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Mastfff Chicago, Illinois PREFACE CONF-92QU37- DB93 010828 PROCEEDINGS OF A WORKSHOP ON MOLECULAR NUCLEAR MEDICINE Embassy Row Hotel, 2015 Massachusetts Avenue, N.W. Was! ington, D.C. January 23-24, 1992 Prepared by: U.S. Department of Energy Medical Applications and Biophysical Research Division Office of Health and Environmental Research Washington, D.C. 20585 Editor, Richard C. Reba The University of Chicago MASTfff Chicago, Illinois PREFACE Molecular Nuclear Medicine is developing into a new research area to improve the health and welfare of the public. Within the Department of Energy, the Program in Molecular Nuclear Medicine will support novel molecular approaches for diagnostic and therapeutic applications of nuclear medicine. To exploit the opportunities presented by the revolution in the biological sciences, the strategy is to integrate the scientific and technical power of molecular biology with the existing nuclear medicine program at the Department of Energy. Research in molecular biology has provided significant Insight Into the mechanisms of macromolecular Interactions underlying normal genetic, cellular and physiological processes. Any Insult (arising from diet, drug abuse, environmental exposure, Infection, etc.) that undermines these natural mechanisms can disrupt macromoiecular interactions and regulatory functions, leading to pathological states and disease. Molecular technologies, when coupled with the range of Instrumentation and techniques of nuclear medicine, have the potential to provide tools of much higher sensitivity and precision for detecting, localizing and, potentially for ameliorating, macromolecular, cellular and systemic pathologies. The Workshop represents the Department of Energy's commitment to accelerate the integration of molecular biology and biotechnology with nuclear medicine, and to develop an Innovative Molecular Nuclear Medicine Research Program. The Nuclear Medicine Research Program has contributed significantly to advances In the use of PET and SPECT for in vivo quantitative estimates of perfusion, metabolism, and receptor concentrations in living subjects. Building on the historic achievements of the DOE program in the area of medical applications, the Program will foster a new generation of novel techniques and instruments. We hope that the present Workshop offers a beginning step toward revolutionary advances in diagp©*TT"and treatment. David J. Associate!^rector for Health and Environmental Research Office of Energy Research TABLE OF CONTENTS January 23, 1992 Executive Summary 1 Proceedings 8 Designing a Molecular Probe for Muscarinic Acetylcholine Receptor Imaging, Dr. William Eckelman 13 Using Steroid Receptors for Function Based Imaging of Breast Tumors, Dr. John Katzenellenbogen 18 Discussion 30 Nuclear Medicine: From Genotype to Phenotype, Dr. Henry Wagner 31 Discussion 36 DNA-Protein Attractions, Or. Rashmi Hegde 48 Drug Design: Crystallography and Computational Approaches, Dr. Dagmar Ringe 56 Discussion 63 References 72 January 24, 1992 Mechanism of Receptors Signaling: The Structure of the Growth Hormone Receptor Complex, Dr. Anthony Kossiakoff 76 Discussion 83 Diagnostic Potential of Newly Discovered Brain Gene Probes, Dr. Craig Venter 93 Discussion 96 TABLE OF CONTENTS Structure and Function Analysis of 6-Protein Coupled Receptors and Potential Diagnostic Ligands, Or. Clair Fraser 100 Discussion 108 Novel Oligonucleotide Probes for In Vivo Detection of Potential Disease/Disorder Genes, Dr. Michael Hogan Ill Discussion 125 Chromosomes as Potential Targets for Nuclear Medicine Imaging, Dr. Janet Rowley 129 Discussion 135 References 155 Participants 157 EXECUTIVE SUMMARY MOLECULAR NUCLEAR MEDICINE WORKSHOP The Office of Health and Environmental Research (OHER) of the Department of Energy (DOE) has increased the emphasis on research in structural biology and molecular biology. The Department has increased support substantially in the area of basic molecular and structural biology research. To exploit the advances in these fields, OHER has sought to apply those advances in their other areas of responsibility, e.g., health effects research, environmental biology, and, in particular, nuclear medicine. The applications of biotechnology have contributed greatly to the productive research efforts of molecular biology. These techniques include gene manipulation for targeted gene delivery; characterization of molecular probes for hormone, tumor, and neuroreceptors; the receptor-agonist/antagonist binding interactions; studies of mechanisms of cellular communication; and the development of in vitro diagnostics such as molecular probes for studying the aging process and patients with mental disorders, cancer, and atherosclerosis. The importance of this work is the reasonable expectation that mainly, through an appreciation of the molecular basis of disease, will the most effective and rapid progress be made toward understanding, identifying, solving, and preventing specific disease processes. Critical questions arising before and during the Workshop are how the following technologies can be applied in a practical clinical research or patient management setting: the recombinant DNA methodology, the technology of engineered monoclonal antibodies, the new methods for protein production and purification, and the production of transgenic animals. The clinical discipline of nuclear medicine has, for some time, used many molecular and structural techniques, primarily in the research directed toward biochemical and molecular substrate-specific radiopharmaceutical drug design. However, the workers in molecular biology and nuclear medicine are not familiar with the advances and strengths, nor the limitations of the techniques of each other and, more importantly, how evolving research in these two fields could benefit from integrated approaches. To this latter end, OHER held the Molecular Nuclear Medicine Workshop in Washington, D.C., on January 23 and 24, 1992. The invited speakers, from the disciplines of nuclear medicine, structural biology, and molecular biology, were asked to make presentations to stimulate discussion that would lead to new directions and new opportunities for integrated research in these areas. The speakers at the Workshop were: Dr. William Eckelman (Positron Emission Tomography Department, National Institutes of Health, Bethesda, Maryland); Dr. John Katzenellenbogen (Department of Chemistry, University of Illinois, Urbana, Illinois); Dr. Henry N. Wagner, Jr., (Director, Division of Nuclear Medicine and Radiation Health Sciences, Johns Hopkins Medical Institutions, Baltimore, Maryland); Dr. Rashmi Hegde (Howard Hughes Medical Institute, New Haven, Connecticut); Dr. Dagmar Ringe (Department of Biochemistry and Chemistry, Brandeis University, Waltham, Massachusetts); Dr. Anthony Kossiakoff (Genentech, Inc., South San Francisco, California); Dr. Craig Venter (National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland); Dr. Claire Fraser (National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland); and Dr. Michael Hogan (Center for Biotechnology, Baylor College of Medicine, The Woodlands, Texas). The Workshop chairman was Dr. Richard Reba (Department of Radiology, University of Chicago, Chicago, Illinois). From the Workshop, specific goals were identified. In order to achieve those goals the following recommendations from the Molecular Nuclear Medicine Workshop are presented: 1. To encourage the incorporation of molecular biology and structural biology techniques into the design, synthesis, validation, and application of a new generation of radiopharmaceuticals. 2. To support attempts to develop labeled probes based on specific interactions with receptors, enzymes, and second messenger molecules, or with specific transcription products. 3. To support efforts to promote programs to encourage nuclear medicine researchers, structural biologists, molecular biologists, and chemists to undertake interdisciplinary, cooperative, integrated research programs. 4. To undertake efforts, through meetings and conferences, to encourage molecular biologists to prioritize defined protein translational products that would serve as useful probes for specific targets for use in in vivo nuclear medicine. 5. To support educational initiatives and conferences to enhance scientific interaction among nuclear medicine researchers and researchers in molecular and structural biology. 6. To continue support for the ongoing research in nuclear medicine, basic science, radiopharmaceutical chemistry, and instrumentation development in the OHER Medical Applications Program which is fundamental to the application of molecular biology to nuclear medicine. Because of the focused nature of the formal program, research in related fields, such as the new and improved high resolution instrumentation required for advanced molecular biology applications, radiopharmaceutical drug design theory, synthesis necessary for the development of new probes, and innovations in the analytical techniques required for in vivo absolute quantification of emission tomography were only peripherally discussed. However, there was unanimous agreement that research in these areas is crucial to the ultimate appropriate clinical application of the new nuclear medicine technology to be developed as the result of this Workshop. The individual presentations by the invited speakers are summarized below. In the presentation, "Designing a Molecular Probe for Muscarinic Acetylcholine
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