents
2.7.4 Quantum Atom�� 33

2.7.5 Discovery of Antimatter�� 34
2.8 The Elementary Particles�� 34
Further Reading �� 35
3 Atoms and Radiation �� 37
3.1 Matter and Energy�� 37
3.1.1 Mass–Energy Relationship �� 37
3.2 Radiation �� 38
3.2.1 Electromagnetic Radiation�� 38
3.3 Classification of Matter�� 39
3.3.1 Chemical Element�� 40
3.4 Atoms�� 40
3.4.1 Atomic Structure�� 41
3.4.2 The Bohr Model of an Atom�� 41
3.5 Nuclear Structure�� 43
3.5.1 Composition and Nuclear Families�� 43
3.5.2 Nuclear Binding Energy �� 43
3.5.3 Nuclear Stability �� 44
3.6 Atomic and Nuclear Emissions�� 45
3.6.1 Emissions from Electron Shells�� 45
3.6.2 Nuclear Emissions�� 46
4 Radioactivity�� 49
4.1 The Discovery �� 49
4.2 Nuclear Disintegration�� 50
4.2.1 Types of Radioactive Decay�� 52
4.2.2 Radioactive Decay Series�� 56
4.2.3 Nuclear Fission �� 58
4.3 Radioactive Decay Equations �� 58
4.3.1 Exponential Decay�� 58
4.3.2 Units of Activity�� 59
4.3.3 Half-Life and Average Lifetime�� 59
4.3.4 Specific Activity�� 60
4.3.5 Serial Radioactive Decay�� 61
5 Radioactivity
Detection: PET and SPECT Scanners �� 63
5.1 Interaction of Radiation with Matter�� 63
5.1.1 Interactions of Charged Articles �� 63
5.1.2 Interaction of High-Energy Photons �� 64
5.1.3 Attenuation�� 66
5.2 Radiation Detectors�� 67
5.2.1 Ionization Detectors�� 67
5.2.2 Scintillation Detectors�� 68
5.3 Radionuclide Imaging Systems�� 71
5.3.1 SPECT/CT Scanner�� 72
5.3.2 PET Scanners�� 75
5.3.3 Small-Animal Imaging Systems �� 82
References�� 85
Contents xvii
6 Chemistry: Basic Principles�� 87

6.1 Chemical Elements �� 87
6.1.1 Chemistry and Radioactivity�� 87
6.1.2 Periodic Table �� 88
6.1.3 Chemical Bonding�� 91
6.2 Chemical Reactions�� 95
6.2.1 Types of Chemical Reactions�� 95
6.2.2 Chemical Equilibrium�� 97
6.3 Organic Chemistry�� 100
6.3.1 Hydrocarbons�� 101
6.4 Biochemistry �� 106
6.4.1 Proteins �� 106
6.4.2 Carbohydrates �� 108
6.4.3 Lipids�� 109
6.4.4 Nucleic Acids�� 112
7
Cell and Molecular Biology�� 117
7.1 Introduction�� 117
7.2 Cell Structure and Function�� 117
7.2.1 The Plasma Membrane �� 118
7.2.2 Cytoplasm and Its Organelles �� 120
7.2.3 Cytoskeleton �� 121
7.2.4 Nucleus �� 122
7.3 Cell Reproduction �� 122
7.3.1 The Cell Cycle�� 122
7.3.2 Rates of Cell Division�� 123
7.4 Cell Transformation and Differentiation�� 124
7.5 Normal Growth �� 125
7.5.1 Cell Types �� 125
7.5.2 Tissue Types�� 125
7.6 Cell-to-Cell Communication�� 126
7.6.1 Cell–Cell Interaction�� 126
7.6.2 Cell Signaling and Cellular Receptors�� 127
7.7 Transport Through the Cell Membrane�� 128
7.7.1 Diffusion �� 130
7.7.2 Active Transport�� 131
7.7.3 Transport by Vesicle Formation�� 132
7.7.4 Transmission of Electrical Impulses �� 132
7.8 Cellular Metabolism�� 133
7.8.1 Role of ATP�� 133
7.9 DNA and Gene Expression �� 135
7.9.1 DNA: The Genetic Material�� 135
7.9.2 Gene Expression and Protein Synthesis�� 138
7.10 Disease and Pathophysiology�� 141
7.10.1 Homeostasis�� 141
7.10.2 Disease Definition�� 142
7.10.3 Pathophysiology�� 142
xviii Contents
8 Production of Radionuclides �� 147

8.1 Natural Radioactivity�� 147
8.1.1 Decay Chain�� 147
8.2 Nuclear Transformation�� 148
8.2.1 Artificial Production of Radioactivity�� 149
8.2.3 Nuclear Reactions �� 151
8.3 Production of Radionuclides by Accelerators�� 153
8.3.1 Linear Particle Accelerator (LINAC)�� 154
8.3.2 Cyclotron�� 156
8.3.3 PET Radionuclides�� 158
8.3.4 SPECT Radionuclides�� 165
8.3.5 Therapy Radionuclides �� 166
8.4 Production of Radionuclides in a Nuclear Reactor�� 168
8.4.2 Radionuclides Produced by Fission�� 169
8.4.3 Radionuclides Produced by Neutron Activation�� 170
8.4.4 Beta Emitting Radionuclides for Therapy�� 171
8.4.5 Alpha Emitting Radionuclides for Therapy�� 176
8.5 Radionuclide Generators�� 176
8.5.1 Generators for SPECT/PET Imaging�� 178
8.5.2 Generators for Radionuclide Therapy�� 179
References�� 181
9 Radiopharmaceuticals
for Molecular Imaging �� 185
9.1 Radiotracer Vs. Radiopharmaceutical�� 185
9.1.1 Radiopharmaceutical Vs. Radiochemical �� 185
9.2 Radiopharmaceuticals for Molecular Imaging (RP-MI)�� 186
9.2.1 Molecular Medicine and Theranostics�� 188
9.2.2 RPMI: Categories and Types�� 191
9.2.3 Choice of Radionuclide for SPECT and PET �� 192
9.2.4 General Criteria for the Design of RP-MI�� 194
9.2.5 General Methods of Radiolabeling �� 206
9.2.6 Automated Synthesis Modules �� 208
10 Radiohalogens
for Molecular Imaging (Fluorine and Iodine) �� 213
10.1 Fluorine-18 Radiopharmaceuticals for Molecular Imaging�� 213
10.1.1 Halogens �� 214
10.2 Chemistry of 18F-Labeled Radiopharmaceuticals �� 215
10.2.1 Production of Fluorine-18�� 215
10.2.2 F-18 Radiochemistry�� 217
10.2.3 Fluorination Reactions�� 218
10.2.4 Radiotracers Based on Nucleophilic Reactions�� 221
10.2.5 Radiotracers Based on Electrophilic Reaction�� 229
10.2.6 F-18 Labeling of Peptides and Biomolecules �� 230
10.3 Radioiodinated Radiopharmaceuticals�� 233
10.3.1 Production of 123I and 124I�� 233
10.3.2 Chemistry of Iodine and Radioiodination�� 234
10.3.3 123/131I-Labeled Radiopharmaceuticals�� 236
Contents xix
11
Organic Radionuclides for Molecular Imaging (C, N, and O)�� 243
11.1 Advantages of Organic Radionuclides�� 243
11.2 11C-Labeled Radiopharmaceuticals�� 244
11.2.1 Production of 11C�� 244
11.2.2 11C Precursors�� 245
11.2.3 Synthesis of 11C Labeled MIPs �� 248
11.3 13N-Labeled Radiopharmaceuticals�� 254
11.3.1 [13N]Ammonia (NH3)�� 254
11.3.2 Synthesis of [13N]Gemcitabine �� 255
11.4 15O-Labeled Radiotracers�� 255
11.4.1 15O-Labeled Gases�� 255
11.4.2 Synthesis of [15O]Water�� 256
12
Metal Radionuclides for Molecular Imaging�� 259
12.2 Radiometals for PET and SPECT �� 260
12.2.1 Specific Activity of Radiometals�� 261
12.2.2 Decay Characteristics of Radiometals�� 261
12.3 Chemistry of Radiometals�� 263
12.3.1 Chelators for Metal Complexation�� 263
12.3.2 Chemistry of Post-transition Metals �� 270
12.3.3 Chemistry of Transition Metals�� 275
12.4 Immuno-PET and SPECT�� 279
12.4.1 ImmunoPET: Applications�� 280
12.5 Tecnetium-99m Chemistry�� 283
12.5.1 Tc-Tricarbonyl Core, [Tc(CO)3]+�� 285
13 Pharmacokinetics and Modeling�� 291
13.1 Quantitation�� 291
13.1.1 Standardized Uptake Value �� 291
13.2 Physiological Modeling�� 292
13.2.1 Radiotracer Binding�� 293
13.2.2 Tracer Kinetics�� 295
14
Molecular Imaging in Oncology �� 303
14.1 Cancer and Molecular Imaging�� 303
14.1.1 Radiopharmaceuticals for Molecular
Imaging �� 304
14.2 Tumor Pathology and Biology�� 305
14.2.1 Histopathology�� 305
14.3 Molecular Basis of Cancer�� 306
14.3.1 Hallmarks of Cancer �� 306
14.3.2 Genetic Changes �� 307
14.3.3 Tumor Angiogenesis �� 309
14.3.4 Tumor Microenvironment �� 310
14.4 PET and SPECT Radiopharmaceuticals in
Oncology�� 310
14.4.1 Objectives�� 310
xx Contents
14.4.2 Radiopharmaceuticals: Biochemical Basis of

Localization�� 311
14.4.3 Antigen-Antibody Binding �� 354
15 Molecular
Imaging in Neurology�� 375
15.1 Neuroscience�� 375
15.1.1 The Nervous System �� 375
15.1.2 Nerve Cells�� 375
15.1.3 The Human Brain�� 377
15.1.4 Neural Signaling �� 379
15.1.5 Synaptic Transmission�� 379
15.1.6 Neurotransmitters and Receptors�� 380
15.2 Neurodegenerative Diseases �� 382
15.2.1 Dementia �� 383
15.2.2 Parkinson’s Disease�� 386
15.3 Radiopharmaceuticals for Brain Imaging
in Neurology �� 386
15.3.1 Cerebral Blood Flow and Perfusion�� 387
15.3.2 Cerebral Oxygen Metabolism �� 390
15.3.3 Cerebral Glucose Metabolism�� 392
15.3.4 β-Amyloid Neuritic Plaque Density�� 394
15.3.5 Tau Imaging in Dementia�� 400
15.3.6 Dopaminergic System�� 402
15.3.7 Neuroinflammation �� 409
15.4 Epilepsy�� 413
15.4.1 Blood Flow and Metabolism�� 414
15.5 Neurooncology�� 415
15.5.1 Imaging in Neuro-oncology�� 415
15.5.2 PET Radiotracers in Neuro-oncology�� 416
16 Molecular
Imaging in Cardiology�� 425
16.1 Nuclear Cardiology�� 425
16.2 The Clinical Problem�� 426
16.2.1 Coronary Artery Disease�� 426
16.2.2 Congestive Heart Failure�� 429
16.2.3 Cardiomyopathy�� 430
16.2.4 Fibrosis�� 431
16.3 Radiopharmaceuticals in Nuclear Cardiology�� 431
16.3.1 Myocardial Blood Flow/Perfusion�� 431
16.3.2 Myocardial Metabolism�� 436
16.3.3 Myocardial Presynaptic Adrenergic
Neuronal Imaging �� 442
16.3.4 Cardiac Sarcoidosis (CS)�� 446
16.3.5 Cardiac Amyloidosis (CA)�� 448
16.3.6 Cardiac Fibrosis�� 451
16.3.7 Inflammation and Atherosclerosis�� 453
Contents xxi
17 Radiopharmaceuticals for Therapy�� 461

17.2 Radiopharmaceuticals �� 462
17.2.1 Therapy Radiopharmaceuticals�� 462
17.3 Radionuclides for Therapy�� 464
17.3.1 Radionuclides-Emitting Beta Particles �� 464
17.3.2 Radionuclides-Emitting Alpha Particles �� 470
17.3.3 Radionuclides Emitting Low-Energy Electrons �� 474
17.3.4 In Vivo Radionuclide Generators�� 475
17.3.5 Mechanism and Biological Effects �� 475
17.3.6 Biological Effectiveness of
Radionuclide Therapy �� 478
17.4 Design of Radiopharmaceuticals for TRT�� 479
17.4.1 Ideal Characteristics�� 479
17.4.2 Selection of Therapeutic Radionuclide�� 480
17.4.3 Theranostic Pair of Radionuclides�� 481
17.4.4 Biological Target and Targeting Vehicle �� 481
17.4.5 Radiolabeling Methods �� 483
17.5 Therapy Radiopharmaceuticals Approved
for Clinical Use �� 484
17.5.1 Inorganic Ions �� 485
17.5.2 Inorganic Chelate Complex�� 487
17.5.3 Particulate Carriers�� 488
17.5.4 Small Organic Molecules�� 489
17.5.5 Regulatory Peptides Hormone Analogs�� 490
17.5.6 Monoclonal Antibodies�� 492
17.6 Prostate Specific Membrane Antigen (PSMA) �� 495
17.6.1 PSMA Inhibitors �� 495
18 Chemistry of Therapeutic Radionuclides�� 501
18.1 Targeted Radionuclide Therapy�� 501
18.1.1 Radionuclides for Therapy�� 501
18.1.2 Production of Radionuclides�� 502
18.2 Chemical Groups Radionuclides�� 506
18.3 Chemistry of Halogens �� 508
18.3.1 Iodine and Radioiodination�� 509
18.3.2 Chemistry of Astatine �� 512
18.4 Chemistry of Radiometals�� 515
18.4.1 Chelators for Metal Complexation�� 515
18.4.2 Bifunctional Chelating Agents�� 521
18.4.3 Alkaline Earth Metals �� 523
18.4.4 Transition Metals�� 524
18.4.5 Post-Transition Metals�� 526
18.4.6 Lanthanides �� 527
18.4.7 Actinides �� 528
xxii Contents
19 Radiolabeled
Antibodies for Imaging and Targeted Therapy�� 533
19.2 Antibody Structure and Function�� 536
19.2.1 Pharmacokinetics of Antibodies and Fragments�� 538
19.3 Hallmarks of Cancer �� 539
19.4 Cancer and Immunotherapy�� 540
19.4.1 Mechanisms of Action of mAbs �� 540
19.5 Radiolabeled Antibodies �� 541
19.5.1 FDA-Approved Radiolabeled Antibodies for Imaging
and Therapy�� 542
19.5.2 Tumor Antigen Targets and Targeting Vehicles�� 543
19.5.3 Radionuclides for Antibody Therapy and Imaging�� 544
19.5.4 Radiolabeling and Bioconjugation Strategies of
Antibodies �� 548
19.6 Radioimmunotherapy (RIT)�� 551
19.6.1 Direct and Indirect RIT Strategies�� 552
19.7 RIT: Clinical Applications�� 552
19.7.1 Hematological Malignancies�� 552
19.7.2 Solid Tumors�� 558
19.8 Strategies to Increase the Therapeutic Efficacy of RIT�� 561
19.8.1 Dose Fractionation�� 561
19.8.2 Pretargeted RIT (PRIT)�� 562
19.8.3 Combination RIT�� 563
19.9 Immuno-PET and SPECT of Cancer�� 564
19.9.1 89Zr for ImmunoPET �� 564
19.9.2 124I for ImmunoPET�� 565
19.9.3 ImmunoPET: Applications�� 566
19.9.4 Molecular Imaging for Cancer Immunotherapy �� 569
20 Design
of Radiolabeled Peptide Radiopharmaceuticals �� 577
20.1.1 Proteinogenic and Non-proteinogenic AAs�� 577
20.1.2 Peptide Therapeutics�� 580
20.1.3 Advantages and Disadvantages of Peptides�� 581
20.2 Design of Peptide Radiopharmaceuticals (PRP)�� 582
20.2.1 Peptide Modification and Insertion of Non-natural AAs��
583
20.2.2 Peptide Cyclization �� 584
20.2.3 Insertion of β-Amino Acids�� 586
20.2.4 Substitution of Amides with Sulfonamides�� 587
20.2.5 N-Methylation (N-Alkylation)�� 587
20.2.6 PEGylation�� 588
20.2.7 Glycosylation�� 588
20.2.8 Albumin Binding�� 590
20.2.9 Spacers/Linkers�� 591
20.2.10 Dimerization and Multimerization�� 591
Contents xxiii
20.3 Radiolabeling of Peptides �� 593

20.3.1 Radionuclides�� 593
20.3.3 Peptide Labeling with Radioiodine�� 594
20.3.4 Peptide Labeling with Fluorine-18 �� 595
20.3.5 Peptide Labeling with Trivalent Radiometals�� 596
20.3.6 Peptide Labeling with 99mTc�� 602
21 Theranostics in Neuroendocrine Tumors�� 609
21.1.1 Carcinoid Syndrome �� 610
21.1.2 Therapeutic Modalities �� 611
21.2 Theranostics in NETs�� 612
21.2.1 Biological Targets �� 614
21.2.2 Radionuclides for Imaging and Therapy�� 614
21.3 Somatostatin Receptors and SST Analogs�� 617
21.3.1 Imaging SSTR-Positive NETs Radiolabeled SST
Agonist Analogs for Imaging�� 620
21.3.2 Therapy of SSTR-2-Positive NETs�� 627
21.3.3 Therapy with Alpha Particles�� 632
21.4 Norepinephrine Transporter (NET): Imaging and Therapy
Agents �� 633
21.4.1 MIBG Analogs for Imaging�� 633
21.4.2 Therapy with MIBG (Azedra®)�� 635
21.5 Glucose Transporters (GLUT)�� 637
21.6 Amino Acid Transporters (AATs)�� 638
21.6.1 [11C]-5-HTP�� 639
21.6.2 [18F]FDOPA�� 639
21.7 Glucagon-Like Peptide 1 Receptor (GLP-IR)�� 640
21.8 Cholecystokinin-2 Receptor (CCK2R) �� 642
21.9 Neurotensin Receptor 1 (NTR1)�� 642
21.10 Chemokine Receptor-4 (CXCR-4)�� 644
21.11 Tumor Antigens and RIT�� 646
21.12 Embolization Therapy with 90Y-Microspheres�� 647
22
Theranostics in Prostate Cancer�� 655
22.1 Prostate Cancer �� 655
22.1.1 Screening and Diagnosis�� 655
22.1.2 Treatment for Localized Prostate Cancer�� 656
22.1.3 Role of Imaging in Prostate Cancer�� 657
22.2 Biological Targets in mCRPC�� 658
22.2.1 Bone Matrix�� 658
22.2.2 Androgen Receptor (AR)�� 660
22.2.3 Prostate-Specific Membrane Antigen (PSMA)�� 662
22.2.4 Gastrin Releasing Peptide Receptor (GRPR) �� 665
xxiv Contents
22.3 Radionuclides for Imaging and Therapy�� 666

22.3.1 Beta vs. Alpha Dosimetry �� 666
22.4 Radiopharmaceuticals for SPECT and PET �� 669
22.4.1 Bone Matrix�� 670
22.4.2 Glucose Metabolism �� 670
22.4.3 Lipid Metabolism�� 672
22.4.4 Amino Acid (AA) Transport �� 673
22.4.5 Androgen Receptor �� 674
22.4.6 Radiolabeled Antibodies �� 676
22.4.7 Small-Molecule PSMA Inhibitors�� 678
22.4.8 Bombesin and GRPR Analogs�� 687
22.5 Radiopharmaceuticals for Bone Pain Palliation�� 688
22.5.1 89Sr Dichloride (Metastron®)�� 688
22.5.2 Bisphosphonates: 153Sm-EDTMP (Quadramet®)�� 689
22.6 Radiopharmaceuticals for Targeted Therapy�� 690
22.6.1 223Ra Dichloride (Xofigo)�� 690
22.6.2 RIT with 177Lu- or 225Ac-Labeled J591 mAb�� 691
22.6.3 Small-Molecule PSMA Inhibitors�� 693
22.7 Combination Therapy �� 696
Index�� 705
About the Author
Shankar Vallabhajosula attended high school in the small town of Bobbili,

Andhra Pradesh, India. He graduated from Andhra University with a BS in
Pharmacy and an MS in Pharmaceutical analysis. After migrating to the Unites
States, Vallabhajosula obtained his PhD in 1980 in Biomedicinal Chemistry
and Radiopharmacy from the University of Southern California. After receiv-
ing the doctorate, he first worked at Mount Sinai Medical Center in New York
and since 1997 has been a Professor of Radiochemistry and Radiopharmacy in
Radiology at Weill Cornell Medicine and New York Presbyterian Hospital. Dr.
Vallabhajosula was the President, and Chief Scientific Officer at NCM USA
Bronx LLC from 2018 through 2021. He is now Professor Emeritus in
Radiochemistry and Radiopharmacy in the Department of Radiology at Weill
Cornell Medicine, Cornell University, New York, NY.
xxv
Molecular Imaging and Targeted
Radionuclide Therapy: 1
Introduction
We really are not treating individuals yet; we are

treating with therapies tailored for a population.
By having the next generation of therapies custom-
ized for a given individual’s genetic makeup we
have the opportunity to truly move towards person-
alized medicine. (Sam Gambhir, May 2005)
1.1 Nuclear Medicine
Nuclear medicine can be defined quite simply as

the use of radioactive materials for the diagnosis
and treatment of patients, and the study of human
disease [1]. Chemistry is the language of health
and disease since the entire body is a collection
and vast network of millions of interacting mol-
ecules. If the definition of the disease is molecu-
lar, the diagnosis is also molecular. Because the
treatment of many diseases is chemical, it
becomes increasingly appropriate that the chem-
istry be the basis of diagnosis and the planning
and monitoring of a specific treatment. Nuclear Fig. 1.1 George de Hevesy. The Nobel Prize in
medicine, therefore, is a medical specialty that is Chemistry, 1943
based on the examination of the regional chemis-
try of the living human body. Weiss, two physicians at the Massachusetts
In the 1920s, George de Hevesy (Fig. 1.1) General Hospital, injected solutions of radium-
coined the term radioindicator or radiotracer C (214Bi) into the veins of healthy persons, and
and introduced the tracer principle in biomedi- patients with heart disease to study the velocity
cal sciences. One of the most important char- of blood. Due to their pioneering work in
acteristics of a true tracer is that it can facilitate nuclear medicine, Hevesy is regarded as the
the study of the components of a homeostatic father of nuclear medicine, while Blumgart
system without disturbing their function. In the came to be known as the father of diagnostic
late 1920s, Hermann Blumgart and Soma nuclear medicine.
© Springer Nature Switzerland AG 2023 1

S. Vallabhajosula, Molecular Imaging and Targeted Therapy,
https://doi.org/10.1007/978-3-031-23205-3_1
2 1 Molecular Imaging and Targeted Radionuclide Therapy: Introduction
In the 1930s, the discovery of artificial radio- functions from those of healthy people under cir-
activity by Irene Curie and her husband Frederic cumstances that are as close as possible to that of
Joliot, and the discovery of the cyclotron by a person of the same sex and age of the patient.
Ernest Lawrence, opened the door to produce The term homeostasis is used by physiologists to
radiotracers of every element, thus enabling mean maintenance of static, or constant, condi-
investigators to design radiotracers for the study tions in the internal environment by means of
of specific biochemical processes. Following the positive and negative feedback of information.
detection of radioactivity with the Geiger coun- Approximately 56% of the adult human body is
ter, it was discovered that thyroid accumulated fluid. Most of the fluid is intracellular; however,
131
I as radioiodide. Consequently, it was soon one-third is extracellular, which is in constant
realized that 131I can be used to study abnormal motion throughout the body and contains the ions
thyroid metabolism in patients with goiter and (sodium, chloride, and bicarbonate) and the
hyperthyroidism. More specifically, in patients nutrients (oxygen, glucose, fatty acids, and amino
with thyroid cancer, distant metastases were acids) needed by cells for the maintenance of life.
identified by scanning the whole body with the Claude Bernard (1813–1878) described extracel-
Geiger counter. The names radioisotope scan- lular fluid as the internal environment of the body
ning and atomic medicine were introduced to and hypothesized that the same biological pro-
describe the medical field’s use of radioisotopes cesses that make life possible are also involved in
for the purpose of diagnosis and therapy. The era disease. In other words, the laws of disease are
of nuclear medicine, as a diagnostic specialty the same as the laws of life. All the organs and
began following the discovery of the gamma tissues of the body perform functions that help
camera based on the principle of scintillation maintain homeostasis. As long as the organs and
counting, first introduced by Hal Anger in 1958. tissues of the body perform functions that help
Since then, nuclear medicine has dramatically maintain homeostasis, the cells of the body con-
changed our view of looking at disease by pro- tinue to live and function properly.
viding images of regional radiotracer distribu- At birth, molecular blueprints collectively
tions and biochemical functions. Over the last make up a person’s genome or genotype, which is
four decades, several hundreds of radiopharma- translated into cellular structure and function. A
ceuticals have also been designed and developed single gene defect can lead to biochemical abnor-
to image the structure and function of many malities that produce many different clinical
organs and tissues. manifestations of disease (or phenotypes), a pro-
cess referred to as pleiotropism. Several gene
abnormalities can result in the same clinical man-
1.2 Molecular Medicine ifestations of disease, a process called genetic
heterogeneity. Thus, diseases can be defined as
At the present time, the precise definition of the abnormal processes as well as abnormalities in
disease is as difficult as defining what exactly life molecular concentrations of different biological
is. Defining disease at the cellular and molecular markers, signaling molecules, and receptors [3].
level, however, is much easier than defining dis- In 1839, Theodor Schwann discovered that all
ease at the level of an individual. Throughout the living organisms are made up of discrete cells. In
history of medicine, two main concepts of dis- 1858, Rudolph Virchow observed that a disease
ease have been dominant [2]. The ontological cannot be understood unless it is realized that the
concept views a disease as an entity that is inde- ultimate abnormality must lie in the cell [4].
pendent, self-sufficient, and runs a regular course Virchow correlated disease with cellular abnor-
with a natural history of its own. The physiologi- malities as revealed by chemical stains and, thus,
cal concept defines disease as a deviation from founded the field of cellular pathology. He also
normal physiology or biochemistry; the disease aptly defined pathology as physiology with
is a statistically defined deviation of one or more obstacles.
1.3 Molecular Imaging 3
Most diseases begin with a cell injury that 8]. This traditional distinction between structural
occurs if the cell is unable to maintain homeosta- and functional imaging has increasingly become
sis. Since the time of Virchow, gross pathology blurred by CT, MRI, and other techniques that
and histopathology have been a foundation of the provide both functional and structural informa-
diagnostic process and the classification of dis- tion [9].
eases. Traditionally, the four aspects of a disease Molecular imaging (MI) aims to integrate
process that form the core of pathology are etiol- patient-specific and disease-specific molecular
ogy, pathogenesis, morphologic changes, and information derived from diagnostic imaging
clinical significance [5]. The altered cellular and studies [10]. The goal of MI is the noninvasive
tissue biology, and all forms of loss of function of localization and quantification of certain molecu-
tissues and organs, are, ultimately, the result of lar events in vivo, including endogenous or exog-
cell injury and cell death. Therefore, knowledge enous gene expression, signal transduction,
of the structural and functional reactions of cells protein–protein interaction, and transcriptional
and tissues to injurious agents, including genetic regulation. Among a variety of possible target
defects, is the key for understanding the disease applications, the use of MI will lead to further
process. Disease may be considered a genetic or insights into the molecular pathology of animal
environmental reprogramming of cells to gain or models of human diseases, as well as to the
lose specific functions that are characteristic of development of new molecular-targeted drugs
disease. Currently, diseases are defined and inter- and to the design and implementation of improved
preted in molecular terms and not just with gen- patient-tailored therapies.
eral descriptions of altered structure. Most, but not all, of the functional imaging
Pathology is evolving into a bridging disci- studies performed in traditional nuclear medicine
pline that involves both basic science and clinical can be regarded as MI. The use of 123I sodium
practice. More specifically, pathology is devoted iodide to assess thyroid function, and imaging
to the study of the structural and functional somatostatin receptor (SSTR)-positive neuroen-
changes in cells, tissues, and organs that underlie docrine tumors using 111In-DTPA-Octreotide
diseases [5]. Molecular, genetic, microbiologic, (OctreoScan®) or 68Ga-DOTATATE (NetSpot)
immunologic, and morphologic techniques are are clearly the best examples of MI. In contrast,
also helping us to understand both, the ontologi- 99m
Tc-DTPA and 99mTc-MAG3, which are used to
cal and physiological causes of disease. In molec- study kidney function, are not appropriate exam-
ular medicine, normal and disease states are ples of MI procedures.
defined at the cellular and molecular levels [6]. Although MI is not necessarily new, what is
Therapeutic drugs are designed based on these new is “molecular and anatomic correlation.”
definitions of disease and are being used to treat Positron emission tomography (PET) is a highly
diseases by correcting abnormal cellular or sensitive, noninvasive technology that is ideally
molecular processes. suited for imaging cancer biology based on [18F]
Fluorodeoxyglucose (FDG), a glucose analog
and substrate for the enzyme hexokinase. With
1.3 Molecular Imaging the introduction of “hybrid imaging” techniques
which combine, for example, FDG-PET and CT
In the past, much of biological and medical imag- or FDG-PET and MRI, and thus providing ana-
ing was driven by anatomy-based imaging or tomic and functional or molecular information in
structural imaging, such as computed tomogra- one image, a new era of MI has arrived. Clearly,
phy (CT) and magnetic resonance imaging this will have implications for the education of
(MRI). The field of nuclear medicine, by con- not only nuclear physicians, but also radiologists.
trast, has focused on studying molecular events in More specifically, the former will need to learn
living subjects, based on radiotracers, and is cross-sectional anatomy and the latter the con-
regarded as functional or physiologic imaging [7, cepts of tracer techniques and functional i maging.
MI is also likely to lead to a further blurring of • MI quantification is the determination of

the distinction between diagnosis and treatment regional concentrations of MI agents and bio-
and to a paradigm shift to early diagnosis that logical parameters. Further, MI quantification
will lead to image-guided, individualized molec- provides measurements of processes at the
ular therapy. Further, biomarkers will be able to molecular and cellular levels. This quantifica-
be imaged and quantified to provide early evi- tion is a key element of MI data and image
dence of the efficacy of a specific treatment. analysis, especially for inter- and intrasubject
comparisons.
• MI has enormous relevance for patient care: it
1.3.1 Definitions reveals the clinical biology of the disease pro-
cess; it personalizes patient care by character-
In 2005, the Radiological Society of North izing specific disease processes in different
America (RSNA) and the Society of Nuclear individuals; and it is useful in drug discovery
Medicine (SNM) jointly convened a workshop and development, for example, for studying
on MI [11]. At that time, the group developed the pharmacokinetics and pharmacodynamics.
following definition of MI, successfully testing it
against the existing variety of imaging tools MI aims to integrate patient-specific and
available in humans and in animal experimental disease-specific molecular information with tra-
contexts: ditional anatomical imaging readouts. The infor-
MI techniques directly or indirectly monitor and mation provided by this field may ultimately
record the spatiotemporal distribution of molecular lead to noninvasive or minimally invasive molec-
or cellular processes for biochemical, biologic, ular diagnostic capabilities, better clinical risk
diagnostic, or therapeutic applications. stratification, more optimal selection of disease
The members of the Molecular Imaging Center therapy, and improved assessment of treatment
of Excellence (MICoE) Standard Definitions efficacy. Development of an MI strategy for a
Task Force recently developed the following four particular disease requires addressing four key
standard definitions and terms that will serve as questions [10]:
the foundation of all communications, advocacy,
and education activities for MICoE and the • Is there a molecular target relevant to the dis-
Society of Nuclear Medicine (SNM) [12]. ease of interest?
• Once a target is selected, is there a high-
• MI is the visualization, characterization, and affinity ligand (for example, a peptide, engi-
measurement of biological processes at the neered antibody, or another small molecule)
molecular and cellular levels in humans and that will bind to the target?
other living systems. To elaborate, MI typi- • What is the appropriate MI system to provide
cally includes two- or three-dimensional imag- the required spatial resolution, sensitivity, and
ing, as well as quantification over time. The depth penetration for the disease?
techniques used include radiotracer imaging/ • For a given imaging system, can an agent be
nuclear medicine, MR imaging, MR spectros- synthesized to detect the desired molecular
copy, optical imaging (OI), and ultrasound. target?
• MI agents are “probes used to visualize, char-
acterize, and measure biological processes in MI has the potential to improve the under-
living systems. Both endogenous molecules standing of disease in several biological models
and exogenous probes can be molecular imag- and systems. MI targets should be able to define
ing agents.” MI instrumentation comprises the disease status earlier than conventional imag-
tools that enable the visualization and quanti- ing methods, identify the underlying molecular
fication in space and over time of signals from events in disease initiation and progression, dis-
MI agents. tinguish between aggressive and indolent disease
states, and represent downstream targets in a signal-to-noise and contrast-to-noise ratio, which
well-characterized molecular network or permits reduction in overall scan length and
pathway. improvement in spatial resolution. The magnetic
field strength for small-animal imaging systems
is also increasing, with 9.4 T magnets becoming
1.3.2 Molecular Imaging standard. These systems produce microscopic
Technologies resolution (tens of micrometers range) images in
small-animal models and allow for the analysis
A wide range of technologies are available for of physiologic and molecular markers [19]. A
noninvasive in vivo MI studies [10, 13–17]. number of paramagnetic (e.g., gadolinium)- and
Various technical features of several MI technol- super paramagnetic (e.g., iron oxide)-based MI
ogies are summarized and compared in Table 1.1. agents have been tested for preclinical and clini-
cal MI applications. The primary disadvantage of
1.3.2.1 Magnetic Resonance Imaging MRI is its inherently low sensitivity for the detec-
The primary advantage of MRI as an MI tech- tion of targeted agents compared with nuclear
nique is its ability to provide soft tissue and func- imaging techniques.
tional information by exploiting proton density,
perfusion, diffusion, and biochemical contrasts 1.3.2.2 Optical Imaging
[18]. MRI offers two main advantages over One of the most successful MI modes for pre-
nuclear imaging techniques: higher special reso- clinical studies is optical imaging, which is based
lution (<1 mm) and the ability to obtain anatomic, on the detection of light photons after their inter-
physiologic, and metabolic information in a sin- action with the tissue. The two major OI methods
gle imaging session. In addition, MRI offers are bioluminescence imaging (BLI) and fluores-
good depth penetration, like PET and CT [10]. cence imaging (FLI).
MR scanners are frequently identified by their BLI requires the cellular expression of an
magnetic field strength expressed in tesla enzyme known as luciferase that is responsible
(1 T = 10,000 gauss). With higher T scanners, the for making some insects, jellyfish, and bacteria
magnet is stronger, both in general and within the glow [20]. The gene for this enzyme is incorpo-
bore of the machine. Most MR scanners are 1.5 T rated into the DNA of cells in the animal models
or 3.0 T, and more recently, up to 7.0 T. Increasing of disease. When an appropriate substrate (such
MRI field strength is designed to increase the as D-luciferin) interacts with the enzyme, a sub-
Table 1.1 Noninvasive in vivo molecular imaging modalities

Acquisition Probe mass Sensitivity of Depth of
Imaging Form of energy Spatial resolution (mm) time/frame required detection penetration
modality used Clinical Animal (s) (ng) Mol/l (mm)
PET Annihilation 3–8 1–3 1–300 1–100 10−11–10−12 >300
photons
SPECT γ-photons 5–12 1–4 60–2000 1–1000 10−10–10−11 >300
CT X-rays 0.5–1 0.03–0.4 1–300 – – >300
MRI Radiofrequency 0.2–0.1 0.025–0.1 50–3000 103–106 10−3–10−5 >300
waves
Ultrasound High-frequency 0.1–1.0 0.05–0.1 0.1–100 103–106 – 1–200
sound waves
BLI Visible to – 3–10 10–300 103–106 10−13–10−16 1–10
infrared light
FLI Visible to – 2–10 10–2000 103–106 10−9–10−11 1–20
infrared light
tle glow of visible light (400–700 nm with ener- 1.3.2.3 Ultrasound Imaging
gies of 1.5–3.0 eV) called bioluminescence (BL) Molecular ultrasound imaging or targeted
is emitted. The detection of BL can be used to contrast- enhanced ultrasound (CEUS) offers
monitor the cellular and genetic activity of every high spatial resolution (<1 mm) and can provide
cell that expresses the luciferase enzyme. The excellent anatomical information for co-
in vivo applications of BLI systems are most use- registration with molecular information.
ful for small mouse models of disease since most Ultrasound contrast agents are conjugated to
of the organs of interest are found no more than ligands that bind with specific biomarkers in the
1–2 cm deep within the tissue. To obtain the best areas of interest which can then be quantified
depth sensitivity, the camera system should be using ultrasound technology. A number of tar-
particularly sensitive to the red and near-infrared geted MI agents have been designed for ultra-
(NIR) portion of the BL emission spectrum sound imaging (UI) using microbubbles,
(700–900 nm). liposomes, or perfluorocarbon emulsions as scaf-
FLI is capable of imaging the surface distribu- folds [22–24]. An important limitation of ultra-
tion of FL signals. FL molecules may be geneti- sound for MI studies is the relatively large size of
cally engineered into a mouse, for example by the imaging agent particles (<250 nm), which can
incorporating the gene for an FL protein as a restrict tissue penetration and, thus, limit applica-
reporter gene, or by using fluorophores or fluo- tion to vascular targets.
rescent particles known as quantum dots to label
a biologically interesting molecule. FLI can be 1.3.2.4 PET and SPECT
performed in both live and fixed cells and no sub- Nuclear imaging approaches, which include PET
strate is required. Fluorochromes can be coupled and SPECT, have the advantages of high intrinsic
to peptides and antibodies and fluorescence sig- sensitivity and unlimited depth penetration. PET
nals may be activatable or switched on and off by has the additional advantages of being fully quanti-
the presence or absence of specific molecules or tative and providing higher spatial resolution than
molecular events, which can help to further SPECT. In addition, hundreds of radiotracers based
reduce the background signal [21]. In contrast, on a wide variety of radionuclides decaying due to
the generation of BL is specific to cells that con- β+ or γ emission have been developed and tested in
tain the luciferase reporter gene and is thus of animal models and clinical studies documenting
limited use for studying genetically manipulated their potential utility as MI probes. With these tech-
cells, transgenic mice, or infectious agents, such niques, the mass of the MI radiotracers is so small
as bacteria or viruses. FLT images molecular pro- (ng or μg) that the toxicity of the administered dose
cesses in 3D, by studying the distribution of is never an issue. In a typical FDG-PET study, the
molecular probes tagged with fluorescent pro- mass of FDG administered is <20 μg. Similarly,
teins, preferably emitting in the NIR for better with somatostatin receptors (SSTR) imaging, the
tissue transmission. mass of PET or SPECT radiotracer administered is
Although the penetration of light through the <10 μg (<nmol); however, the spatial resolution of
tissue is a limitation for all optical imaging meth- both these techniques is much less compared to
ods, attenuation and autofluorescence, however, that of CT and MRI. The fusion of molecular infor-
are minimized in the near-infrared window, per- mation of PET and SPECT with high-resolution
mitting deep tissue imaging up to 10 cm. The anatomical detail from CT or MRI techniques,
advantages of FI methods include improved rela- however, is playing an increasing role in routine
tive sensitivity, high resolution (which may be in clinical MI procedures. As of December 2021, the
the submillimeter range when imaged endo- FDA has approved 20 PET/SPECT radiopharma-
scopically), and the availability of a variety of ceuticals for routine clinical use (Table 1.2). This is
imaging reporters and signal amplification strate- a remarkable progress in the development of MI
gies. In addition, OI offers a convenient way to studies.
co-register surface anatomical information with The [18F]FDG-PET scans based on glucose
molecular information. metabolism of tumor tissue have demonstrated
Table 1.2 FDA-approved PET and SPECT radiopharmaceuticals for MI studies
Chemical Name Trade Name Indications
82
1 Rb chloride Cardiogen-82®, Rubi-fill® To evaluate regional myocardial perfusion 1989
2 [18F]Fludeoxyglucose (FDG) To assess abnormal glucose metabolism in oncology 2000
To assess myocardial hibernation
1.3 Molecular Imaging
To identify foci of epileptic seizures

3 [13N]Ammonia To evaluate regional myocardial perfusion 2000
4 [18F]Sodium Fluoride To delineate areas of altered osteogenesis 2000
5 [18F]Florbetapir Amvid™ To estimate β-amyloid neuritic plaque density in patients with 2012
cognitive impairment
6 [18F]Florbetaben Neuraceq™ To estimate β-amyloid neuritic plaque density in patients with 2014
7 [18F]Flutemetamol Vizamyl™ To estimate β-amyloid neuritic plaque density in patients with 2013
8 [18F]Flortaucipir Tauvid™ To estimate the density and distribution of aggregated tau 2020
neurofibrillary tangles (NFTs)
9 [18F]Piflufolastat Pylarify® To detect PSMA-positive lesions in prostate cancer 2021
10 [11C]Choline To help identify potential sites of prostate cancer recurrence 2012
11 [18F]Fluoroestradiol Cerianna™ For the detection of estrogen receptor-positive lesions in patients 2020
with breast cancer
12 [18F]Fluciclovine Auximin™ Prostate cancer recurrence 2016
13 [18F]Fluorodopa To visualize dopaminergic nerve terminals in the striatum in patients 2020
with suspected parkinsonian syndromes (PS)
68
14 Ga-DOTATATE NETspot For localization of SSTR-positive NETs 2016
64
15 Cu-DOTATATE Detectnet For localization of SSTR-positive NETs 2020
68
16 Ga-DOTATOC For localization of SSTR-positive NETs 2019
68
17 Ga-PSMA-HBED-CC PSMA-positive lesions in prostate cancer 2020
111
18 In-pentetreotide Octreoscan™ For localization of SSTR-positive NETs. 1988
19 [123I]Iobenguane AdreView™ For the detection of primary or metastatic pheochromocytoma or 2008
neuroblastoma
20 [123I]Ioflupane DaTscan™ For dopamine transporter visualization patients with suspected 2011
Parkinsonian syndromes (PS)
7
not only extensive clinical utility in the detection are becoming increasingly useful in the detection
of several types of cancers, but also in the moni- of metastatic lesions in patients with prostate can-
toring and assessment of treatment responses cer compared to the standard 99mTc-MDP bone
(Fig. 1.2). 68Ga-PSMA-PET/CT scans (Fig. 1.3) scans. Somatostatin receptor (SSTR) imaging
a b c
Fig. 1.2 [18F]FDG-PET/CT: New lymph nodes in drain- multiple liver and adrenal metastases (b, arrow); however,
ing basin of regressing metastasis. (A and B) Metastatic new FDG–avid lymph nodes were noted in left inguinal
melanoma (a, arrow) after 4 cycles of combination ipilim- and iliac regions (b, arrowheads). (c) Biopsy of these
umab and nivolumab demonstrated marked regression of lymph nodes shows reactive T cells that resolved on sub-
right thigh lesion and complete metabolic response of sequent scan [25]
a b c
Fig. 1.3 99mTc-MDP bone scan vs. 68Ga-PSMA-PET: A lymph node metastases, for example, mediastinal and left
72-y-old patient with hormone and chemorefractory pros- clavicular (pink arrows). PSA level at time of PET imag-
tate cancer who underwent bone scintigraphy was referred ing was 630 ng/mL, ALP in reference range. Based PSMA
for 223Ra therapy. PSMA PET/CT (c) showed diffuse bone scan, patient was not a candidate for 223Ra therapy, but
and bone marrow metastases, most not detectable by bone underwent radioligand therapy with 177Lu-PSMA-617
scan (a, b). Apart from bone metastases, there were many [26]
with 68Ga-Dotatate illustrates the power and sig- FDA approved and indicated to visualize dopami-
nificance of PET/CT studies to assess the SSTR- nergic nerve terminals in the striatum (Fig. 1.7)
positive lesions compared to SPECT imaging for the evaluation of adult patients with suspected
with Octreoscan™ (Fig. 1.4). In brain tumors, an Parkinsonian syndromes (PS).
amino acid analog, [11C]methionine, and [18F]flu-
orothymidine (FLT) provide more specific tumor 1.3.2.5 Multimodality Molecular
identification than glucose metabolic images with Imaging
FDG (Fig. 1.5). In the area of neuropsychiatric Multimodality imaging has become an attrac-
diseases, molecular imaging with PET and tive strategy for in vivo imaging studies owing
SPECT has shown significant potential in clinical to its ability to provide accurate anatomical
diagnosis and disease management. While FDG- and functional information simultaneously
PET is useful for the differential diagnosis of [31–36]. The combination of CT and PET was
Alzheimer’s disease (AD) from other dementias, introduced commercially in 2001, followed by
several PET radiopharmaceuticals, designed to CT and SPECT in 2004, and PET and MRI in
image the amyloid burden and Tau protein in 2008.
patients with AD, have been FDA approved and At present, a variety of different MI tech-
are in clinical use. (Fig. 1.6) After 3 decades of niques have their advantages, disadvantages,
clinical investigations, [18F]FDOPA is finally and limitations. To overcome these shortcom-
Fig. 1.4 Comparison of 68Ga-Dotatate-PET with tigraphy shows low-grade mesenteric metastases but no
111
In-DTPA-octreotide in a patient with low-grade meta- liver metastases. 68Ga-DOTATATE PET shows multiple
static midgut neuroendocrine tumor (NET). Anterior and metastases in liver and mesentery [30]
posterior whole-body planar 111In-DTPA-octreotide scin-
Fig. 1.5 Relative advantages of MR and PET imaging FDG-PET shows glucose metabolism, while increased
techniques to detect different biochemical processes in cell proliferation can be imaged with specific tracers, such
brain tumors (gliomas). MRI detects alterations of the as [18F]FLT and [11C]methionine [27]
blood–brain barrier and the extent of peritumoral edema,
Fig. 1.6 Amyloid PET and Tau PET scans in a typical clinically unimpaired, typical AD, and an exceptional ager
(>85-year-old APOE4 carrier) [28]
Fig. 1.7 [18F]FDOPA-PET Representative example of anterior commissure-posterior commissure plane and nor-
Benamer grades, adapted to FDOPA uptake in patients malization of color scale on the basal ganglia [29]
with parkinsonian syndromes. PET scans shown in the
ings, it may be beneficial to combine two or protons and α particles can cause direct damage
more detection techniques to create a new imag- to cancer cell DNA by causing double-stranded
ing mode, such as multimodal molecular imag- DNA breaks. Because cells have mechanisms for
ing, to obtain a better result and more information repairing single-strand DNA damage, double-
regarding monitoring, diagnosis, and treatment stranded DNA breaks prove to be the most sig-
[17, 37]. Several dual-purpose imaging agents nificant technique to cause cell death. Radiation
were developed. For example, 64Cu-labeled therapy can be given in three ways:
magnetic nanoparticles as a dual-modality PET/
MR imaging agent were developed [38]. The • External irradiation: External beam radiation
first small-molecule-based αvβ3-targeted NIR-II/ therapy (EBRT or XRT) or teletherapy can be
PET probe 68Ga-SCH2 was evaluated in tumor- carried out using a γ-beam from a radioactive
bearing mice. Excellent imaging properties such cobalt-60 source, or high-energy X-rays from
as good tumor uptake, high tumor contrast and linear accelerators to direct electromagnetic
specificity, tumor delineation, and image-guided rays from outside the body into the tumor. A
surgery were achieved in the small-animal mod- person receiving external radiation is not
els [39]. The development of multimodality radioactive and does not have to follow special
probes is challenging. safety precautions at home.
The use of multimodal imaging probes or bio- • Internal radiation or brachytherapy: A radio-
markers in a single molecule or particle to char- active sealed source is put inside the body into
acterize the imaging subjects such as disease or near the tumor. With some types of brachy-
tissues certainly provides us with more accurate therapy, radiation might be placed and left in
diagnosis and promotes therapeutic accuracy. A the body to work or placed in the body for a
limited number of multimodal imaging probes period and then removed. Iridium-192
are being used in preclinical and potential clini- implants produced in wire form are introduced
cal investigations. The development of multi- through a catheter to the target tumor area in
modal PET/MR and SPECT/MR imaging probes the head and breast. Iridium-192 needles, or
is an emerging research field and the challenges seeds of iodine-125 or palladium-103, are
for designing multimodal probes have been used for early-stage prostate cancer.
addressed by many investigators to offer some • Systemic radiation or endoradiotherapy or
future research directions for this novel interdis- radionuclide therapy (RNT): Radioactive
ciplinary research field [37]. drugs (radiopharmaceuticals) given by mouth
or injected directly into blood circulation
(through a vein or an artery) are used to treat
1.4 Radiation Therapy certain types of cancer. These drugs then
travel throughout the body and deliver the
Radiation therapy or radiotherapy is the medical radioactivity to both cancer cells and normal
use of high-energy electromagnetic waves or par- cells.
ticles (such as X-rays, γ-rays, electron beams, or
protons), generally as part of cancer treatments to Both teletherapy and brachytherapy play a
control malignant cells. Radiation therapy works major role in the treatment of cancer in a specific
by damaging the DNA of cancerous cells. This region in the body, but they are not useful for the
damage is due to either direct or indirect ioniza- treatment of widespread metastases. Since 1936,
tion of the atoms which make up the DNA mole- when Dougherty and Lawrence first introduced
cule. Indirect ionization happens as a result of the 32
P for the treatment of leukemia, the use of
ionization of water, forming free radicals, which radiopharmaceuticals for RNT, and to deliver
then damage the DNA. Charged particles such as therapeutic doses of ionizing radiation, has been
1.4 Radiation Therapy 13
extensively investigated. The use of sodium [131I] pharmaceuticals that are radiolabeled molecules
iodide, discovered in 1938 by Glenn Seaborg and consisting of a target-specific moiety, such as
John Livingood at the University of California, peptides, low molecular weight ligands or anti-
Berkeley, has been the success story in nuclear body or antibody fragments, and particles, linked
medicine. Iodine-131 has the advantage of emit- to an appropriate radionuclide designed to deliver
ting both γ-rays and β− rays, the former enabling therapeutic doses of ionizing radiation to specific
imaging for diagnosis and dosimetry and the lat- disease sites [46, 47]. The goal of TRT is to kill
ter being valuable for molecular radiotherapy of tumor cells selectively by delivering high radia-
hyperthyroidism and thyroid cancer [40]. tion doses to a specific target while minimizing
damage to normal cells. In the last 5 years, there
has been a great progress in the development of
1.4.1 Targeted Radionuclide therapeutic radiopharmaceuticals using a wide
Therapy (TRT) variety of therapeutic radionuclides and target-
specific molecules for treatment of cancers.
Traditional cytotoxic chemotherapy works pri- Targeted therapy is predominantly molecular, in
marily through the inhibition of cell division. In the sense that efficacy is dependent on a thera-
addition to cancer cells, other rapidly dividing peutic advantage offered by interaction of the
cells (such as hair, gastrointestinal epithelium, radiopharmaceutical with key molecular sites
bone marrow) are affected by these drugs. The and receptors on the target tissue. Depending on
primary goal of targeted therapy is to fight cancer the target-specific carrier molecule, TRT may
cells with more precision and with less side also be called peptide receptor radionuclide ther-
effects. Targeted therapeutic agents are designed apy (PRRT), radioimmunotherapy (RIT), radioli-
to block the proliferation of cancer cells by inter- gand therapy (RLT), targeted alpha therapy
fering with specific molecules required for tumor (TAT), and targeted radionuclide therapy
development and growth. Some of these mole- (TRNT).
cules may be present in normal tissues, but they The term unconjugated radiopharmaceutical
are often mutated or overexpressed in cancer has been generally defined as referring to those
cells. Drugs for targeted therapies are primarily radionuclides that target-specific disease sites
small molecule drugs such as tyrosine kinase by virtue of chemical, biologic, or physical
inhibitors (TKIs), interfering RNA molecules, affinity of radioisotope itself, rather than by vir-
microRNA, or monoclonal antibodies (mAbs) tue of carrier agents to which they are tagged.
[41]. Targeted therapy is the foundation of preci- Because of the untagged nature of their use,
sion medicine. Not all cancer patients are candi- unconjugated radiopharmaceuticals are also
dates for targeted therapy. The use of a targeted referred as naked radiopharmaceuticals [46,
therapy may be restricted to patients whose tumor 47]. During the last couple of decades, there
has an appropriate target for a particular target has been significant increase in the application
therapy drug. of conjugated radiopharmaceuticals for tar-
The main objective of targeted radionuclide geted radionuclide therapy (TRT), mainly due
therapy (TRT) or TRNT is the ability to selec- to the development of a range of new carrier
tively deliver cytotoxic radiation to cancer cells molecules, which can transport the radionu-
that causes minimal toxicity to surrounding clide to a molecular target at the disease site.
healthy tissues, using optimized vehicles that The most important factors that influence tumor
deliver a nuclear payload into the tumor cells localization of conjugated radiopharmaceuti-
[42–45]. In nuclear medicine, TRT is based on cals include the chemical and biochemical
delivering therapeutic radionuclides to a specific nature of the carrier molecule transporting the
target site. TRT is based on therapeutic radio- radionuclide of choice to the targeted area. A
century ago, Paul Ehrlich postulated the notion ferent groups—with medical decisions, practices,
that a magic bullet could be developed to selec- interventions, and/or products being tailored to
tively target disease. He envisioned that anti- the individual patient based on their predicted
body molecules could act as magic bullets. The response or risk of disease. The continuing prog-
first demonstration of TRT was the use of ress in biotechnologies in the last couple of
131
I-labeled polyclonal antibodies for the treat- decades opened avenues to a new management of
ment of patients with melanoma. Several radio- many diseases, switching from a “population
pharmaceuticals are now available for the treatment” approach to the concept of “personal-
treatment of different benign diseases and ized medicine” (Fig. 1.8).
malignancies. The current forms of TRT using The word theranostics is derived from the
unconjugated or conjugated radiopharmaceuti- combination of the words, therapeutics, and diag-
cals with specific examples are described in nostics. The concept of “theranostics” was coined
Table 1.3. Several review articles and book by the US consultant John Funkhouser, in a press
chapters have extensively discussed the devel- release from the company Cardiovascular
opment of radiopharmaceuticals for radionu- Diagnostics in August 1998, to describe a mate-
clide therapy [42–44, 46–48]). rial that allows the combined diagnosis, treat-
ment, and follow-up of a disease [49, 50].
Different imaging probes, such as PET/SPECT
1.4.2 Personalized Medicine radiopharmaceuticals, MRI contrast agents (T1
and Theranostics and T2 agents), and fluorescent markers (organic
dyes and inorganic quantum dots), and nuclear
Personalized medicine, or precision medicine, is imaging agents, can be decorated onto therapeu-
a medical model that can separate people into dif- tic agents or therapeutic delivery vehicles to
Table 1.3 Radiopharmaceuticals approved for therapy

Radiopharmaceutical Trade name Indicated for therapy in Year
1 131
I Sodium iodide Thyroid cancer 1971
2 Strontium-89 chloride Metastron Bone pain palliation 1993
3 Samarium-153 Quadramet® Bone pain palliation 1997
lexidronam
4 90
Y Glass microspheres TheraSphere™ Radiation treatment of unresectable 2000, 2020
hepatocellular carcinoma (HCC),
neuroblastoma
5 111
In/90Y- ibritumomab Zevalin® Relapsed or refractory, low-grade, or 2002
tiuxetan follicular B-cell non-Hodgkin’s lymphoma
(NHL)
6 131
I-tositumomab and BEXXAR CD20-positive, relapsed or refractory, 2003
tositumomab low-grade, follicular, or transformed NHL
7 223
Ra-dichloride Xofigo® Treatment of patients with CRPCa 2013
8 90
Y Resin Microspheres SirSpheres™ Radiation treatment of unresectable 2015
hepatocellular carcinoma (HCC)
9 [131I]Iobenguane Azedra® Treatment of iobenguane scan positive, 2018
unresectable, locally advanced or
metastatic pheochromocytoma or
paraganglioma
10 177
Lu-Dotatate Lutathera® Treatment of SSTR-positive GEP-NETs. 2018
11 Lu 177 vipivotide Pluvicto Treatment of patients with metastatic 2022
tetraxetan castration-resistant prostate cancer
(177Lu-PSMA-617) (mCRPC)
Personalized Medicine
Screening Diagnosis Treatment Follow up
Biomarkers
1. At risk patient profile
• In vitro (fluids, cells) 2. Companion biomarker of targeted
• Ex vivo (biopsies) drugs; selection, response
• In vivo (Molecular Imaging) 3. Early diagnosis of recurrecnce
Theranostics
1) Radiodiagnosis and Radiotherapy

MI (PET & SPECT); TRT
Molecular Imaging
2) Imaging guided interventional procedures
Based Guidance
3) Imaging controlled drug delivery
4) Cell therapy
Fig. 1.8 Personalized medicine in nuclear medicine is theranostics based on molecular imaging and targeted radionu-
clide therapy (TRT)
facilitate their imaging and, in so doing, gain ting radionuclide for SPECT or PET imaging,
information about the trafficking pathway, kinet- and it can also be labeled with a therapeutic
ics of delivery, and therapeutic efficacy. This radionuclide decaying by β−, α, or EC (emitting
approach allows the selection of the subpopula- Auger electrons). One of the earliest examples of
tion of patients most likely to benefit from a tar- theranostics are the use of radioactive iodine (123I
geted therapy in accordance with their “molecular and 131I) for treatment of patients with hyperthy-
profile” at a given time-point or, conversely, those roidism and thyroid cancer. The past, present,
patients for whom the risk of adverse effects is and the future of theranostics in nuclear medicine
higher. were extensively discussed in many review arti-
The concept of theranostics integrates two dis- cles [50–56]. Several theranostic radiopharma-
tinct approaches that both encompass all steps of ceuticals of clinical importance are listed in
patients’ management. In personalized medicine, Table 1.4.
diagnostic molecular imaging is often employed The success of theranostics in the clinic has
for selecting appropriate and optimal therapies already been well established with the introduc-
based on the context of a patient’s genetic content tion of somatostatin analogs for PET/SPECT
or other molecular, or cellular analysis. Having imaging and TRT or PRRT in patients with
the ability to look at a patient on an individual SSTR-positive NETs. For example,
basis will allow for a more accurate diagnosis 68
Ga-Dotatate PET/CT scans in two patients
and specific treatment plan. Theranostics in (Fig. 1.9) with well-differentiated NETs who
nuclear medicine is a personalized approach to received 4 cycles of 177Lu-Dotatate treatment. A
treating cancer, using similar (or same) mole- patient with a pancreatic NET shows remission
cules for both imaging (diagnosis) and therapy. A (A), while a patient with ileal NET did not
target-specific biomolecule is designed in such a respond (B) [52]. In a patient with extensive
manner that it can be labeled with a γ or β+ emit- castration-resistant metastatic prostate cancer,
Table 1.4 Radiopharmaceuticals under clinical development in phase II/III trials

Radiopharmaceutical Target Disease/Indication
[18F]PSMA-1007 PSMA Prostate cancer PET/CT
[18F]rhPSMA-7.3
177
Lu-PSMA-617 Prostate-specific membrane Therapy of metastatic castration-resistant prostate
225
Ac-PSMA-617 antigen (PSMA) cancer (mCRPC)
177
Lu-PSMA-I&T
225
Ac-PSMA-I&T
177
Lu-RM2 GRPR
177
Lu-NeoBOMB1
177
Lu-EB-TATE SSTR-2 Therapy of neuroendocrine tumors (NETs)
177
Lu-Dotatoc SSTR-2
(edotreotide) Solucin
177
Lu-Satoreotide tetraxetan SSTR-2
177
Lu-DOTA-JR11 SSTR-2 antagonist
(OPS201)
68
Ga-NODAGA-JR11 SSTR-2 antagonist
(OPS202)
68
Ga-DOTA-Exendin-4 Glucagon-like peptide-1 PET/CT of NETs
(GLP-1R)
68
Ga and 177Lu-Pentixafor CXCR4 Melanoma, multiple myeloma, small-cell lung
cancer, NETs
68
Ga-FAP analogs Fibroblast activation protein Different tumors
90
Y-FAP analogs (FAP)
111
In/177Lu-3B-227 Neurotensin receptor Pancreatic adenocarcinomas
(NTSR1)
131
I-IOMAB, Apamistamab CD-45 Bone marrow ablation in leukemias
177
Lu-lilotomab or CD37 B-cell lymphomas
(lilotomab satetraxetan)
131
I-omburtamab (8H9) mAb B7-H3 (CD 276) Neuroblastoma, glioblastoma
89
Zr/177Lu- HuMab-5B1 CA19-9 Pancreatic carcinomas, hepatocellular, gastric,
mAb colorectal, and breast carcinomas
89
Zr or 18F anti-PD and Immune checkpoint PET/CT of different tumors
PD-L1 mAb inhibitors
(Fig. 1.10) 68Ga-PSMA PET/CT scans revealed imaging [54]. Examples include imaging of
no response to 2 cycles of 177Lu-PSMA-617 beta cancer-associated fibroblasts (FAP inhibitor or
therapy but, significant response to three cycles FAPI), CD8-positive T cells, and programmed
of 225Ac-PSMA-617 alpha therapy [57]. death ligand 1 (PD-L1), which is found in
The future of theranostics is very promising antigen-presenting cells, including macrophages
and several investigational radiopharmaceuticals and myeloid-derived suppressor cells. The next
(Table 1.4) are in phase II/III clinical studies for major advance in theranostics will be the intro-
both imaging and therapy. PET imaging of duction of α therapy based on peptides and
immune cell types in tumor microenvironment antibodies.
(TME) represents future direction of molecular
Fig. 1.9 68Ga-Dotatate PET/CT scans in patients with pancreatic NET), and progression in a nonresponder (a
well-differentiated neuroendocrine tumors (NETs) under- patient with ileal NET presenting with liver metastases
going 177Lu-Dotatate treatment. After 4 cycles of therapy, and peritoneal carcinomatosis). Progression in nonre-
PET scan shows remission in a responder (a patient with sponder is evident even after 4 cycles of treatment [52]
a b c d
Fig. 1.10 68Ga-PSMA-11 PET/CT scans of a patient presented progression (b). In contrast, restaging after sec-
with metastatic castration-resistant prostate cancer ond (c) and third (d) cycles of α emitting 225Ac-PSMA-617
(mCRP). In comparison with initial tumor spread (a), presented impressive response [57]
restaging after 2 cycles of β− emitting 177Lu-PSMA-617
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Science of Atomism: A Brief
History 2
I… a Universe of Atoms, an Atom in the Universe created from the following four elements: water,
(Richard P. Feynman)
earth, fire, and air. They also believed that matter
is continuous; there is no vacuum (space without
any matter). The Greek philosopher Leucippus
2.1 Atomism and his pupil Democritus (460–370 bc) (Fig. 2.1)
conceived the idea of an atom as the smallest
In natural philosophy, atomism is the theory that piece of a substance. The word atom comes from
all the objects in the universe are composed of the Greek word atomos (ατομοσ) meaning “not
very small, indestructible elements—atoms. The cuttable” (unbreakable) and advocated that atoms
notion of atomism first arose because of philo- are in continuous motion and are indestructible.
sophic deduction. This idea of atomism is by no The most famous Greek philosophers Plato
means self-evident. Since ancient times, philoso- (427–347 bc) and Aristotle (384–322 bc), how-
phers in many cultures have been speculating on ever, completely rejected the idea of atomism.
the nature of the fundamental substance or sub- Nevertheless, the ideas of Democritus were fur-
stances of which the universe is composed. These ther developed by the influential Greek
fundamental or basic substances are called ele- Philosopher Epicurus almost a century later. One
ments in English, from a Latin word of unknown of the most important followers of the Epicurean
origin. philosophy was a Roman poet named Titus
In India, during the sixth century bc, Kanada Lucretius Carus (96–55 bc), who explained the
and Pakhuda Katyayana had propounded ideas philosophy of atomism in a long poem entitled,
about the atomic constitution (Anu and De rerun Natura (On Natural Things). One copy
Paramanu) of the material world (Limouris of this poem survived the Dark and Middle Ages
2006). Philosophy and science were not origi- (it was discovered in 1417) and became a major
nally separate but, were born together as natural source of the Greek theory of atomism. The
philosophy in Greece, at the beginning of the French philosopher Pierre Gassendi (1592–1655)
sixth century. In fact, the ancient Greeks were the accepted atomism and spread this doctrine
first to propose that all matter in the universe was throughout Europe.
© Springer Nature Switzerland AG 2023 21

S. Vallabhajosula, Molecular Imaging and Targeted Therapy,
https://doi.org/10.1007/978-3-031-23205-3_2
22 2 Science of Atomism: A Brief History
Fig. 2.1 Democritus, the Greek philosopher (on left), and John Dalton, an English chemist, and physicist (on right)
elementaire de chemie, published in 1789, listed

2.2 Chemical Elements 33 substances as chemical elements under four
major categories: gases, nonmetals, metals, and
The British scientist Robert Boyle (1627–1691) earths.
was strongly influenced by Gassendi’s writings
and was probably the first person to perform
experiments in connection with atomism. Boyle
carefully measured and demonstrated an inverse 2.2.1 Chemical Laws
relationship between the pressure and the volume
of air (known as Boyle’s Law), which clearly sug- Lavoisier advocated the importance of accurate
gested that both atoms and vacuum are real. He, measurements in quantitative experiments of
thus, revived the atomic hypothesis and called it chemical reactions and discovered the law of
the Corpuscular Theory of Matter. Newton also conservation of mass which states that: mass is
wrote in his Opticks that all matter is composed neither created nor destroyed. The principle of
of solid and impenetrable particles—expressing a the constant composition of compounds, known
view similar to Democritus and Boyle. as the law of definite proportions, was discovered
Boyle was also the first chemist to recognize by the Frenchman, Joseph Proust who showed
the significance of a chemical element. In his that a given compound always contains exactly
book, the Skeptical Chemist, published in 1661, the same proportion of elements by mass. Proust’s
he proposed that a substance was an element if it discovery stimulated John Dalton (Fig. 2.1) an
could not be broken into two or more simpler English school teacher, who noted that a series of
substances. In early 1700, the quantitative sci- compounds can be formed by the combination of
ences of physics and chemistry were born, and 15 two elements in different ratios and, thus, discov-
chemical elements came to be known. Following ered the law of multiple proportions. These
the discovery of important gases, such as carbon chemical laws supported the hypothesis that each
dioxide, nitrogen, hydrogen, and oxygen, the element consists of a certain type of atom and
French chemist, Antoine Laurent de Lavoisier that compounds are formed from specific combi-
(1743–1794) in his remarkable book titled, Traite nations of these atoms.
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OREN
Prunus americana
1. Ia. Sta. Bul. 46:285 fig. 1900. 2. Waugh Plum Cult. 174. 1901. 3.
Budd-Hansen Am. Hort. Man. 299. 1903.
Bartlett 1. Bingaman 1.
Waugh places Oren with the “Miner-like” plums but as the variety
grows here it is a typical western Americana—the characters of this
species in leaf, fruit and stone being well shown in the
accompanying plate. It is one of the best of the Americanas in both
fruit and tree. The fruits are large and of good shape, perhaps a little
dull in color and not quite as good in quality as a few other
Americanas but still averaging very well in all fruit-characters. The
flesh is very nearly free from the stone. The trees are typical of the
species, shaggy of trunk and limb, straggling and unkempt in growth
of top, but hardy, robust, healthy and reliable in bearing. It would
seem as if this variety is rather too good to be allowed to pass out of
cultivation until there are more Americanas that are better.
Oren was taken from the wild in Black Hawk County, Iowa, about
1878, by J. K. Oren. Mr. Oren grew trees of this plum on his farm
and permitted all who came to take sprouts, cions and seed until the
variety was very generally disseminated locally. Who introduced it to
the trade and when is not known.
Tree small, spreading, low, dense-topped, hardy, often unproductive;

branches roughish, slightly zigzag, thorny, dark ash-brown, with small
lenticels; branchlets slender, long, twiggy, with internodes of average
length, green changing to dark chestnut-brown, glabrous, with large,
conspicuous, raised lenticels; leaf-buds small, short, obtuse, free.
Leaves falling early, oval or obovate, two inches wide, three and three-
quarters inches long; upper surface dark green changing to golden-yellow
late in the season, smooth and shining, with a narrow, grooved midrib;
lower surface silvery-green, lightly pubescent; apex taper-pointed, base
abrupt, margin coarsely serrate, the serrations ending in sharp points,
eglandular; petiole five-eighths inch long, thick, tinged red, thinly
pubescent, glandless or with one or two prominent, greenish-brown
glands.
Blooming season late and of medium length; flowers appearing after the
leaves, one and one-eighth inches across, white; borne in clusters on
lateral spurs and buds, in pairs or in threes; pedicels five-eighths inch
long, slender, glabrous, green, tinged with red; calyx-tube red,
campanulate, enlarged at the base, glabrous; calyx-lobes narrow,
somewhat obtuse, pubescent on both surfaces and on the margin,
reflexed; petals ovate, somewhat crenate or fringed, tapering below to
long, narrow claws, sparingly hairy along the edge of the base; anthers
yellow; filaments three-eighths inch long; pistil glabrous, shorter than the
stamens.
Fruit intermediate in time and length of ripening season; one and three-
sixteenths inches in diameter, roundish, usually truncate and slightly
oblique, compressed, halves equal; cavity very shallow, flaring; suture a
line; apex roundish or flattened; color dull light or dark red over a yellow
ground, mottled, with thick bloom; dots numerous, very small, light russet,
inconspicuous; stem slender, five-eighths inch long, glabrous; skin tough,
astringent, adhering; flesh dark golden-yellow, juicy, fibrous, soft and
melting, sweet; fair to good; stone semi-free, seven-eighths inch by five-
eighths inch in size, irregularly roundish or ovate, flattened, blunt at the
base and apex, with smooth surfaces; ventral suture strongly winged;
dorsal suture acute, with a narrow and shallow groove.
ORLEANS
Prunus domestica
1. Quintinye Com. Gard. 68. 1699. 2. Langley Pomona 91, Pl. XX fig. 4.
1729. 3. Miller Gard. Dict. 3:1754. 4. Duhamel Trait. Arb. Fr. 2:78, Pl. VII.
1768. 5. Knoop Fructologie 2:52, 55, 56, 57. 1771. 6. Forsyth Treat. Fr.
Trees 19. 1803. 7. Kraft Pom. Aust. 2:32, Tab. 179 fig. 1. 1796. 8.
Brookshaw Pom. Brit. Pl. XI. 1817. 9. Lond. Hort. Soc. Cat. 145, 150.
1831. 10. Prince Pom. Man. 2:62, 67, 85. 1832. 11. Poiteau Pom. Franc.
1:1846. 12. Floy-Lindley Guide Orch. Gard. 289, 290, 383. 1846. 13.
Thomas Am. Fruit Cult. 339. 1849. 14. Elliott Fr. Book 428. 1854. 15.
Thompson Gard. Ass’t 519. 1859. 16. Downing Fr Trees Am. 935. 1869.
17. Mas Pom. Gen. 2:37, fig. 19. 1873. 18. Am. Pom. Soc. Cat. 36. 1875.
19. Oberdieck Deut. Obst. Sort. 414. 1881. 20. Mathieu Nom. Pom. 435.
1882. 21. Hogg Fruit Man. 715. 1884. 22. Guide Prat. 156, 360. 1895.
Anglaise Noire 16, 17, 20, 21, 22. Angloise Noire 5. Brignole? 1.
Brugnole? 1. Brignole Violette 17, 20, 22. Brignole Violette? 5. Common
Orleans 10, 16, 17, 20. Damas Rouge 10. Damas Rouge 5, 9. Damas
Violet? 5. De Monsieur 17, 22. Die Herrnpflaume 7. English Orleans 10,
16, 17, 20. French Orleans 8. Hernnpflaume 17. Herrnpflaume 19.
Herrnpflaume 22. Herzog von Orleans 20, 22. Italian Damask of some 14.
Large Red Orleans 10. Late Monsieur 10, 16, 17, 20. Monsieur 4, 9, 10,
12, 17, 22. Monsieur 10, 13, 14, 15, 16, 20, 21. Monsieur Ordinaire 9, 10,
14, 15, 16, 17, 20, 21, 22. Old Orleans 10, 13, 14, 15, 16, 17, 20, 22.
Orleans 17, 20, 22. Orleans Red Damask 20. Prune de Monsieur 10, 16,
20. Prune de Monsieur 11. Prune d’Orleans 16, 17, 20, 21. Prunelle? 5.
Prune Monsieur 7. Red Damask 10. Red Damask 9, 10, 12, 13, 14, 15,
16, 17, 18, 20, 21, 22. Red Orleans 10, 16, 17, 20. Red Orleans Plum 6.
In Europe Orleans is one of the most renowned of the plums

cultivated. A proof of its popularity is the great number of names, as
shown in the synonymy given above, under which it passes in
England and on the continent. This variety, however, is almost
unknown in America though described by all of the older American
pomologists and probably introduced time and again during the last
hundred years in our orchards. The French fruit books say that the
variety thrives better in southern than northern France and nearly all
of the European writers state that it does best in high, dry, light,
warm soils. It is likely that our climate, and the soils in which plums
are generally grown in America, are not suited to this sort.
Unfortunately this Station has no trees of this variety and the brief
description given is a compilation.
The Orleans has been cultivated for more than two hundred years.
Langley said of it in 1729 “The Orleans Plumb tho a common, is yet
a very valuable Plumb, as well for its fine firm juicy Pulp when well
ripened, as its being a constant and plentiful bearer.” The Red
Damask and the Brugnole mentioned by Quintinye in 1699 are
probably the Orleans; but the Prune de Monsieur of Knoop and the
Monsieur of Tournefort, which are yellow, are distinct. The variety is
evidently of French origin. Mas in his Pomologie Generale, 1873,
states that it first bore the name Brignole Violette, but later was given
the name it now bears in honor of Monsieur, Duke of Orleans,
brother of Louis XIV. Damas Rouge is an old synonym, though
Duhamel described it as a distinct variety. Herrnpflaume is the
common name of the Orleans in Germany and Austria, while in
France, it is often called the Monsieur. It has never been common in
America, yet it was entered on the American Pomological Society
catalog list in 1875.
Tree large, vigorous, hardy, productive, bearing annually; branches
grayish, pubescent; leaves large, ovate, with crenate margins; flowers
large, blooming early; petals roundish, imbricated.
Fruit early mid-season; medium in size, roundish-truncate, sides
unequal; cavity usually shallow, wide; suture distinct; apex flattened; color
dark or purplish-red, overspread with thin bloom, with a sprinkling of pale
reddish dots; stem thick, short; skin tender; flesh yellowish, juicy, usually
melting when properly matured, sweet near the skin but sprightly toward
the center, pleasant-flavored; good; stone free, small, oval, flattened, with
roughish surfaces.
OULLINS
OULLINS
Prunus domestica
1. Hogg Fruit Man. 374. 1866. 2. Downing Fr. Trees Am. 935. 1869. 3.
Pom. France 7: No. 15. 1871. 4. Mas Le Verger 6:43. 1866-73. 5. Am.
Pom. Soc. Cat. 38. 1877. 6. Cat. Cong. Pom. France 366. 1887. 7.
Mathieu Nom. Pom. 446. 1889. 8. Waugh Plum Cult. 117. 1901. 9.
Thompson Gard. Ass’t 4:158. 1901.
Massot 6, 7. Monstrueuse d’Oullins 2, 7. Ouillin’s Gage 2, 7. Oullins
Golden 1. Oullin’s Golden 2, 9. Oullin’s Golden 3, 4, 6, 7. Oullin’s Golden
Gage 2, 7. Oullins Golden Gage 5. Oullin’s Green Gage 8. Prune-Massot
3. Reine-Claude d’Oullins 1, 2, 7, 9. Reine-Claude D’Oullins 3, 4, 6.
Reine-Claude Prêcoce 1, 2, 3, 6, 7, 9. Reine-Claude von Oullins 7. Roi-
Claude 3, 7.
Oullins came to America with the best of recommendations from

European growers but it has fallen so far short of its reputation in
Europe that it was dropped from the fruit list of the American
Pomological Society and is gradually disappearing from cultivation.
The fault is in the fruit which is but indifferent in quality for a plum of
the Reine Claude group. In Europe the variety is rated as one of the
best dessert sorts; in America it is hardly second-rate in quality. This
difference may be due to differences in climate and soil; more
probably, it is due to the greater number of better Reine Claude
varieties grown in America with which it must compete. Hand,
Jefferson, Washington, McLaughlin, Yellow Gage, Spaulding and
Imperial Gage, the cream of the Reine Claude plums, are all
Americans similar to Oullins but much better in quality. Oullins is
hardly surpassed by any of its group in tree-characters and might
well be used for breeding purposes as there are so few sorts of its
kind having satisfactory trees.
This variety, probably a Reine Claude seedling, was found at
Coligny, France, on the estate of M. Filliaud; it was propagated by M.
Corsaint, gardener to the Baron de Toisy, near Cuiseaux
(Department of Saone-et-Loire) and was introduced at Oullins
(Department of Rhone) by M. Massot, nurseryman. The name is
seldom spelled correctly in American fruit books, being either written
with an apostrophe and s or with both left off, these spellings coming
from the supposition that the name comes from that of a man, a
mistake as the history shows. Oullins was placed on the American
Pomological Society catalog fruit list in 1875 but was dropped when
the catalog was revised in 1897.
Tree large, vigorous, spreading, open-topped, hardy, productive;
branches ash-gray, somewhat rough, with numerous, large, raised
lenticels; branchlets stout, the bark rough, medium to above in thickness,
short, with short internodes, greenish-red changing to brownish-red, dull,
lightly pubescent, overspread with faint bloom, with numerous, small
lenticels; leaf-buds large, long, pointed, free; leaf-scars swollen.
Leaves oval or obovate, two inches wide, four and one-quarter inches
long, thick; upper surface dark green, covered with fine hairs, the midrib
grooved; lower surface pale green, pubescent; apex acute or abruptly
pointed, base acute, margin serrate or crenate, with small black glands;
petiole three-quarters inch long, thick, pubescent, tinged red, with from
two to four globose, greenish-brown glands variable in size, usually on the
stalk.
Blooming season medium to late, of average length; flowers appearing
after the leaves, one and one-quarter inches across, white, with a faint
yellowish tinge; arranged on lateral spurs, singly or in pairs; pedicels
eleven-sixteenths inch long, pubescent, greenish; calyx-tube green,
campanulate, pubescent; calyx-lobes broad, obtuse, pubescent on both
surfaces, glandular-serrate, reflexed; petals broadly obovate, crenate,
tapering to short, broad claws; anthers yellowish; filaments three-eighths
inch long; pistil glabrous, equal to the stamens in length.
Fruit early, season short; medium to below in size, roundish, halves
equal; cavity shallow, below medium in width, abrupt; suture an indistinct
line; apex flattened or depressed; color greenish-yellow changing to dull
light yellow, overspread with thin bloom; dots numerous, small, whitish,
inconspicuous, clustered about the apex; stem of medium thickness and
length, adhering well to the fruit; skin thin, slightly astringent, separating
readily; flesh greenish-yellow or pale yellow, somewhat dry, firm, sweet,
not high in flavor; good; stone half-free or free, three-quarters inch by five-
eighths inch in size, broadly oval, flattened, roughened and pitted, blunt at
the base and apex; ventral suture rather narrow, furrowed, with a distinct
but not prominent wing; dorsal suture broadly and deeply grooved.
PACIFIC
PACIFIC
Prunus domestica
1. U. S. D. A. Rpt. 292. 1893. 2. Am. Pom. Soc. Rpt. 150. 1895. 3.

Oregon Sta. Bul. 45:31. 1897. 4. Oregon Hort. Soc. Rpt. 474. 1898. 5. Am.
Pom. Soc. Cat. 40. 1899. 6. Waugh Plum Cult. 117. 1901. 7. Oregon
Agriculturist 17: No. 24, 370. 1908.
Pacific 3. Pacific Prune 2, 3. Willamette 4, 5, 7. Willamette Prune 3.
No part of America is so well adapted to plum culture as the

Pacific Coast and especially the inter-mountain valleys in Oregon.
From the last-named State, though fruit-growing is a very recent
development, a number of meritorious plums have been added to
pomology. One of the best of these, as they grow in New York, is the
Pacific, the fruits of which are well shown in the color-plate. Few
purple plums are more beautiful than this in color and shape, few
equal it in size and very few of its color excel it in quality. The trees
are unusually robust, perfectly hardy and productive. In Oregon the
Pacific has not proved a good prune-making plum but is reported as
standing eastern shipment very well, which, if true, indicates that this
plum would succeed as a market fruit in New York. Pacific is well
worth trying in New York as a commercial variety.
This plum is hopelessly confused with the Willamette. The
following is an abridged account of the two fruits as written us by H.
M. Williamson, Secretary of the Oregon State Board of Horticulture,
and one of the leading authorities on fruit-growing on the Pacific
Coast.
“About 1875 Jesse Bullock of Oswego, Oregon, sent to Germany for

pits of the Italian or Fellenberg prune, and planted the pits received in a
nursery row. When the trees from these began to bear, Mr. C. E. Hoskins
went to Mr. Bullock’s place, examined the fruit and selected trees which
seemed promising, giving to each tree a number. From at least six of
these trees he took scions, propagated them, and named them Bullock
No. 1, Bullock No. 2, etc. He finally decided that only two of these, Bullock
No. 1 and Bullock No. 6, were of sufficient value to justify their further
propagation. Bullock No. 1 was named Champion and Bullock No. 6,
Willamette. Mr. Hoskins told me these names were given by the State
Horticultural Society, but I find no record of this action. He propagated and
sold a good many trees of both varieties, but more of the Willamette than
of the Champion.
“Mr. Hoskins was strongly of the opinion that the Pacific is identical with
the Willamette. I am as strongly of the opinion that they are distinct
varieties. I base my opinion, first, upon the history of the origin of the
Pacific given me by Henry Freeboro, Portland, Oregon, who introduced it;
and, second, upon what appear to me to be marked differences in the two
prunes. A number of years ago I went to Mr. Freeboro’s place when
prunes were ripe and obtained from him a supply of Pacific prunes grown
on trees propagated by him from scions taken from the original Pacific
tree. I took these prunes to Springbrook and compared them with the
Willamette grown on Mr. Hoskins’ place. I was thoroughly convinced that
the two were decidedly different in character, but Mr. Hoskins did not think
so. I noticed first a marked difference in the habits of growth of the trees.
The Pacific trees were of unusually vigorous growth and had a decided
upright tendency. The Willamette trees were very similar to the Italian in
vigor and had the rather spreading habit of growth of the Italian. The
Pacific prunes are larger in size than the Willamette and vary much more
in size. One of the most decided indications of difference is the far greater
tendency to brown-rot of the fruit of the Pacific than is the case with the
fruit of the Willamette. This has been observed when scions of the
Willamette and of the Pacific have been grafted on the same tree for the
purpose of comparison. I have never seen a well dried specimen of the
Pacific, but this may have been the fault of the men who dried the
specimens I have seen. The Willamette dries easily for a prune of its size
and gives a larger percentage of dried to fresh fruit than the Italian,
according to Mr. Hoskins.
“I believe the Willamette is well worthy of more attention in the
Willamette Valley, whereas the Pacific, on account of its extreme
susceptibility to the brown-rot, does not appear to be a safe variety here,
although when perfect it is a magnificent prune for eating fresh, and one of
the very largest known. I am told that in eastern Oregon where climatic
conditions keep out the brown-rot, the Pacific is proving one of the best
varieties for shipping fresh. At the present time the two varieties are much
confused. When the Pacific prune was introduced, Mr. Hoskins and other
recognized authorities, pronounced it the Willamette, and nurserymen
therefore obtained scions from Willamette trees and sold the propagated
trees as Pacifies, and in a more limited way the reverse was done. The
greater part of the trees supposed to be Pacifics are in fact Willamettes.”
At this Station we have the two plums under discussion, the

Pacific having been obtained from Fred E. Young, nurseryman,
Rochester, New York, and the Willamette, under the name Pacific,
from the Oregon Wholesale Nursery Company, Salem, Oregon. The
differences between the two plums in New York are essentially those
given by Mr. Williamson as distinguishing characters in Oregon.
Tree of medium size, upright-spreading, open-topped, hardy, productive;

branches ash-gray, smooth, with small, raised lenticels; branchlets above
medium in thickness, short, with short internodes, greenish-red changing
to brownish-red, covered with heavy bloom and sparingly pubescent, with
indistinct small lenticels; leaf-buds plump, of medium size and length,
obtuse, free.
Leaves obovate, two inches wide, four inches long, the oldest thick and
leathery; upper surface dark green, covered with fine hairs, with a widely
and deeply grooved midrib; lower surface pale green, pubescent; apex
acute or obtuse, base acute, margin crenate, with small dark glands;
petiole seven-eighths inch long, thick, pubescent, tinged red, with from two
to four large, globose, yellowish-green glands usually on the stalk.
Blooming season of medium length; flowers appearing after the leaves,
one and three-sixteenths inches across, white; borne on lateral spurs and
buds, singly or in pairs; pedicels five-sixteenths inch long, thick,
pubescent; calyx-tube green, campanulate, pubescent only at the base;
calyx-lobes broad, obtuse, lightly pubescent on both surfaces but heavily
pubescent along the serrate margin, reflexed; petals oval, dentate,
tapering to short, broad claws; stamens inclined to develop into
rudimentary petals; anthers yellow; filaments seven-sixteenths inch long;
pistil glabrous, equal to the stamens in length.
Fruit intermediate in time and length of ripening season; two inches by
one and five-eighths inches in size, ovate, halves equal; cavity shallow,
narrow, flaring; suture shallow, indistinct; apex bluntly pointed; color bluish,
overspread with thick bloom; dots small, brown, conspicuous, clustered
about the apex; stem thick, one-half inch long, pubescent, adhering well to
the fruit; skin thin, tough, separating readily; flesh pale golden-yellow,
juicy, firm, sweet, spicy; good; stone free, one inch by five-eighths inch in
size, flattened, irregularly broad-oval, obliquely contracted at the base,
blunt at the apex, with rough and pitted surfaces; ventral suture narrow,
with numerous deep furrows, usually blunt; dorsal suture widely and
deeply grooved.
PALATINE
Prunus domestica
This plum, scarcely known outside of two counties in New York, is
of distinctly good quality and if all accounts are true is fairly immune
to black-knot. In size and appearance the fruits are superior to many
other Reine Claude plums, with which it must be compared, so much
so that the variety is probably worth growing outside the region
where the following interesting history shows it has been cultivated
for nearly a century and a half.
Palatine, according to Mr. Washington Garlock of New York,
originated in 1760 when a family of Palatines by the name of Best
came from Germany to the United States and settled in Livingston
Manor (East Camps) now Columbia County, New York. They brought
with them plum pits which they planted and from them secured one
tree. In 1762 they moved to Schoharie County, New York, taking with
them the seedling tree. In their new home they propagated the
variety, which they named Palatine, and disseminated it so
industriously that it became thoroughly established throughout
Montgomery and Schoharie counties and attained great popularity
because of its apparent freedom from black-knot. That this popularity
is merited is attested by the fact that after one hundred and fifty
years it is still extensively grown in that vicinity.
Tree large, vigorous, spreading, dense-topped, productive; branches
thick; branchlets lightly pubescent; leaves flattened, slightly drooping,
obovate, one and five-eighths inches wide, three and one-quarter inches
long, thick, rugose; margin coarsely crenate, eglandular or with few, small
glands; petiole pubescent, glandless or with one or two small glands;
blooming season intermediate in time, short; flowers appearing after the
leaves, more than one inch across, white with yellow tinge at the apex of
the petals; borne singly; calyx-lobes thickly pubescent on both surfaces,
strongly reflexed.
Fruit intermediate in time and length of ripening season; about one and
one-half inches in diameter, roundish or roundish-oval, dull yellowish-
green becoming greenish-yellow at full maturity, mottled and indistinctly
blushed on the sunny side, overspread with thin bloom; skin thin, slightly
sour; flesh light golden-yellow, juicy, fibrous, firm, sweet, pleasant in flavor;
good to very good; stone dark colored, free or nearly so, seven-eighths
inch by one-half inch in size, oval, with thickly pitted surfaces; ventral
suture blunt or with a short, narrow wing; dorsal suture wide, shallow.
PAUL EARLY
Prunus domestica
1. N. Y. Exp. Sta. Rpt. 12:611. 1893. 2. W. N. Y. Hort. Soc. Rpt. 42:83.

1897.
Paul’s Earliest 1, 2.
This variety seems to be under test only at this Station where it

has fruited for a number of years. It is so similar to Early Rivers, a
variety of small account in America, as to be an almost worthless
addition to the list of plums. Paul Early originated with and was sent
out by J. M. Paul, North Adams, Massachusetts, about 1888.
Tree very large, vigorous, round-topped, dense, very productive;

branches covered with numerous fruit-spurs; branchlets twiggy, thickly
pubescent; leaf-buds strongly appressed; leaves flattened, obovate or
oval, two and three-eighths inches wide, four inches long; margin crenate,
with few, small, dark glands; petiole reddish, pubescent, glandless or with
one or two large glands; blooming season intermediate in time, short;
flowers appearing before the leaves, one inch across; borne in scattering
clusters, usually in pairs; pedicels very thick and pubescent; anthers
tinged red.
Fruit very early, season short; one and three-eighths inches by one and
one-quarter inches in size, roundish-oval, dark purplish-black, overspread
with thick bloom; skin tender, slightly sour; flesh greenish-yellow becoming
yellowish, tender, sweet near the surface but sour next the pit, mild; good;
stone clinging, seven-eighths inch by five-eighths inch in size, irregular-
oval, with roughened and thickly pitted surfaces; ventral suture prominent,
seldom winged; dorsal suture with a narrow, shallow groove.
PEACH
Prunus domestica
1. N. E. Farmer Dict. 266. 1797. 2. Prince Treat. Hort. 27. 1828. 3.

Prince Pom. Man. 2:106. 1832. 4. Downing Fr. Trees Am. 307. 1845. 5.
Horticulturist 1:113, 114 fig. 34, 147. 1846. 6. Poiteau Pom. Franc. 1:1846.
7. Thomas Am. Fruit Cult. 335, 336 fig. 262. 1849. 8. Horticulturist 6:132.
1851. 9. Elliott Fr. Book 422. 1854. 10. Downing Fr. Trees Am. 367. 1857.
11. Hooper W. Fr. Book 250. 1857. 12. Am. Pom. Soc. Cat. 86. 1862. 13.
Hogg Fruit Man. 375. 1866. 14. Mas Le Verger 6:73. Pl. XXXVII. 1866-73.
15. Pom. France 7: No. 7. 1871. 16. Gard. Chron. N. S. 17:144. 1882. 17.
Mich. Hort. Soc. Rpt. 466. 1883. 18. Wickson Cal. Fruits 353. 1891. 19.
Wash. Hort. Soc. Rpt. 136. 1893. 20. Guide Prat. 156, 361. 1895. 21. Cat.
Cong. Pom. France 462 fig. 1906.
Apricot Plum 5 incor. Caledonian 15, 20. Calvels Pfirschenpflaume 14,
20. D’Abricot (of Streets of Paris) 20. Duane’s Purple 5 incor, 6, 11.
Howells Large 15, 20, 21. Jenkin’s Imperial 15, 20. Large Peach 16. Large
Peach Plum 3. Nectarine 15, 20. Nectarine Rouge 21. Peach 15, 20.
Peach Plum 3, 5, 14, 20. Peach Plum 7, 8, 9, 10, 11, 12, 17. Pêche 14,
15, 20, 21. Pêche de Calvel 20. Prune Pêche 3, 7, 9, 10, 14, 18. Prune
Pêche 4, 5, 6, 20. Prune-Pêche De Calvel 14. Reine-Claude De Berger
13, 16. Rothe Nektarine 15, ?20.
Peach, the largest early plum, is not high in quality but is justly
esteemed where it can be grown for its earliness, large size and
handsome appearance. Unfortunately this variety is capricious
beyond most other plums as to climate and soils and refuses to
thrive unless its needs are very well supplied in the matter of
environment. In America it seems to find congenial soil and climate
only on the Pacific Coast, and even then refuses to bear well except
on strong, rich soils. In New York, even when grown upon soils
similar to those upon which it does well elsewhere, the fruits are few
and lacking in quality, though the trees are large, vigorous and about
all that could be desired in a good plum tree. It may be possible to
grow Peach in favorable locations in the East; in which case, a plum
of its appearance and quality, coming as early in the season as it
ripens, would make a most desirable addition to the list of plums.
From its behavior elsewhere the situation that would suit it best in
New York is a sunny exposure with a warm, rich, clay loam.
The origin of the Peach is unknown. Poiteau was unable to find
any reference to it in the Eighteenth Century European literature and
thought, therefore, that it must have been unknown to this period.
Samuel Deane mentions a Peach plum in New England in 1797. It is
doubtful, however, whether it is the Peach of this discussion, the
name having been applied indiscriminately to several varieties, the
Goliath, Nectarine and Apricot in particular. Prince, in 1832,
described a Large Peach Plum which he said “had been introduced
a few years since” but as his variety is oval and a clingstone, it is not
the same as the Peach of Poiteau, the one discussed here, this plum
being nearly round and a freestone. Judge James C. Duane of
Schenectady, New York, seems to have first imported the Peach
plum, with several others, from France, in 1820. The name of this
variety was lost during the shipment and as the invoice called for an
Apricot Plum, the names Apricot and Duane’s Plum became locally
applied to what afterwards turned out to be the Peach. C. H.
Tomlinson of Schenectady and A. J. Downing in 1846 made a careful
study of these imported plums and showed conclusively that this
Apricot or Duane’s Plum was the Peach of the French. In 1862, the
American Pomological Society added Peach to the fruit catalog list
and recommended it for the eastern and western sections of New
York.
Tree large, very vigorous, spreading, round or flat-topped, hardy,

medium in productiveness; branches stocky, smooth, dark ash-brown, with
lenticels of medium number and size; branchlets thick, with internodes one
inch long, light brown, covered with short, heavy pubescence; leaf-buds
large, of medium length, conical.
Leaves large, oval, of average thickness; upper surface dark green;
lower surface pale green, pubescent; apex obtuse, margin doubly crenate,
with small glands; petiole three-quarters inch long, thick, pubescent, with a
trace of red, usually with two, small, globose, greenish glands at the base
of the leaf.
Fruit early; thick-set, without a neck, one and seven-eighths inches in
diameter, roundish, slightly angular, halves equal; cavity deep, wide,
compressed; suture shallow, distinct; apex flattened or depressed; color
dark purplish-red, overspread with thin bloom; dots numerous, large,
conspicuous; stem eleven-sixteenths inch long, glabrous, adhering well to
the fruit; skin tough, adhering; flesh golden-yellow, medium juicy, firm,
subacid, mild; good; stone free, one inch by three-quarters inch in size,
roundish-oval, flattened, with rough and pitted surfaces, blunt at the base
and apex; ventral suture wide, prominent, often distinctly winged; dorsal
suture with a wide, deep groove.
PEARL
PEARL
Prunus domestica
1. Burbank Cat. 5. 1898. 2. Am. Gard. 21:36. 1900. 3. Waugh Plum

Cult. 118. 1901.
One can grow seedlings of some plums with considerable
certainty of getting respectable offspring—plums worth having in an
orchard—but the chances of growing a variety of superior qualities
are small indeed. It is a piece of good luck, a matter almost wholly of
luck, when, as in this case, but one parent is known, to secure as
fine a fruit as the Pearl plum. The variety now under notice is one to
be pleased with if it came as a chance out of thousands; its rich,
golden color, large size, fine form, melting flesh and sweet, luscious
flavor, place it among the best dessert plums. In the mind of the
writer and of those who have assisted in describing the varieties for
The Plums of New York, it is unsurpassed in quality by any other
plum. The tree-characters, however, do not correspond in desirability
with those of the fruits. The trees, while of medium size and
seemingly as vigorous and healthy as any, are unproductive. In none
of the several years they have been fruiting at this Station have they
borne a large crop. If elsewhere this defect does not show, the
variety becomes at once one of great value. The fruits of Pearl are
said to cure into delicious prunes—to be readily believed by one who
has eaten the fresh fruits. This variety ought to be very generally
tried by commercial plum-growers and is recommended to all who
grow fruit for pleasure.
Pearl is a recent addition to the list of plums and though its history
is well known its parentage is in doubt. In 1898, Luther Burbank
introduced the variety as a new prune grown from the seed of the
well-known Agen. The male parent is not known but from the fruit
and tree, one at once surmises that it was some variety of the Reine
Claude group, its characters being so like those of the plum named
that no one could suspect that it came from the seed of a plum so far
removed from the Reine Claude as the Agen.
Tree of medium size, vigorous, vasiform, dense-topped, hardy,

unproductive; branches ash-gray, with numerous, small, raised lenticels;
branchlets twiggy, thick, long, with long internodes, greenish-red changing
to brownish-red, very pubescent early in the season becoming less so at
maturity, with numerous, small, raised lenticels; leaf-buds large, above
medium in length, conical, appressed; leaf-scars prominent.
Leaves broadly oval, one and seven-eighths inches wide, three and
one-half inches long, thick, leathery; upper surface dark green, rugose,
covered with fine hairs, with a grooved midrib; lower surface pale green,
pubescent; apex abruptly pointed, base abrupt, margin serrate or crenate,
with small, black glands; petiole seven-eighths inch long, thick, pubescent,
tinged red, glandless or with from one to three small, globose, brownish
glands on the stalk.
Blooming season intermediate in time and length; flowers appearing
after the leaves, showy on account of their size, averaging one and five-
eighths inches across, white, with a tinge of yellow at the apex of the
petals; borne on lateral spurs and buds, usually singly; pedicels one-half
inch long, thick, strongly pubescent, greenish; calyx-tube green,
campanulate, pubescent; calyx-lobes broad, obtuse, pubescent on both
surfaces, glandular-serrate and with marginal hairs, strongly reflexed;
petals obovate or oblong, entire, tapering to short, broad claws; anthers
yellow; filaments nearly one-half inch long; pistil glabrous, shorter than the
stamens.
Fruit intermediate in time and length of ripening season; one and three-
quarters inches by one and one-half inches in size, roundish-oval,
compressed, halves unequal; cavity shallow, narrow, abrupt; suture a line;
apex depressed; color golden-yellow, obscurely striped and splashed with
dull green, mottled, overspread with thin bloom; dots numerous, small,
whitish, inconspicuous, clustered about the apex; stem thick, three-
quarters inch long, thickly pubescent, adhering well to the fruit; skin tough,
separating readily; flesh deep yellow, juicy, a little coarse and fibrous, firm
but tender, very sweet, with a pleasant, mild flavor, aromatic; very good to
best; stone clinging, one inch by five-eighths inch in size, long-oval,
slightly necked at the base, bluntly acute at the apex, with rough surfaces;
ventral suture broad, blunt; dorsal suture with a wide, shallow groove.
PETERS

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Molecular Imaging and Targeted Therapy: Radiopharmaceuticals and Clinical Applications, 2nd 2nd Edition Shankar Vallabhajosula

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Molecular Imaging and Targeted

Therapy: Radiopharmaceuticals and

Receptive Music Therapy Techniques Clinical

Treating Cancer with Immunotherapy and Targeted Therapy

Medical Image Synthesis: Methods and Clinical

Monte Carlo Techniques in Radiation Therapy:

Implant Therapy Clinical Approaches and Evidence of

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ISBN 978-3-031-23203-9 ISBN 978-3-031-23205-3 (eBook)

© Springer Nature Switzerland AG 2023

Molecular imaging is a term that is now used frequently to describe much

Molecular Imaging: Radiopharmaceuticals for PET and SPECT is not a

New York Presbyterian Hospital Stanley J. Goldsmith, MD

I am delighted to provide a “foreword” to this second edition of Molecular

Department of Radiology Richard L. Wahl, MD, FACR

tions of molecular imaging, it is my way of paying tribute to those extraordi-

New York, NY, USA Shankar Vallabhajosula, PhD

The primary goal of targeted radionuclide therapy (TRT) is to fight cancer

gratitude to my research staff, specifically, Drs. Paresh Kothari, Anastasia

New York, NY, USA Shankar Vallabhajosula, PhD

1 Molecular Imaging and Targeted Radionuclide

2.7.4 Quantum Atom�������������������������������������������������������������� 33

6 Chemistry: Basic Principles������������������������������������������������������������ 87

8 Production of Radionuclides ���������������������������������������������������������� 147

14.4.2 Radiopharmaceuticals: Biochemical Basis of

17 Radiopharmaceuticals for Therapy������������������������������������������������ 461

20.3 Radiolabeling of Peptides ������������������������������������������������������ 593

22.3 Radionuclides for Imaging and Therapy�������������������������������� 666

Shankar Vallabhajosula attended high school in the small town of Bobbili,

We really are not treating individuals yet; we are

1.1 Nuclear Medicine

Nuclear medicine can be defined quite simply as

© Springer Nature Switzerland AG 2023 1

MI is also likely to lead to a further blurring of • MI quantification is the determination of

Table 1.1 Noninvasive in vivo molecular imaging modalities

To identify foci of epileptic seizures

Table 1.3 Radiopharmaceuticals approved for therapy

Screening Diagnosis Treatment Follow up

1) Radiodiagnosis and Radiotherapy

Table 1.4 Radiopharmaceuticals under clinical development in phase II/III trials

1.5 Summary of nuclear medicine. Philadelphia: WB Saunders;

© Springer Nature Switzerland AG 2023 21

elementaire de chemie, published in 1789, listed

Tree small, spreading, low, dense-topped, hardy, often unproductive;

In Europe Orleans is one of the most renowned of the plums

Oullins came to America with the best of recommendations from

1. U. S. D. A. Rpt. 292. 1893. 2. Am. Pom. Soc. Rpt. 150. 1895. 3.

No part of America is so well adapted to plum culture as the

“About 1875 Jesse Bullock of Oswego, Oregon, sent to Germany for

At this Station we have the two plums under discussion, the

Tree of medium size, upright-spreading, open-topped, hardy, productive;

1. N. Y. Exp. Sta. Rpt. 12:611. 1893. 2. W. N. Y. Hort. Soc. Rpt. 42:83.

This variety seems to be under test only at this Station where it

Tree very large, vigorous, round-topped, dense, very productive;

1. N. E. Farmer Dict. 266. 1797. 2. Prince Treat. Hort. 27. 1828. 3.

Tree large, very vigorous, spreading, round or flat-topped, hardy,

New York, NY, USA Shankar Vallabhajosula, PhD

New York, NY, USA Shankar Vallabhajosula, PhD

1 Molecular Imaging and Targeted Radionuclide

2.7.4 Quantum Atom�� 33

6 Chemistry: Basic Principles�� 87

8 Production of Radionuclides �� 147

14.4.2 Radiopharmaceuticals: Biochemical Basis of

17 Radiopharmaceuticals for Therapy�� 461

20.3 Radiolabeling of Peptides �� 593

22.3 Radionuclides for Imaging and Therapy�� 666

1.1 Nuclear Medicine

1.5 Summary of nuclear medicine. Philadelphia: WB Saunders;