Nuclear Imaging in Drug Discovery, Development, and Approval

347 Pages·1993·10.14 MB·English

by  Leslie Lars Iversen (auth.)

Nuclear Imaging in Drug Discovery,
Development, and Approval
Nuclear Imaging
in Drug Discovery,
Development, and
Approval
Edited by
H. Donald Burns
Raymond E. Gibson
Robert F. Dannals
Peter K. S. Siegl
With a Foreword by
Henry N. Wagner, Jr.
Birkhauser
Boston· Basel . Berlin
Library of Congress Cataloging-in-Publication Data
Nuclear imaging in drug discovery, development, and approval I edited
by H. Donald Burns ... ret aI.] : with a foreword by Henry N.
Wagner, Jr.
p. cm.
Includes bibliographical references and index.
ISBN 0-8176-3601-3 (H : alk. paper). -- ISBN 3-7643-3601-3 (H :
alk. paper)
I. Drugs--Resarch--Methodology. 2. Radioisotope scanning.
3. Radioisotope tracers in biochemistry. I. Burns, H. Donald (Hugh
Donald), 1946-
[DNLM: 1. Autoradiography. 2. Drug Design. 3. Drug Evaluation.
4. Tomography, Emission-Computed. WN 160 N9645]
RM301.25.N8 1993
615.I'072--dc20
DNLMlDLC 92-48930
for Library of Congress CIP
Printed on acid-free paper.
© Birkhauser Boston 1993.
Softcover reprint of the hardcover 1s t edition 1993
Copyright is not claimed for works of U.S. Government employees.
All rights reserved. No part of this publication may be reproduced, stored in a retrieval
system, or transmitted, in any form or by any means, electronic, mechanical, photo
copying, recording, or otherwise, without prior permission of the copyright owner.
The use of general descriptive names, trademarks, etc. in this publication even if the
former are not especially identified, is not to be taken as a sign that such names, as
understood by the Trade Marks and Merchandise Marks Act, may accordingly be used
freely by anyone.
While the advice and information in this book are believed to be true and accurate at the
date of going to press, neither the authors nor the editors nor the publisher can accept
anylegal responsibility for any errors or omissions that may be made. The publisher
makes no warranty, express or implied, with respect tothe material contained herein.
Permission to photocopy for internal or personal use of specific clients is granted by
Birkhauser Boston for libraries and other users registered with the Copyright Clearance
Center (CCC), provided that the base fee of $6.00 per copy, plus $0.20 per page is paid
directly to CCC, 21 Congress Street, Salem, MA 01970, U.S.A. Special requests should
be addressed directly to Birkhauser Boston, 675 Massachusetts Avenue, Cambridge, MA
02139, U.S.A.
ISBN-13: 978-1-4684-6810-6 e-ISBN-13: 978-1-4684-6808-3
DOl: 10.1007/978-1-4684-6808-3
Camera-ready copy prepared by the editors.
987654321
Contents
Foreword
Henry N. Wagner, Jr. ....................................... vii
1. Nuclear Imaging in Drug Development-Introduction
Leslie Lars Iversen ........................................ 1
2. Nuclear Medicine Physics, Instrumentation, and Data
Processing in Pharmaceutical Research
Jonathan M. Links ........................................ 11
3. Accelerators for Positron Emission Tomography
Alfred P. Wolf and David J. Schlyer ....................... 33
4. Chemistry of Tracers for Positron Emission Tomography
Robert F. Dannals, Hayden T. Ravert, and Alan A. Wilson .... 55
5. Single Photon, Gamma Emitting Radiotracers
for Use in Imaging
H. Donald Bums, Kwamena E. Baidoo, and Alan A. Wilson .. 75
6. The Design of Site-Directed Radiopharmaceuticals
for Use in Drug Discovery
William C. Eckelman and Raymond E. Gibson ............. 113
7. Applications of Autoradiography to Drug Discovery
Raymond E. Gibson, Holly T. Beauchamp, Susan Iversen,
Barry Everitt, James McCulloch, and Christopher Wallace . 135
8. Quantitative Whole Body Autoradiographic Microimaging
for Pharmaceutical Research
Prantika Som and Zvi H. Oster ........................... 149
9. Cerebral Metabolic Rates of 2-[18F]Fluoro-
2-Deoxy-D-Glucose in the Presence of
Ofloxacin A GABAA Receptor Antagonist
Edwaldo E. Camargo, Zmlt Szabo, Robert F. Dannals,
and Henry N. Wagner, Jr. ................................. 167
10. Positron Emission Tomography, Enzymes and Drug
Research and Development
Joanna S. Fowler, Nora D. Volkow, and Alfred P. Wolf ..... 179
11. The Role of Positron Emission Tomography
in Assessing and Monitoring Dopamine Active Drugs
Dean F. Wong and Babington Yung ...................... 201
12. Iodinated Dopamine 011 and O Receptor
2
Imaging Agents for SPECT
Hank F. Kung ......................................... 227
13. Radiolabeled Atrial Natriuretic Peptide and Somatostatin
for In Vivo Imaging of Receptors
Richard J. Flanagan ................................... 245
14. Use of Radionuclides in Experimental
Vascular Thrombosis
Linda W. Schaffer, John T. Davidson,
and Peter K. S. Siegl. .................................. 265
15. Application of Nuclear Imaging to Drug Delivery
Evaluation and Development: A Review of Radiolabeled,
Injectable, Colloidal Systems of Delivery
Nancy J. Brenner, Christine Fioravanti,
and H. Donald Bums .................................. 283
16. The Gastrointestinal Transit and Systemic
Absorption of Diltiazem HCL
from a Modified Release Dosage Form
Donald L. Heald, John A. Ziemniak, and Ian R. Wilding .. 301
17. The Potential Uses of Radiopharmaceuticals
in the Pharmaceutical Industry
Raymond E. Gibson, H. Donald Bums,
and William C. Eckelman ............................... 321
Index ................................................ 333
Foreword
It is the purpose and business of the pharmaceutical industry to dis
cover, develop, and make available drugs for the care of the sick.
The purpose of universities and national laboratories is to provide
people and scientific knowledge that can help in the process. This
book presents the combined efforts of scientists from the drug in
dustry, academic laboratories and national laboratories to describe
advances in radiotracer technology in studies on experimental ani
mals and living human beings. The authors believe that the technol
ogy is now ready for widespread application in the pharmaceutical
industry. The goal of this book is to help bring this about.
The field of Nuclear Medicine is based on the concept that, if
treatment of disease is chemical, the patient's diagnosis should be
chemical. Anatomy and histopathology have been the principle ba
sis for making a diagnosis. Histopathologic data suffer from being
descriptive, subjective, not quantifiable, and based on the study of
dead tissue. The era of histopathology as the dominant concept in
medical practice is coming to an end. Histopathologic findings are
often heterogeneous and a single biopsy will at times not reveal the
true nature of the disease, such as the grading of malignancy. Far
greater accuracy of staging of disease and in the planning of treat
ment is possible through chemistry, as well as by making possible a
more suitable selection of a histological biopsy site. Basic science ad
vances in genetics, molecular biology, oncology, metabolic diseases,
and infectious diseases can be extended to medical practice by means
of radiotracer technology. The methods go far beyond anatomy into
the domains of physiology and in vivo biochemistry; these methods
are the topic of this book.
Implicit in the development and use of drugs in medical prac
tice is answering the questions: What is wrong? What is going to
happen? What can be done about it? Has the treatment been effec
tive? This book proposes that the diagnostic technology for measur
ing intercellular communication and the planning and monitoring of
treatment should become a major focus of drug design and develop
ment. A strong relationship exists between the areas of radioisotopic
methods of diagnosis and currently developed drugs. I like to refer
to the radiotracers as nanoDx molecules, and that the basis of treat
ment will be using nanoRx molecules. The prefix nano- indicates that
nano- or picomolar quantities of radiotracers are involved in in vivo
diagnosis by measuring their emissions of ionizing radiation. NanoRx
molecules correct regional chemical abnormalities that characterize
disease.
NanoDx probes, the radiotracers described in this book, measure
specific, general or regional metabolic activity or the state of recog
nition sites, enzymes, or transport processes. For example, if a pi
tuitary tumor contains dopamine receptors (measured with Carbon-
11 labeled N-methylspiperone), the receptor can be stimulated by
the administration of the dopamine receptor agonist, bromocryptine.
This drug activates the dopaminergic system which in turn inhibits
the secretion of prolactin by the prolactin-secreting cells of the pi
tuitary tumor. The beneficial effect of the bromocryptine therapy
can be demonstrated on the same day that the treatment is begun
by measuring its inhibiting effect on glucose or other substrate uti
lization by means of radiolabeled glucose, amino acids or thymidine.
Photon-emitting radiotracers can characterize a lesion, aid in the
planning of treatment, and determine whether or not the treatment
has been effective, an approach which goes far beyond relying on
clinical manifestations or anatomical changes which may take weeks
or months before they occur. This same methodology can be used to
demonstrate efficacy of new, experimental drugs in much the same
way that the beneficial effect of bromocryptine has been shown.
Amines, such as dopamine and carfentanil, and peptides, such
as octreotide, are examples of chemical messengers developed by the
pharmaceutical industry that were subsequently labeled in the uni
versity community with photon-emitting radiotracers for studies of
regional chemistry in living humans. Peptides and proteins can be
made in large quantities by means of genetic engineering, and their
detailed structure characterized by x-ray crystallography. Knowl
edge of the stereospecific and other determinants of binding can be
incorporated into new ratiotracers for use in human studies, em
ploying external imaging techniques. Radiotracers, with appropri
ate structure, charge and hydrophobic/hydrophilic properties, search
out and characterize abnormalities in regional chemistry. They also
make possible, studies of pharmacokinetics, structure/activity rela
tionships, and receptor-specific binding of novel molecules.
For example, patients with neuroendocrine and other types of
cancer, including cancer of the breast, are characterized by contain
ing somatostatin receptors in measurable quantities. Characteriza
tion of the disease by its receptor sites results in specific treatment
with a somatostatin receptor-stimulating analogue. Imaging can also
be used to show that new drugs do, in fact, interact with somato
statin receptors in vivo.
Nuclear medicine does not just provide new tests for old· dis
eases, but new ways of defining and detecting disease. Chemical
changes can almost always be detected before clinical signs of dis
ease, and make possible more specific characterization of the disease.
For example, if a metastatic breast tumor contains estrogen receptors
it can be treated with the estrogen receptor antagonist, tamoxifen.
Both the planning of treatment and the response to treatment can
be based on regional biochemistry.
The mechanism of action of many drugs involves stimulation
or inhibition of recognition sties - enzymes, transport processes or
chemoreceptors - all of which have been extensively studied by PET
and SPECT. Hundreds of reports have involved the dopaminergic
system, first successfully imaged in living human brain in 1983 with
Carbon-ll NMSP and Fluorine-18 L-DOPA. It is now possible to
image the regional synthesis of dopamine in the human brain, the
binding of dopamine to post-synaptic receptors, and the re-uptake
of dopamine into vesicles via pre-synaptic transporter sites. Six dif
ferent dopamine receptor subtypes have been cloned, and are now
available for detailed study in pure form.
Defining diseases in terms of brain chemical abnormalities helps
in developing new forms of drug treatment, beyond what would be
possible on the bases of subjective symptoms or mental performance
tests. In AIDS, for example, chemical changes in the brain can be
detected before any neurological signs are present. Such findings are
important because of the value of early treatment of HIV infections.
This book provides a timely overview of nuclear medicine tech
nology and its application to the discovery and development of new
pharmaceuticals. The potential for use of this technology by the
pharmaceutical industry has been recognized but just barely tapped.
Its use can greatly reduce the cost and time required for chemicals
to be transformed into FDA approved drugs. The goal of this book
is to provide the pharmaceutical industry with a look at how this
technology can contribute to increasing the efficiency of drug devel
opment and to shorten the time from initial synthesis to approval of
new drugs.
Henry N. Wagner, Jr.