Fundamentals of Nuclear Pharmacy Fourth Edition Springer Science+Business Media, LLC Gopal B. Saha, Ph.D. Director of Nuclear Chemistry and Pharmacy Department of Nuclear Medicine The Cleveland Clinic Foundation Fundatnentals of Nuclear Phannacy Fourth Edition With 113 illustrations , Springer Gopal B. Saha, Ph.D. Director of Nuclear Chemistry and Pharmacy Department of Nuclear Medicine The Cleveland Clinic Foundation Cleveland, OH 44195 USA Library of Congress Cataloging-in-Publication Data Saba, Gopal B. Fundamentals of nuclear pharmacy / Gopal B. Saba. - 4th ed. p. cm. Includes index. 1. Radiopharmaceuticals. 2. Nuclear medicine. I. Title. RS431.R34S24 1997 616.07'575--dc21 97-34137 Printed on acid-free paper. ISBN 978-1-4757-2936-8 ISBN 978-1-4757-2934-4 (eBook) DOI 10.1007/978-1-4757-2934-4 © 1998 Springer Science+Business Media New York Originally published by Springer-Verlag New York, Inc in 1998. Softcover reprint of the hardcover 4th edition 1998 All rights reserved. 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The publisher makes no warranty, express or implied, with respect to the material contained herein. Production managed by Steven Pisano; manufacturing supervised by Joe Quatela. Typeset by Asco Trade Typesetting Ltd., Hong Kong 9 8 7 6 5 4 3 2 1 SPIN 10645048 ~ To ~ my --;it w~"'Iife, ~ Sos. ip~ ra I::S a:;:: n::S d ~ my is ch'=:::: il~ dr~ en:;::"' , ~ Pra:;:: n.... t~ ik I::S a:;:: n"'I::S d ~ Tr-s inI::S a Preface Since the third edition of The Fundamentals of Nuclear Pharmacy was pub lished in 1992, radiopharmaceutical chemistry and various aspects of nuclear medicine have experienced significant growth and development. The new information plus the appreciation of the book in the nuclear medicine community have prompted us to publish a new edition. As with the past editions, this fourth edition is primarily based on the contents of various courses given over several decades to nuclear pharmacy students, nuclear medicine and radiology residents, and nuclear medicine technology students. The book is written in chronological order from the basic atomic structure to the clinical uses of radiopharmaceuticals. It serves as a textbook on nuclear pharmacy for nuclear pharmacy and nuclear medi cine technology students as well as a reference book for many professionals interested in nuclear medicine, such as nuclear medicine physicians and radiologists. There are 15 chapters in the book. At the end of each chapter a set of pertinent questions and some suggested reading materials are included. Chapters 1 to 6 have only minor changes from previous editions, because the materials in these chapters are basic in nature and do not change over time. Some new radionuclides have been added to Table 4.1. Minor changes in the section Design of New Radiopharmaceuticals and some additions in 99mTc chemistry have been made in Chapter 6. Chapter 7 is thoroughly revised with obsolete radiopharmaceuticals removed and new and useful ones included. Chapters 8 to 10 do not have any major changes, except in Tables 8.1,8.2, and 10.1, which are updated for new radiopharmaceuticals. Chapter 11 is a new chapter titled "Radiation Regulations and Protection," the contents of which are from the old Chapter 10 but with the inclusion of all current changes in regulations. The radioimmunoassay section in Chapter 12 has been revised slightly. Many changes have been made in Chapter 13 to include all new radiopharmaceuticals for different organ studies. Chapter 14 is a new chapter titled "Therapeutic Uses of Radio pharmaceuticals" to highlight different radiopharmaceuticals for therapy. Adverse reactions and iatrogenic alterations in biodistribution of radio- vii viii Preface pharmaceuticals are included in Chapter 15. Only partial but relevant refer ences have been included in Chapters 7 and 13. I am grateful to Dr. Raymundo T. Go, chairman of our department, for his continued support and understanding. I would like to express my sincere thanks and appreciation to Ms. Rita Buzzelli for typing the manuscript very efficiently and conscientiously, and for timely completion of this edition of the book. The continued support of the publisher, Springer-Verlag, is greatly appreciated. Finally, my wife Sipra's forbearance, encouragement and understanding made it easier to complete the edition. Gopal B. Saha Contents Preface ................................................................. vii Chapter 1 The Atom................................................. 1 Electronic Structure of the Atom ................................... 1 Chemical Bonds ..................................................... 3 Electrovalent or Ionic Bond ...................................... 4 Covalent Bond ............................................... . . . . . 5 Coordinate Covalent Bond ....................................... 5 Complex Formation.............................................. 5 Structure of the Nucleus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Nomenclature..................................................... 8 Questions ............................................................ 10 Suggested Reading .................................................. 10 Chapter 2 Radioactive Decay ....................................... 11 Decay of Radionuclides ............................................. 11 Spontaneous Fission .............................................. 11 Alpha (ex) Decay .................................................. 12 Beta (P-) Decay................................................... 12 Positron or (p+) Decay ........................................... 14 Electron Capture (EC) ............................................ 14 Isomeric Transition (IT) .......................................... 15 Radioactive Decay Equations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 General Equation ................................................. 17 Half-Life and Mean Life.......................................... 19 Units of Radioactivity............................................ 20 Calculations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Successive Decay Equations......................................... 22 General Equation ................................................. 22 Transient Equilibrium ............................................ 22 Secular Equilibrium............................................... 24 Statistics of Counting. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 ix x Contents Error, Accuracy, and Precision................................... 26 Standard Deviation ............................................... 26 Standard Deviation of Count Rates .............................. 27 Propagation of Errors. . .. . . . . . .. . .. . . .. .. . .. . . .. . .. . . . .. . . .. . .. . . . 28 Questions ............................................................ 28 Suggested Reading .................................................. 30 Chapter 3 Instruments for Radiation Detection and Measurement 31 Gas-Filled Detectors ................................................ 31 Dose Calibrators ... . . .. .. . . .. .. . .. . .. . .. .. . . . . . .. . . . . . . . . . . . . . . . . . 31 Geiger-Muller Counters..... . ............... ....... .............. . 33 Scintillation Detecting Instruments ................................. 34 Collimator ........................................................ 34 Detector........................................................... 35 Photomultiplier Tube ............................................. 36 Preamplifier ....................................................... 36 Linear Amplifier .................................................. 36 Pulse Height Analyzer............................................ 37 Display or Storage ................................................ 37 Scintillation Camera. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 Collimator ........................................................ 39 Detector. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 X, Y Positioning Circuit .......................................... 40 Pulse Height Analyzer ............................................ 41 Display or Storage................................................ 41 Tomographic Imagers. . . .. . . . . . . . . . . . . . . .. . . . .. . . . . . . . . . . . . . . . . . . . . . 43 Single Photon Emission Computed Tomography ................ 43 Positron Emission Tomography.................................. 44 Questions ............................................................ 45 Suggested Reading .................................................. 46 Chapter 4 Production of Radionuclides ............................. 47 Cyclotron-Produced Radionuclides ................................. 48 Gallium-67 ........................................................ 50 Iodine-123 ......................................................... 50 Indium-Ill........................................................ 51 Thallium-20l ...................................................... 51 Short-Lived Radionuclides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 Reactor-Produced Radionuclides ................................... 53 Fission or (n,J) Reaction......................................... 54 Iodine-13l ......................................................... 55 Molybdenum-99 .................................................. 55 Neutron Capture or (n, y) Reaction............................... 55 Target and Its Processing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 Contents xi Equation for Production of Radionuclides . . . . . . . . . . . . . . . . . . . . . . . . . . 57 Specific Activity ..................................................... 60 Questions ............................................................ 63 Suggested Reading .................................................. 63 Chapter 5 Radionuclide Generators................................. 65 Principles of a Generator. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Important Radionuclide Generators ................................ 68 99Mo_99mTc Generator ........................................... 68 I13Sn_113mIn Generator........................................... 76 68Ge_68Ga Generator. '" ................ , ....... .. .. .. ..... . ..... 76 82Sr_82Rb Generator (Cardiogen-82) ............................. 77 62Zn_62Cu Generator. ... ... . ... . . . . . ... . ... . ... .. . ...... . .. .... . . 77 81Rb_81mKr Generator........................................... 77 Questions ............................................................ 77 References and Suggested Reading ................................. 78 Chapter 6 Radiopharmaceuticals and Methods of Radiolabeling . . 80 Definition of a Radiopharmaceutical ............................... 80 Ideal Radiopharmaceutical. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 Easy Availability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 Short Effective Half-Life.......................................... 81 Particle Emission. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 Decay by Electron Capture or Isomeric Transition .............. 82 High Target-to-Nontarget Activity Ratio ........................ 83 Design of New Radiopharmaceuticals .............................. 84 General Considerations ........................................... 84 Factors Influencing the Design of New Radiopharmaceuticals .. 85 Methods of Radiolabeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 Isotope Exchange Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 Introduction of a Foreign Label.................................. 89 Labeling with Bifunctional Chelating Agents .................... 89 Biosynthesis ....................................................... 90 Recoil Labeling ................................................... 90 Excitation Labeling ............................................... 90 Important Factors in Labeling ...................................... 90 Efficiency of the Labeling Process ................................ 91 Chemical Stability of the Product ................................ 91 Denaturation or Alteration ....................................... 91 Isotope Effect ..................................................... 91 Carrier-Free or No-Carrier-Added (NCA) State................. 91 Storage Conditions................................................ 91 Specific Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 Radiolysis ......................................................... 92