Table Of ContentDRUGS AND THE PHARMACEUTICAL SCIENCES
A Series of Textbooks and Monographs
edited by
James Swarbrick
School of Pharmacy
University of North Carolina
Chape! Hill, North Carolina
1. Pharmacokinetics, MHo Gibaldi and Donald Perrier
2. Good Manufacturing Practices for Pharmaceuticais: A Plan for Totai
Quaiity Control, Sidney H. Wi/iig, Murray M. Tuckerman, and William S.
Hitchings IV
3. Microencapsulation, edited by J. R. Nixon
4. Drug Metabolism: Chemical and Biochemical Aspects, Bernard Testa and
Peter Jenner
5. New Drugs: Discovery and Development, edited by Alan A. Rubin
6. Sustained and Controiied Release Drug Delivery Systems, edited by
Joseph R. Robinson
7. Modern Pharmaceutics, edited by Gilbert S. Banker and Christopher T.
Rhodes
8. Prescription Drugs in Short Supply: Case Histories, Michael A. Schwartz
9. Activated Charcoai: Antidotal and Other Medical Uses, David O. Cooney
10. Concepts in Drug Metabolism (in two parts), edited by Peter Jenner and
Bernard Testa
11. Pharmaceutical Analysis: Modern Methods (in two parts), edited by
James W. Munson
12. Techniques of Solubilization of Drugs, edited by Samuel H. Yalkowsky
13. Orphan Drugs, edited by Fred E. Kerch
14. Novel Drug Delivery Systems: Fundamentals, Developmental Concepts,
Biomedical Assessments, Yie W. Chien
15. Pharmacokinetics: Second Edition, Revised and Expanded, MHo Gibaldi
and Donald Perrier
16. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total
Quality Control, Second Edition, Revised and Expanded, Sidney H.
\MHig, Murray M. Tuckerman, and William S. Hitchings IV
17. Formuiation of Veterinary Dosage Forms, edited by Jack Biodinger
18. Dermatological Formulations: Percutaneous Absorption, Brian W. Barry
19. The Clinical Research Process in the Pharmaceutical Industry, edited by
Gary M. Matoren
20. Microencapsulation and Related Drug Processes, Patrick B. Deasy
21. Drugs and Nutrients: The Interactive Effects, edited by Daphne A. Roe
and T. Colin Campbell
22. Biotechnology of Industrial Antibiotics, Erick J. Vandamme
23. Pharmaceutical Process Validation, edited by Bernard T. Loftus and
Robert A. Nash
24. Anticancer and Interferon Agents: Synthesis and Properties, edited by
Raphael M. Ottenbrite and George B. Butler
25. Pharmaceutical Statistics: Practical and Clinical Applications, Sanford
Bolton
26. Drug Dynamics for Analytical, Clinical, and Biological Chemists, Benja
min J. Gudzinowicz, Burrows T. Younkin, Jr., and Michael J. Gudzino-
wicz
27. Modern Analysis of Antibiotics, edited by Adjoran Aszalos
28. Solubility and Related Properties, Kenneth C. James
29. Controlled Drug Delivery: Fundamentals and Applications, Second Edi
tion, Revised and Expanded, edited by Joseph R. Robinson and Vincent
H. Lee
30. New Drug Approval Process: Clinical and Regulatory Management,
edited by Richard A. Guarino
31. Transdermal Controlled Systemic Medications, edited by Yie W. Chien
32. Drug Delivery Devices: Fundamentals and Applications, edited by
Praveen Tyle
33. Pharmacokinetics: Regulatory • Industrial • Academic Perspectives,
edited by Peter G. Welling and Francis L. S. Tse
34. Clinical Drug Trials and Tribulations, edited by Alien E. Cato
35. Transdermal Drug Delivery: Developmental Issues and Research Ini
tiatives, edited by Jonathan Hadgraft and Richard H. Guy
36. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, edited
by James W. McGinity
37. Pharmaceutical Pelletization Technology, edited by Isaac Ghebre-
Sellassie
38. Good Laboratory Practice Regulations, edited by Alien F. Hirsch
39. Nasal Systemic Drug Delivery, Yie W. Chien, Kenneth S. E. Su, and
Shyi-Feu Chang
40. Modern Pharmaceutics: Second Edition, Revised and Expanded, edited
by Gilbert S. Banker and Christopher T. Rhodes
41. Specialized Drug Delivery Systems: Manufacturing and Production Tech
nology, edited by Praveen Tyle
42. Topical Drug Delivery Formulations, edited by David W. Osborne and
Anton H. Amann
43. Drug Stability: Principles and Practices, Jens T. Carstensen
44. Pharmaceutical Statistics: Practical and Clinical Applications, Second
Edition, Revised and Expanded, Sanford Bolton
45. Biodegradable Polymers as Drug Delivery Systems, edited by Mark
Chasin and Robert Langer
46. Preclinical Drug Disposition; A Laboratory Handbook, Francis L. S. Tse
and James J. Jaffe
47. HPLC in the Pharmaceutical Industry, edited by Godwin W. Fong and
Stanley K. Lam
48. Pharmaceutical Bioequivalence, edited by Peter G. Welling, Francis L. S.
Tse, and Shrikant V. Dinghe
49. Pharmaceutical Dissolution Testing, Umesh V. Banakar
50. Novel Drug Delivery Systems: Second Edition, Revised and Expanded,
Yie W. Chien
51. Managing the Clinical Drug Development Process, David M. Cocchetto
and Ronald V. Nardi
52. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total
Quality Control, Third Edition, edited by Sidney H. WiiUg and James R.
Stoker
53. Prodrugs: Topical and Ocular Drug Delivery, edited by Kenneth B. Sloan
54. Pharmaceutical Inhalation Aerosol Technology, edited by Anthony J.
Hickey
55. Radiopharmaceuticals: Chemistry and Pharmacology, edited by Adrian
D. Nunn
Additional Volumes in Preparation
Pharmaceutical Process Validation: Second Edition, Revised and Ex
panded, edited by ira R. Berry and Robert A. Nash
Chemistry and Pharmacology
edited by
Adrian D. Nunn
Bristoi-Myers Squibb
Pharmaceutical Research Institute
New Brunswick, New Jersey
Marcel Dekker, Inc. New York • Basel • Hong Kong
ISBN: 0-8247-8624-6
This book is printed on acid-free paper.
Copyright © 1992 by Marcel Dekker, Inc. All Rights Reserved.
Neither this book nor any part may be reproduced or transmitted in any
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Current printing (last digit):
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PRINTED IN THE UNITED STATES OF AMERICA
PREFACE
Nuclear medicine exists in two forms which use slightly different
technology to produce images of the in vivo distribution of injected radioactive
compounds. For routine clinical use single photon emission tomography
(SPECT) predominates and uses mainly Technetium-99m. On the other hand,
there is an extensive research effort using positron emission tomography
(PET), and here Carbon-11, Fluorine-18 and Oxygen-15 are most used. As yet
PET has not been widely used in a clinical setting because the radionuclides it
uses are short lived and cyclotron produced.
Clinically, nuclear medicine has been viewed as the Cinderella of medical
imaging because it is seen as being ’low tech* (having been around for much
longer), is relatively inexpensive to perform, and because the resolution of
nuclear imaging devices is inferior to that of the newer CT or MRJ machines.
This means that morphological images obtained by the latter devices are in
almost all cases superior. Radiopharmaceuticals have held a similar position
relative to therapeutic drugs because of the dominant position of metal
complexes which has isolated the practitioners from the main pharmaceutical
chemistry population. Coupled with the scarcity of knowledge of the element
most frequently used in radiopharmaceutical chemistry, technetium (a result of
current stocks of the element being totally man-made), this has generated a
view of radiopharmaceutical chemistry as being something of a 'Black Art’ and
an imprecise one at that.
iii
Iv Preface
In recent years the pressure on nuclear medicine to relinquish
morphological imaging to better techniques has fueled attempts to develop
functional imaging. Here nuclear medicine has an advantage over the other
techniques as the quantities of tracer injected are many orders of magnitude
less than those used for CT or MRI and so do not disturb the very processes
that are being measured. In addition, the availability of radionuclides of
carbon, fluorine and oxygen allows the study of compounds that are well
known in conventional pharmaceutical circles. As a result, nuclear medicine
has started to exploit its true niche, that of measuring regional function. Along
with this has come an evolution, some would say a revolution, in
radiopharmaceutical chemistry.
Some ten years ago the routine clinical field, dominated by technetium,
concentrated on increasing the delivery of drug to specific tissues. For
example, about 50% of the injected dose of phosphonate complexes are taken
up by the skeleton within about half an hour after injection and used to depict
blood flow which is indicative of new bone deposition around métastasés.
About 90% of the injected dose of iminodiacetic acid complexes can be
excreted by the liver within about the same time to measure the excretory
functions of this organ and its associated systems. In recent years attention has
concentrated on designing compounds that measure perfusion and here the
common targets of the myocardium and the brain have presented much more
formidable problems. Needless to say, there are now a variety of technetium
compounds that are efficacious for the measurement of perfusion in these
tissues and a large body of structure distribution (as opposed to activity)
relationships has been constructed. This knowledge includes not only
information on the stereo specific interaction of metal complexes with enzyme
systems and transport mechanisms, information which is adaptable to
compounds other than metal complexes.
Preface
In the PET field the blossoming of knowledge of receptor systems has
proven irresistible, and much work has been expended in radiolabelling
receptor binders and using them to gain quantitative information on receptors
in vivo as a function of disease or therapy. To a limited extent this has also
occurred in the SPECT field. In many cases this has led to significant
interaction between pharmaceutical companies and PET centers in attempts to
better understand the pharmacology of new (and old!) therapeutic drugs. In
addition, as measurement techniques have improved, the routine analysis of
metabolism using PET techniques has occurred. The use of PET techniques is
not just an extension of classical drug metabolism and pharmacological
techniques; it provides a quantum leap in information. Already the use of such
techniques to examine, for instance, receptor occupancy in psychoactive drug
therapy is being discussed as are means of diagnosing or staging disease and
therapy by measuring receptor density or occupancy.
This book is arranged somewhat along the traditional competitive lines of
SPECT vs PET. In the past there has been a great gulf between the clinical
usefulness of SPECT agents vs PET and the scientific elegance of PET vs
SPECT. This gulf is rapidly closing. The clinical use of PET agents is
becoming routine and technetium-based SPECT agents are now as
scientifically elegant as their PET counterparts.
The authors were asked to write their chapters in such a way as to provide
a review for the practitioners of the disciplines embodied in them yet still
provide easily obtainable information to non-practitioners. It is not the intent
of this book to list every radioactive compound made and used in vivo and
how to make it; rather it is to describe the philosophy behind why one
approach is better than another.
In addition, an attempt has been made to present the current state of
knowledge such that others may glean as yet unseen information from it. The
chapters on technetium agents should displace any misconceptions that abound
