Radiopharmaceuticals for Therapy - Springer Link

Radiopharmaceuticals for Therapy

F.F. (Russ) Knapp • Ashutosh Dash

Radiopharmaceuticals for Therapy

F.F. (Russ) Knapp Nuclear Security and Isotope Division Oak Ridge National Laboratory OAK RIDGE USA

Ashutosh Dash Isotope Production and Applications Division Bhabha Atomic Research Centre Mumbai India

ISBN 978-81-322-2606-2 ISBN 978-81-322-2607-9 DOI 10.1007/978-81-322-2607-9

(eBook)

Library of Congress Control Number: 2015960843 Springer New Delhi Heidelberg New York Dordrecht London © Springer India 2016 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 use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. 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. Printed on acid-free paper Springer (India) Pvt. Ltd. is part of Springer Science+Business Media (www.springer.com)

The authors dedicate this book to their families, mentors, and colleagues who have so strongly affected their professional careers. Russ Knapp offers his dedication to his parents, who inspired and supported a strong interest in science at an early age; to his wife and best friend Toni, who for over 50 years encouraged and, even in many cases, tolerated his professional work; and to their children Michael and Gina, who have made his more important personal life such a joy. He also expresses his personal thanks to his deceased important friend, Mr. A. P. Callahan, who as a mentor and colleague had taught him so much about science and life. Ashutosh Dash gives his dedication to his wife Sarita and son Shaswat, who stood by him through thick and thin, lifted him up when he was low, pushed him forward at difficult times, and never complained at all when times were difficult. Through lonely and difficult times, they gave him strength and encouraged him. He also expresses his personal thanks to Dr. Russ Knapp for believing, encouraging, understanding, and tolerating through the whole process of completing this book.

Foreword

The use of radioactivity for treatment of disease is more than a century old and began with the use of naturally occurring radium-226 in the early part of the twentieth century. However, the field of radionuclide therapy (RNT) had not progressed as rapidly as probably anticipated due to the early failure due to absence of suitable targeting mechanisms. The use of artificially produced phosphorus-32 for the treatment of polycythemia vera beginning in the 1930s was a positive step which had stimulated the growth of this field. The major breakthrough for RNT, however, was the use of iodine-131 for the treatment of thyroid cancer which began in 1946. The uptake of radioactive iodide anions is governed by a well-defined mechanism involving the sodium iodide symporter protein and is the most basic and finest example of molecular nuclear medicine. Normal thyroid tissue takes up around 30 % of ingested iodine, which represents the highest targeting that a drug can achieve. Iodine-131 continues to be widely used post surgically for the ablation of remnant cancer cells. Although a variety of radiopharmaceuticals were subsequently introduced in later years for treatment of some types of cancer and for palliation of pain due to bone metastases, widespread/routine use has not yet gained broad acceptability. Generally, the majority of the patients who have undergone unsuccessful treatment by alternative nonradioactive strategies who have few other options for success are often referred for nuclear medicine RNT as a last resort and mainly for palliative therapy. In fact, none of the other therapeutic radiopharmaceuticals introduced in the last century have been anywhere nearly successful like the use of iodine-131 for the treatment of thyroid cancer. In this regard, introduction of peptide receptor radionuclide therapy (PRRNT) in the beginning of the current millennium for the treatment of neuroendocrine tumors (NETs) with beta-emitting is an important seminal exception. PRRNT utilizes low molecular weight radiolabeled peptides targeting to specific cell surface receptors which are very often upregulated on cancer cells. Although several radioisotopes have been identified that are used for PRRNT, lutetium-177 and yttrium-90 are two key examples as radionuclides used for both PRRNT and radioactive antibody targeting. Currently, PRRNT using somatostatin analog peptides is the most efficacious mode of therapy for the treatment of inoperable NETs. However, NETs are tumors with relatively low incidence, and hence the total number of patients benefitted is still very small. Another important developing theme is the use of alpha-emitting radioisotopes for therapy, and the commercialization and vii

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routine clinical introduction of the Xofigo® (radium-223 chloride) for the treatment of castration-resistant prostate cancer is an important advance for the therapeutic arena. However, the real success of PRRNT, as an example, will be demonstrated when suitable radiopharmaceuticals are developed for the treatment for major cancer entities, and success in this direction is already on the horizon. The pharmacophore, N-acetyl aspartyl glutamate (NAAG), radiolabeled with 68 Ga, for instance, is providing excellent PET images of patients presenting with prostate cancer. Adenocarcinoma of the prostate gland overexpresses prostate-specific membrane antigen (PSMA) which is targeted by NAAG. Because this is a small peptide, the radioactivity not attached to the targeted cancer cells is rapidly excreted, thereby providing excellent PET images of the cancer-affected areas. Lutetium-177-labeled NAAG is also under evaluation for the treatment of prostate cancer, and the male patient population who can benefit from this PET technology is very large and is expected to dramatically change the trajectory of targeted therapy. Growth in the development of therapeutic radiopharmaceuticals is linked to advances in many related disciplines, and molecular biology identifies suitable targets for different types of cancer. An in-depth understanding of the biochemical reactions occurring within the body is important to provide information which will help identify new targets. Once suitable target-seeking molecules are identified, subsequent detailed research is required to develop a successful therapeutic radiopharmaceutical. These efforts include an evaluation for modification of the target-seeking pharmacophore to provide suitable radiolabeling without compromising the affinity to the target. In addition, both in vitro and in vivo biological studies are required to demonstrate the targeting property, and preclinical evaluation and finally the demonstration of the clinical efficacy must be established. A major goal which presents these challenges is the subsequent use in humans. Current regulations in most countries mandate that a radiopharmaceutical undergoes the same phase 0, I, II, and III studies before its market introduction as a product. Compliance with these regulatory requirements is difficult for a commercial radiopharmaceutical manufacturer to justify, since the modest market volume for therapeutic radiopharmaceuticals will often not qualify the high investment required for a clinical trial. The usual short shelf lives of radiopharmaceuticals do not allow large-scale manufacturing, and it is difficult for patent holders to overcome the competition of use of generic radiopharmaceutical products. Hence, most discoveries in the therapeutic radiopharmaceutical arena are not used to the most effective extent for the benefit of mankind. Nevertheless, the scientists working in this area put forth extensive efforts to develop new therapeutic radiopharmaceuticals. There are many young colleagues who wish to work in the fascinating multidisciplinary field of therapeutic radiopharmaceuticals, which, by nature, requires broad knowledge in many fields, which includes radioisotope production, chemistry, radiochemistry, and biology and physiology. There is extensive literature available on therapeutic radiopharmaceuticals; however, a primary source which will provide basic knowledge is highly useful, not only for new investigators in this area but also for those scientists, physicians, and

Foreword

Foreword

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other professionals already working in the field of nuclear medicine. For these reasons this book on “radiopharmaceuticals for therapy” authored by Prof. F. F. (Russ) Knapp and Dr. A. Dash is expected to fill an important niche in the literature. The 17 chapters span all key aspects describing the development and use of therapeutic radiopharmaceuticals. The expertise and extensive experience of these authors are reflected in the appropriate selection of chapters and their contents. This book will be highly useful to scientists and nuclear medicine physicians working in this fascinating field, and I am honored to have been given the opportunity to provide the Foreword to Therapeutic Radiopharmaceuticals. Cochin, India

M.R.A. Pillai, PhD, DSc

Acknowledgments

The authors extend their sincere appreciation to Dr. M. R. A. Pillai, Ph.D., D.Sc., for his vision in conceiving the important need for a book on therapeutic radiopharmaceuticals and for providing the Foreword. He had initially recommended this book to Springer Verlag and had encouraged the authors to move forward. The authors also thank their families for their patience and their colleagues who have helped in many different ways and who had provided information and insights which encouraged the authors. Special thanks are also extended to Mr. Mark Dickey, a senior member of the ORNL technical library staff, for his enthusiastic assistance in identifying and obtaining reference and reprint materials.

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Contents

Part I

Radiopharmaceuticals

1

Introduction: Radiopharmaceuticals Play an Important Role in Both Diagnostic and Therapeutic Nuclear Medicine . . . . . . 1.1 Introduction: Use of Radioisotopes in Nuclear Medicine . . . 1.2 Key Examples of Nuclear Medicine . . . . . . . . . . . . . . . . . . . . 1.2.1 Nuclear Medicine Imaging . . . . . . . . . . . . . . . . . . . . . 1.2.2 Molecular Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.3 In Vivo Function Tests. . . . . . . . . . . . . . . . . . . . . . . . . 1.2.4 Nuclear Medicine Therapy . . . . . . . . . . . . . . . . . . . . . 1.3 Radiopharmaceuticals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3.1 Diagnostic Radiopharmaceuticals . . . . . . . . . . . . . . . . 1.3.2 Nuclear Medicine Imaging . . . . . . . . . . . . . . . . . . . . . 1.4 Therapeutic Radiopharmaceuticals . . . . . . . . . . . . . . . . . . . . 1.4.1 Traditional Applications of Therapeutic Radiopharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . 1.4.2 Current and New Therapeutic Applications . . . . . . . . 1.5 Historical Timeline of Nuclear Medicine . . . . . . . . . . . . . . . . 1.6 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Therapeutic Radionuclides Decay with Particle Emission for Therapeutic Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Criteria for Selection of Therapeutic Radionuclides . . . . . . . 2.2.1 Particle Emission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2 Tissue Treatment Morphology . . . . . . . . . . . . . . . . . . 2.2.3 Radionuclide Half-Life . . . . . . . . . . . . . . . . . . . . . . . . 2.2.4 Radionuclide Decay Products . . . . . . . . . . . . . . . . . . . 2.2.5 Radionuclide Purity . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.6 Gamma Emissions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.7 Radiolabeling Chemistry . . . . . . . . . . . . . . . . . . . . . . . 2.2.8 Economic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Beta-Particle-Emitting Radionuclides . . . . . . . . . . . . . . . . . . 2.4 Alpha-Particle-Emitting Radionuclides . . . . . . . . . . . . . . . . . 2.5 Low-Energy Electron Emitters . . . . . . . . . . . . . . . . . . . . . . . . 2.6 Radionuclide Production . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3 3 4 4 4 6 6 6 8 9 13 14 15 17 20 21 25 25 27 27 28 28 28 28 28 29 29 29 29 30 30

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3

4

2.6.1 Targets for Irradiation . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.2 Production of Therapeutic Radionuclides . . . . . . . . . . 2.6.3 Auger Electron-Emitting Radionuclides . . . . . . . . . . . 2.6.4 Alpha-Particle-Emitting Radionuclides . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

32 33 33 33 34

Alpha Radionuclide Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Alpha Particles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1 Energy Dissipation of Alpha Particles in a Medium . . 3.2.2 Linear Energy Transfer (LET). . . . . . . . . . . . . . . . . . . 3.2.3 Relative Biological Effectiveness (RBE) . . . . . . . . . . 3.2.4 Interaction of Alpha Particles in a Biological System . . . . . . . . . . . . . . . . . . . . . . . . 3.2.5 Basis of Alpha Radionuclide Therapy. . . . . . . . . . . . . 3.2.6 Dosimetry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Alpha-Particle-Emitting Radionuclides for Radiotherapy . . . 3.3.1 Astatine-211 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.2 Terbium-149 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.3 Actinium-225 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.4 Bismuth-213 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.5 Bismuth-212 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.6 Radium-223 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.7 Radium-224 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.8 Thorium-227 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 Summary: Future Prospects of Alpha Radionuclide Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

37 37 38 38 38 39

Auger Electron-Based Radionuclide Therapy . . . . . . . . . . . . . . 4.1 Introduction: Cancer Treatment with Radioisotopes . . . . . . . 4.2 Particle Emission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3 The Auger Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4 Cell Killing with Auger Electron Emitters . . . . . . . . . . . . . . . 4.5 The Importance of Auger Electron-Emitting Radionuclides for Cancer Therapy. . . . . . . . . . . . . . . . . . . . . 4.6 Key Auger Emitters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6.1 Iodine-125 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6.2 Platinum-195m . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6.3 Rhodium-103m . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6.4 Holmium-161 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7 Dosimetry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7.1 Electron Transport Evaluation and Dosimetry Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7.2 Auger Electron Spectra . . . . . . . . . . . . . . . . . . . . . . . . 4.7.3 Energy Loss by Auger Electrons . . . . . . . . . . . . . . . . . 4.7.4 Dosimetry Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

40 40 41 42 42 47 47 50 51 51 52 52 53 53 57 57 57 58 58 60 61 61 61 62 63 63 64 64 64 65 65 65

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Part II

Production, Processing and Availability of Therapeutic Radioisotopes

5

Reactor-Produced Therapeutic Radionuclides . . . . . . . . . . . . . 5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 Reactor Production of Radionuclides . . . . . . . . . . . . . . . . . . . 5.3 Calculation of Production Yield . . . . . . . . . . . . . . . . . . . . . . . 5.4 Direct (n, γ) Activation (Radiative Route) . . . . . . . . . . . . . . . 5.5 Neutron Activation Followed by β− Decay (n, γ → β−) . . . . . . 5.6 The (n, p) Production Reaction . . . . . . . . . . . . . . . . . . . . . . . 5.7 Beta-Particle-Emitting Radionuclides . . . . . . . . . . . . . . . . . . 5.7.1 Arsenic-77 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7.2 Copper-67 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7.3 Erbium-169 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7.4 Gold-198 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7.5 Gold-199 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7.6 Holmium-166 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7.7 Iodine-131 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7.8 Lutetium-177 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7.9 Phosphorous-32 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7.10 Praseodymium-143 . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7.11 Promethium-149 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7.12 Rhenium-186 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7.13 Rhenium-188 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7.14 Rhodium-105 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7.15 Samarium-153 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7.16 Scandium-47 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7.17 Silver-111 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7.18 Strontium-89 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7.19 Terbium-161 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7.20 Thulium-170 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7.21 Tin-117 m . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7.22 Ytterbium-175 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7.23 Yttrium-90 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.8 Auger Electron-Emitting Radioisotopes. . . . . . . . . . . . . . . . . 5.8.1 Iodine-125 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.9 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

71 71 71 71 73 73 74 74 74 76 76 77 77 77 79 81 84 87 87 88 89 90 91 92 93 93 96 98 99 99 100 101 102 103 103

6

Accelerator-Produced Therapeutic Radionuclides . . . . . . . . . . 6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2 Accelerators for Radionuclide Production . . . . . . . . . . . . . . . 6.2.1 Calculation of Production Yield . . . . . . . . . . . . . . . . . 6.2.2 Saturation Factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3 Key Accelerator-Produced Therapeutic Radionuclides . . . . . 6.3.1 Actinum-225 and Radium-223 . . . . . . . . . . . . . . . . . . 6.3.2 Astatine-211 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

115 115 115 116 117 118 118 119

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6.3.3 Copper-67 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.4 Gallium-67 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.5 Indium-111 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.6 Rhenium-186 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4 Tin-117 m . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

8

Radionuclide Generator Systems Represent Convenient Production Systems to Provide Therapeutic Radionuclides . . . 7.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2 Production of Parent Radionuclides . . . . . . . . . . . . . . . . . . . . 7.3 Decay and In-Growth Principles . . . . . . . . . . . . . . . . . . . . . . 7.4 Radiochemical Separation of Therapeutic Radionuclides . . . 7.5 Methods for Parent–Daughter Separation . . . . . . . . . . . . . . . 7.5.1 Ion Exchange Column Chromatography . . . . . . . . . . . 7.5.2 Solvent Extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5.3 Distillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5.4 Precipitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5.5 Extraction Chromatography . . . . . . . . . . . . . . . . . . . . 7.5.6 Solid-Phase Column Extraction . . . . . . . . . . . . . . . . . 7.5.7 Electrochemical Separation . . . . . . . . . . . . . . . . . . . . . 7.6 Key Examples of Therapeutic Radioisotopes Available from Radionuclide Generator Systems . . . . . . . . . . . . . . . . . 7.6.1 Radionuclide Generator Systems Which Provide Beta-Emitting Radioisotopes . . . . . . . 7.6.2 Radionuclide Generator Systems Which Provide Alpha-Emitting Radioisotopes . . . . . . . . . . . 7.6.3 Radionuclide Generator Systems Which Provide Auger Electron-Emitting Radioisotopes . . . . . . . . . . . 7.6.4 Ruthenium-103/Rhodium-103m Generator . . . . . . . . 7.7 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Availability of Alpha-Emitting Radioisotopes by Reactor and Accelerator Production and via Decay of Naturally Occurring Parents . . . . . . . . . . . . . . . . . . . . 8.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2 Production and Processing of Alpha Emitters in the Thorium Series . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2.1 Actinium-225 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2.2 Actinium-227 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2.3 Bismuth-212 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2.4 Radium-223 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2.5 Radium-224 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2.6 Radium-226 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2.7 Thorium-226 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2.8 Thorium-227 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

121 124 125 125 126 126 126 131 131 132 133 136 137 137 138 139 140 140 140 141 141 142 146 149 150 151 152

159 159 159 159 161 161 163 164 165 165 165 165 165

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Part III

9

Therapeutic Radiopharmaceuticals for Cancer Therapy

Radioimmunotherapy (RIT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2 Identification of Cell Surface Markers . . . . . . . . . . . . . . . . . . 9.3 Antibodies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.3.1 B Cells and T Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.3.2 Polyclonal and Monoclonal Antibodies . . . . . . . . . . . 9.3.3 Monoclonal Antibodies (mAbs) . . . . . . . . . . . . . . . . . 9.4 Antigens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.4.1 Affinity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.4.2 Avidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.4.3 Specificity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.4.4 Cross-Reactivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.5 Lymphomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.6 Radioimmunotherapy (RIT) . . . . . . . . . . . . . . . . . . . . . . . . . . 9.6.1 Advantages of RIT . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.6.2 Selection of Target Antigen . . . . . . . . . . . . . . . . . . . . . 9.6.3 Antibody Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.6.4 Selection of a Radionuclide for RIT . . . . . . . . . . . . . . 9.7 Treatment of Non-Hodgkin’s B-Cell Lymphoma . . . . . . . . . . 9.8 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

169 169 169 170 170 171 171 173 175 175 175 175 175 176 177 177 178 179 179 181 183

10 Peptide Receptor Radionuclide Therapy (PRRT) . . . . . . . . . . . 10.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2 Amino Acids, Peptides, and Proteins . . . . . . . . . . . . . . . . . . . 10.2.1 Amino Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2.2 Peptides and Proteins . . . . . . . . . . . . . . . . . . . . . . . . . 10.2.3 Regulatory Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2.4 Peptides as Therapeutic Vectors . . . . . . . . . . . . . . . . . 10.2.5 Advantages of Peptides for Therapy . . . . . . . . . . . . . . 10.2.6 Limitations of Peptides for Therapy . . . . . . . . . . . . . . 10.2.7 Development of Peptide-Based Radiopharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . 10.2.8 Preparation of Radiolabeled Peptides . . . . . . . . . . . . . 10.2.9 Radionuclides for Receptor-Mediated Peptide Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.3 Peptide Receptor Radionuclide Therapy (PRRT) for Neuroendocrine Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . 10.3.1 PRRT Studies with [111In-DTPA]octreotide . . . . . . . . 10.3.2 Somatostatin Receptor Radiotherapy with [90Y-DOTA0,Tyr3]octreotide (90Y-DOTATOC) and [90Y-DOTA0,Tyr3]octreotate (DOTATATE). . . . . . 10.3.3 Somatostatin Receptor Radiotherapy with [177Lu-DOTA0,Tyr3]octreotate (DOTATATE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

185 185 185 185 186 187 188 189 189 190 190 191 193 194

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10.4 10.5 10.6 10.7 10.8 10.9

Bombesin Peptide Analogs. . . . . . . . . . . . . . . . . . . . . . . . . . . Vasoactive Intestinal Peptide (VIP) Analogs . . . . . . . . . . . . . Cholecystokinin (CCK)/Gastrin Peptide Analogs . . . . . . . . . Neurotensin Peptide Analogs . . . . . . . . . . . . . . . . . . . . . . . . . Glucagon-Like Peptide (GLP) Analogs . . . . . . . . . . . . . . . . . RGD Peptides for Targeting Integrin αvβ3 Expression . . . . . . 10.9.1 Angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.9.2 RGD Peptide-Based Radiotherapeutics Targeting Integrin αvβ3 . . . . . . . . . 10.10 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Therapeutic Radiopharmaceuticals for Treatment of Primary and Metastatic Hepatic Cancer . . . . . . . . . . . . . . . . 11.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.2 Direct Intratumor Implantation. . . . . . . . . . . . . . . . . . . . . . . . 11.3 Radioimmunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.4 Trans-arterial Radioisotope Therapy (TART). . . . . . . . . . . . . 11.5 Selection of Radionuclide for TART . . . . . . . . . . . . . . . . . . . 11.6 Selection of Microspheres . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.7 Common Microsphere Materials . . . . . . . . . . . . . . . . . . . . . . 11.8 Radionuclide Used for Treatment of HCC . . . . . . . . . . . . . . . 11.9 Radioisotopes for TART . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.9.1 Iodine-131-Lipiodol . . . . . . . . . . . . . . . . . . . . . . . . . . 11.9.2 90Y-Labeled Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.9.3 Rhenium-188 Lipiodol/Microspheres . . . . . . . . . . . . . 11.9.4 Holmium-166 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.10 Comparison of Properties of Radioisotopes Used for TART . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.11 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Part IV

197 198 199 199 199 200 200 202 202 203 209 209 210 211 211 212 212 212 213 213 213 214 215 217 217 218 219

Therapeutic Radiopharmaceuticals for Treatment of Chronic Disease

12 Therapeutic Radiopharmaceuticals for Bone Pain Palliation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.2 Treatment of Metastatic Bone Pain with Therapeutic Radioisotopes . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.3 Commercially Available Beta-Particle-Emitting Approved Agents for Bone Pain Palliation . . . . . . . . . . . . . . 12.3.1 Rhenium-186 HEDP . . . . . . . . . . . . . . . . . . . . . . . . . . 12.3.2 Samarium-153 EDTMP (“Quadramet®”). . . . . . . . . . 12.3.3 Stronium-89 Chloride . . . . . . . . . . . . . . . . . . . . . . . . . 12.4 Examples of Bone Pain Palliation Agents under Development and in Clinical Trials . . . . . . . . . . . . . . . . . . . . 12.4.1 Iodine-131 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.4.2 Phosphorus-32 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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12.4.3 Yttrium-90-Labeled Citrate and EDTMP . . . . . . . . . . 12.5 New Radiolabeled Agents Being Developed for Bone Pain Palliation . . . . . . . . . . . . . . . . . . . . 12.5.1 Rhenium-188 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.5.2 Lutetium-177 Diphosphonates . . . . . . . . . . . . . . . . . . 12.5.3 Samarium-153 and Holmium-166 . . . . . . . . . . . . . . . . 12.5.4 Thulium-170 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.5.5 Ytterbium-175 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.6 Bone Pain Palliation Agents Using Radioisotopes Which Have Minimal Soft Tissue Penetration . . . . . . . . . . . . 12.6.1 Tin-117m (117mSn) DTPA. . . . . . . . . . . . . . . . . . . . . . . 12.6.2 Radium-223 Chloride . . . . . . . . . . . . . . . . . . . . . . . . . 12.7 Soft Tissue Penetration and Efficacy of Radioisotopes for Bone Pain Palliation . . . . . . . . 12.8 The Possibility of Therapeutic Effects on Bone Metastases with High Activity Doses of Agents Used for Bone Pain Palliation . . . . . . . . . . . . . . . . . . . . . . . . 12.9 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

231

245 246 246

13 Locoregional Radionuclide Therapy for Nonmelanoma Skin Cancer (NMSC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.2 Radioisotopes for Treatment of Skin Cancer . . . . . . . . . . . . . 13.3 Strategies for Treatment on NMSC . . . . . . . . . . . . . . . . . . . . 13.4 Topical Use of Radioisotopes for NMSC Therapy . . . . . . . . . 13.4.1 Holmium-166 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.4.2 Phosphorus-32 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.4.3 Rhenium-188 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.4.4 Yttirum-90 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.5 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

253 253 253 253 254 255 256 258 260 263 264

14 Radionuclide Synovectomy: Treatment of Inflammation of the Synovial Joints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.1.1 Advantages of Radiosynovectomy . . . . . . . . . . . . . . . 14.1.2 Selection of Radionuclides . . . . . . . . . . . . . . . . . . . . . 14.2 Dosimetry and Dose Rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.3 Key Therapeutic Radioisotopes Used for Synovectomy . . . . 14.3.1 Dysprosium-165 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.3.2 Erbium-169 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.3.3 Gold-198 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.3.4 Holmium-166 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.3.5 Lutetium-177. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.3.6 Phosphorus-32. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.3.7 Rhenium-186. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.3.8 Rhenium-188. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.3.9 Samarium-153 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

265 265 265 266 269 270 270 270 270 270 271 271 272 272 272

231 231 236 237 237 238 239 240 242 244

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14.3.10 Yttrium-90. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.4 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Inhibition of Arterial Restenosis Following Balloon Angioplasty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.2 Radioisotopes for Intravascular Irradiation (IVRT) of Coronary Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.2.1 Solid Radioactive Sources for Vessel Irradiation . . . . 15.2.2 Dosimetry of Vessel Wall Irradiation Is an Important Issue . . . . . . . . . . . . . . . . . . . . . . . . . . 15.2.3 Radioactive Liquid-Filled Balloons for Vessel Wall Irradiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.3 Examples of Clinical Trials with 188Re-Filled Balloon Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.3.1 The SPARE Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.3.2 The DRAIN Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.4 Radioisotopes for IVRT of the Peripheral Vessels . . . . . . . . . 15.5 Use of 188Re Balloons for IVRT of the Peripheral Vessels . . . 15.6 Other Therapeutic Applications of 188Re-Liquid-Filled Balloons . . . . . . . . . . . . . . . . . . . . . . . 15.7 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Part V

273 273 274 279 279 280 280 280 283 285 286 286 287 288 288 288 289

Looking Ahead: New Radiopharmaceutical Strategies for Therapeutic Applications

16 Moving Forward: Expected Opportunities for the Development of New Therapeutic Agents Based on Nanotechnologies. . . . . . 16.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.2 Therapeutic Strategies Based on Nanotargeting . . . . . . . . . . . 16.3 Selection of Radionuclides for NP Therapy . . . . . . . . . . . . . . 16.3.1 Passive NP Targeting . . . . . . . . . . . . . . . . . . . . . . . . . . 16.3.2 Active NP Targeting . . . . . . . . . . . . . . . . . . . . . . . . . . 16.4 Ligand Conjugation Strategies . . . . . . . . . . . . . . . . . . . . . . . . 16.4.1 Pre-conjugation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.4.2 Post-formulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.4.3 Bioconjugation Based on Covalent Approaches . . . . . 16.4.4 Bioconjugation Based on Non-covalent Approaches. . . 16.4.5 Influence of the Architecture of Actively Targeted NPs . . . . . . . . . . . . . . . . . . . . . . . . 16.5 NP Targeting Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.5.1 Monoclonal Antibodies . . . . . . . . . . . . . . . . . . . . . . . . 16.5.2 Antibody Fragments . . . . . . . . . . . . . . . . . . . . . . . . . . 16.5.3 Other Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.5.4 Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

295 295 296 297 298 299 300 301 301 301 302 302 302 303 304 305 305

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16.5.5 Aptamers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.5.6 Vitamins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.5.7 Specific Ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.6 Radiolabeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.7 Nanoparticles for Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . 16.7.1 Particle Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.7.2 Composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.7.3 Surface and Ligand Charge . . . . . . . . . . . . . . . . . . 16.7.4 Surface Hydrophobicity . . . . . . . . . . . . . . . . . . . . . 16.7.5 Mechanical Properties . . . . . . . . . . . . . . . . . . . . . . 16.7.6 NP Surface Coating . . . . . . . . . . . . . . . . . . . . . . . . 16.8 Biomedically Important NPs . . . . . . . . . . . . . . . . . . . . . . . . 16.8.1 Organic NPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.8.2 Liposomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.8.3 Dendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.8.4 Micelles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.9 Inorganic NPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.9.1 Gold Nanoparticles. . . . . . . . . . . . . . . . . . . . . . . . . 16.10 Quantum Dots (QDs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.11 Iron Oxide Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.12 Silica Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.13 Summary, Challenges, and Future Directions . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Translation of Radiopharmaceuticals from Bench to Bedside: Regulatory and Manufacturing Issues . . . . . . . . . . 17.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.2 The Radiopharmaceutical Manufacturing Process Elements. . . . . . . . . . . . . . . . . . . . . 17.2.1 Quality Assurance (QA). . . . . . . . . . . . . . . . . . . . . 17.2.2 Good Manufacturing Practices (GMP) for Radiopharmaceuticals . . . . . . . . . . . . . . . . . . . . . . 17.2.3 Quality Control (QC) . . . . . . . . . . . . . . . . . . . . . . . 17.3 Personnel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.4 Active Pharmaceutical Ingredient (API) . . . . . . . . . . . . . . . 17.5 Radionuclide Production . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.6 Radiopharmaceutical Manufacture . . . . . . . . . . . . . . . . . . . 17.6.1 Sterile Production . . . . . . . . . . . . . . . . . . . . . . . . . . 17.6.2 Terminal Sterilization . . . . . . . . . . . . . . . . . . . . . . . 17.6.3 Aseptic Sterilization . . . . . . . . . . . . . . . . . . . . . . . . 17.6.4 Sanitation and Hygiene . . . . . . . . . . . . . . . . . . . . . 17.7 Documentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.7.1 Site Master File . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.7.2 Drug Master Files (DMF) for Individual Batches . . . . . . . . . . . . . . . . . . . . . . . . . 17.7.3 Validation Master File . . . . . . . . . . . . . . . . . . . . . . 17.7.4 Specifications for Materials . . . . . . . . . . . . . . . . . .

306 306 307 307 308 308 308 308 308 309 309 310 310 310 311 312 312 312 313 314 315 316 317 323 323 323 323 324 325 326 326 327 327 327 328 328 329 330 330 331 331 331

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17.8 Container Labeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.9 Centralized Radiopharmacy (CRPh) Concept . . . . . . . . . . . 17.10 Infusion of Automation in Radiopharmaceutical Production . . . . . . . . . . . . . . . . . . . . . 17.11 Constraints in the Transition of Radiopharmaceuticals from Bench to Bedside . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.12 Barriers to Success . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.13 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

332 332

334 337 342 342

Glossary: Definitions and Terminology . . . . . . . . . . . . . . . . . . . . . .

345

333

Abbreviations

ADME AE BFCA CD Ci C-K CT DES DNA DOTA DTPA EC HAMA HCC HDR HEHA HER-2 HSA HSA IC IT IVRT LATO LER LET LSA MABG mCi MDP MeV MIBG MIBI MRI MTB NIS NMSC

Adsorption, distribution, metabolism, and excretion Auger electron Bifunctional chelating agent Cluster of differentiation Curie Coster–Kroenig Computed tomography Drug eluting stent Deoxyribonucleic acid 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid Diethylenetriamine pentaacetic acid Electron capture Human automouse antibody Hepatocellular carcinoma High-dose radiation 1, 4, 7, 10, 13, 16-hexaazacyclohexane-N, N′, N″, Nು, Nಿಿಿಿ, Nಿಿಿಿಿ-hexanoic acid Receptor tyrosine-protein kinase erbB-2 (CD340) High specific activity Human serum albumin Internal conversion Isomeric transition Intravascular radiation therapy Late acute thrombotic occlusion Lower extremity revascularization Linear energy transfer Low specific activity Meta-astatobenzyl guanidine Millicurie Methylene diphosphonate Mega (million) electron volts Metaiodobenzylguanidine Methoxy isobutyl nitrile (ligand) Magnetic resonance imaging Maximal tolerated dose Sodium iodide transporter Nonmelanoma skin cancer xxiii

Abbreviations

xxiv

PET PLA PPRT RAD RAIT RBE RDG RNT SA σ SIRC SIRT SKID SPECT Super-C–K TACE TARE TART TATE TOC US

Positron emission tomography Polylactic acid Peptide receptor radionuclide therapy Radiation adsorbed dose Radioimmunotherapy Relative biological effectiveness Arginine–glycine–aspartate acid (tripeptide sequence) Radionuclide therapy Specific activity Sigma, neutron cross section, cm24 Surgically created resection cavity Selective internal radiation therapy Severe combined immunodeficiency Single-photon emission computerized tomography Super Coster–Kroenig Trans-arterial chemoembolization Trans-arterial radioembolization Trans-arterial radionuclide therapy Peptide sequence Peptide sequence, DOTA0–Phe1–Tyr3 Ultrasound