Nuclear Imaging in Drug Discovery, Development, and Approval

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1 Nuclear Imaging in Drug Discovery, Development, and Approval

2 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

3 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 (H : alk. paper). -- ISBN (H : alk. paper) I. Drugs--Resarch--Methodology. 2. Radioisotope scanning. 3. Radioisotope tracers in biochemistry. I. Burns, H. Donald (Hugh Donald), [DNLM: 1. Autoradiography. 2. Drug Design. 3. Drug Evaluation. 4. Tomography, Emission-Computed. WN 160 N9645] RM N I'072--dc20 DNLMlDLC for Library of Congress Printed on acid-free paper. Birkhauser Boston Softcover reprint of the hardcover 1 st edition CIP 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, photocopying, 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: DOl: / e-isbn-13: Camera-ready copy prepared by the editors

4 Contents Foreword Henry N. Wagner, Jr.... vii 1. Nuclear Imaging in Drug Development-Introduction Leslie Lars Iversen Nuclear Medicine Physics, Instrumentation, and Data Processing in Pharmaceutical Research Jonathan M. Links Accelerators for Positron Emission Tomography Alfred P. Wolf and David J. Schlyer Chemistry of Tracers for Positron Emission Tomography Robert F. Dannals, Hayden T. Ravert, and Alan A. Wilson Single Photon, Gamma Emitting Radiotracers for Use in Imaging H. Donald Bums, Kwamena E. Baidoo, and Alan A. Wilson The Design of Site-Directed Radiopharmaceuticals for Use in Drug Discovery William C. Eckelman and Raymond E. Gibson Applications of Autoradiography to Drug Discovery Raymond E. Gibson, Holly T. Beauchamp, Susan Iversen, Barry Everitt, James McCulloch, and Christopher Wallace Quantitative Whole Body Autoradiographic Microimaging for Pharmaceutical Research Prantika Som and Zvi H. Oster Cerebral Metabolic Rates of 2-[ 18 F]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

5 10. Positron Emission Tomography, Enzymes and Drug Research and Development Joanna S. Fowler, Nora D. Volkow, and Alfred P. Wolf The Role of Positron Emission Tomography in Assessing and Monitoring Dopamine Active Drugs Dean F. Wong and Babington Yung Iodinated Dopamine 011 and O2 Receptor Imaging Agents for SPECT Hank F. Kung Radiolabeled Atrial Natriuretic Peptide and Somatostatin for In Vivo Imaging of Receptors Richard J. Flanagan Use of Radionuclides in Experimental Vascular Thrombosis Linda W. Schaffer, John T. Davidson, and Peter K. S. Siegl 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 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 The Potential Uses of Radiopharmaceuticals in the Pharmaceutical Industry Raymond E. Gibson, H. Donald Bums, and William C. Eckelman Index

6 Foreword It is the purpose and business of the pharmaceutical industry to discover, 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 industry, academic laboratories and national laboratories to describe advances in radiotracer technology in studies on experimental animals and living human beings. The authors believe that the technology 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 basis 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 treatment is possible through chemistry, as well as by making possible a more suitable selection of a histological biopsy site. Basic science advances 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 practice is answering the questions: What is wrong? What is going to happen? What can be done about it? Has the treatment been effective? This book proposes that the diagnostic technology for measuring intercellular communication and the planning and monitoring of treatment should become a major focus of drug design and development. A strong relationship exists between the areas of radioisotopic methods of diagnosis and currently developed drugs. I like to refer

7 to the radiotracers as nanodx molecules, and that the basis of treatment 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 recognition sites, enzymes, or transport processes. For example, if a pituitary 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 pituitary 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 utilization 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 university 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. Knowledge of the stereospecific and other determinants of binding can be incorporated into new ratiotracers for use in human studies, employing external imaging techniques. Radiotracers, with appropriate structure, charge and hydrophobic/hydrophilic properties, search out and characterize abnormalities in regional chemistry. They also make possible, studies of pharmacokinetics, structure/activity relationships, and receptor-specific binding of novel molecules.

8 For example, patients with neuroendocrine and other types of cancer, including cancer of the breast, are characterized by containing somatostatin receptors in measurable quantities. Characterization 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 somatostatin receptors in vivo. Nuclear medicine does not just provide new tests for old diseases, but new ways of defining and detecting disease. Chemical changes can almost always be detected before clinical signs of disease, 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 different 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 technology 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

9 technology can contribute to increasing the efficiency of drug development and to shorten the time from initial synthesis to approval of new drugs. Henry N. Wagner, Jr.

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