PET STUDIES ON AMINO ACID METABOLISM AND PROTEIN SYNTHESIS Developments in Nuclear Medicine VOLUME 23 Series Editor. Peter H. Cox The titles published in this series are listed at the end of this volume. PET Studies on Amino Acid Metabolism and Protein Synthesis Proceedings of a Workshop held in Lyon, France within the framework of the European Community Medical and Public Health Research edited by B. M. MAZOYER Groupe d'lmagerie Neuro-fonctionelle, Service Hospitalier Frederic Joliot, CEA-DRIPP Orsay, et Höpital R. Debre, Paris, France W. D. HEISS Max-Planck-Institute for Neurological Research, Cologne, Germany and D. COMAR E. E.C. Concerted Action on PET Investigations of Cellular Regeneration and Degeneration, Service Hospitalier Frederic Joliot, Höpital d'Orsay, Orsay, France Springer Science+Business Media, B.V. Library of Congress Cataloging-in-Publication Data PET studie s o f amino aci d metabolis m an d protei n synthesi s : proceedings o f workshop hel d i n Lyon, franc e withi n th e framework of the European Community medica l an d publi c healt h researc h / edite d by B.M. Mazoyer, W.-D. Heiss , and D. Comar. p. cm . — (Developments i n nuclear medicin e ; 23) Includes bibliographica l reference s an d index . ISBN 978-94-010-4706-7 ISBN 978-94-011-1620-6 (eBook) DOI 10.1007/978-94-011-1620-6 1. Amino acids—Metabolism—Congresses . 2 . Tomography, Emission- -Congresses. 3 . Proteins—Synthesis—Congresses . 4 . Brain—Tumors - -Diagnosis—Congresses . I . Mazoyer, B. M. II . Heiss, W.-D. (Wol f -Dieter) , 1939- III . Coma,r D. IV . European Economic Community. V. Series . [DNLM: 1 . Amino Acids—metabolism—congresses . 2 . Proteins - -biosynthesis—congresses . 3 . Tomography, Emission-Computed- -congresses. W 1 DE998KF v.23 ] QP561.P84 199 3 612.3'98--dc2 0 DNLM/DCL for Librar y o f Congress 92-4895 1 ISBN 978-94-010-4706-7 Printed on acid-free paper All Rights Reserved © 1993 Springer Science+Business Media Dordrecht Originally published by Kluwer Academci Publishers in 1993 No part of the material protected by this copyright notice may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording or by any information storage and retrieval system, without written permission from the copyright owner. MEDICAL AND HEALTH RESEARCH PROGRAMME OF THE EC BIOMEDICAL ENGINEERING IN THE EUROPEAN COMMUNITY The involvement of the European Community (EC) in the field of Medical and Health Research started in 1978 with the first Programme which contained three projects. Since then, it has steadily expanded and it will include around 120 projects by the end of the fourth Programme (1987-1991). The general goal of the programme is clearly to contribute to a better quality of life by improving health, and its distinctive feature is to strengthen European collaboration in order to achieve this goal. The main objectives of this collaboration are: increase the scientific efficiency of the relevant research and development efforts in the Member States through their gradual coordination at Community level following the mobiliza tion of the available research potential of national programmes, and also their economic efficiency through sharing of tasks and strengthening the joint use of available health research resources, improve scientific and technological knowledge in the research and development areas selected for their importance to all Member States, and promote its efficient transfer into practical applications, taking particular account of potential industrial and economic developments in the areas concerned, optimize the capacity and economic efficiency of health care efforts throughout the countries and regions of the Community. The current programme consists of six research targets. Four are related to major health problems: CANCER, AIDS, AGE-RELATED PROBLEMS, and PERSONAL ENVIRONMENT AND LIFE-STYLE RELATED PROBLEMS; two are related to health resources: MEDICAL TECHNOLOGY DEVELOPMENT and HEALTH SERVICES RESEARCH. Funds are provided by the Community for relevant "concerted action" activities which consist of research COLLABORATION and COORDINATION in EC Member States and/or in other European participant countries. NElWORKS of research institutes can be set up and supported by means of meetings, workshops, short-term staff exchanges/visits to other countries, information dissemination and so on; centralized facilities such as data banks, computing, and preparation and distribution of reference materials can also be funded. The funds are not direct research grants; the institutes concerned must fund the research activities carried out within their own countries - it is the international coordination activitie~ ,\'hich are eligible for Community support. Each such research network is placed under the responsibility of a PROJECT LEADER chosen from among the leading scientists in the network, with the assistance of a PROJECT MANAGEMENT GROUP representing the teams participating in the network. The Commission of the European Communities is assisted in the execution of this programme by a Management and Coordination Advisory Committee (CGC - Medical and Health Research), and by Concerted Action Committees (COMACs) and Working Parties, composed of repre sentatives and of scientific experts respectively, designated by the competent authorities of the Member States. Other European countries, not belonging to the EC but participating in COST (Cooperation on Science and Technology) may take part in the Programme. The present work was conducted according to the advice of COMAC-BME which supervises the coordination of research in biomedical engineering (BME) within the Medical Technology Development target. More information may be obtained from: Commission of the European Communities Directorate General XII-F-6 200 Rue de la Loi B - 1049 Brussels CONTENTS Preface xi List of Contributors Xlll PART ONE: Biochemistry and animal studies 1. Cerebral protein turnover: aspects and problems 1 A. Lajtha, D. Dunlop, and M. Banay-Schwartz 2. Determination of regional rates of cerebral protein synthesis in vivo with L-[ 1-14C]leucine as the tracer amino acid 19 C. Beebe Smith 3. Methionine metabolism in rat brain 41 P. Bobillier, E. Grange, A. Gharib, M. Leclerc, N. Sarda and P. Lepetit 4. Protein synthesis studies in rats with methionine 53 A.M. Planas, C. Prenant, B.M. Mazoyer, S. Chadan, D. Comar and L. DiGiamberardino Discussion 69 PART TWO: PET Radiochemistry 5. Carbon-l1 amino acids, labeling and metabolites 75 W. Vaalburg, P.H. Elsinga and A.M.J. Paans 6. Quality control aspects in the preparation of [llC]-methionine 81 K. Nagren 7. Production of L-[18P]fluoro amino acids for protein synthesis: overview and recent developments in nucleophilic syntheses 89 C. Lemaire 8. Biochemistry and evaluation of fluoroamino acids 109 H.H. Coenen Discussion 131 viii PART THREE: Amino acid uptake modeling 9. Kinetic modeling of fluorotyrosine uptake 133 K. Wienhard, K. Herholz, H.H. Coenen, J. Rudolf, P. Kling, G. Stocklin and W.-D. Heiss 10. Kinetic modeling of carbon-ll labeled amino acids 149 G. Blomqvist 11. Carbon-ll labeled tyrosine as a probe for modeling the protein synthesis rate 161 A.M.J. Paans, P.H. Elsinga and W. Vaalburg 12. Kinetic modeling of carbon-ll labeled methionine 175 H. Lundqvist 13. Approaches to quantitative analysis of amino acid transport and metabolism 183 G.-J. Meyer, J. van den Hoff, W. Burchert and H. Hundeshagen 14. HC-methionine and rubidium uptake in human brain tumors: 82 comparison of carrier dependent blood-brain barrier transport 197 U. Roelcke, E.W. Radii and K.L. Leenders Discussion 201 PART FOUR: Clinical applications 15. Tracers for clinical evaluation of gliomas: a neurologist's view 203 K. Herholz 16. PET studies of amino acid metabolism: integration in clinical routine and current research on intracranial tumours 215 K. Ericson 17. Uptake of [llC]methionine in non-brain tumors 223 S. Leskinen-Kallio 18. Utilization of amino acid transport rates for the differential diagnosis of brain tumors 227 G.-J. Meyer, W. Burchert, K.-F. Gratz and H. Hundeshagen ix 19. Use of amino acid uptake and protein synthesis rates for tumour diagnosis 237 H. Lundqvist 20. HC-methionine uptake in brain tumors measured by PET: early clinical results 243 B. Sadzot, B. Kaschten, G. Delfiore, J.M. Peters, A. Stevenaert, G. Franck and D. Comar 21. HC-labeled methionine uptake in gliomas: modification after therapy and metabolic correlations 255 M.-C. Petit-Taboue, F. Dauphin and J.-M. Derlon 22. In vivo incorporation of labeled methionine into proteins in brain tumors 265 A.M. Planas, B. Kaschten, B. Sadzot, A. Stevenaert, L. DiGiamberardino and D. Comar Discussion 267 PREFACE Parameters such as membrane transport, metabolism and protein incorporation govern the fate of amino acids in living tissue. Is it possible to use positron tomography to measure some of them, and what is their meaning in normal and pathological situations? These questions have been addressed for a long time and no satisfactory answer has yet been given. This book, which derives from an EEC workshop organized in the frame of the Concerted Action on 'PET Investigation of Cellular Regeneration and Degeneration', held in Lyon in February 1992, gives the present state of knowledge in this field based on the most recent studies. Contributions from 24 leading European and American scientists are presented and discussed in the following four parts: biochemistry and animal studies; amino acids labelling with positron emittors, quality control and metabolites measurement; kinetic modelling of amino acids transport, metabolism, and protein incorporation; clinical use of amino acids. The book will aid and interest biochemists, radiochemists, pharmacologists, neurologists, oncologists and medical imaging scientists. The editors wish to express their gratitude to Y. Guillet (Hopital R. Debre, Paris) and D. Wietrich (E.C. Concerted Action, Orsay) for their invaluable assistance in preparing this book. The Editors LIST OF CONTRIBUTORS G. Blomqvist, Department of Clinical Neurophysiology, Karolinska Hospital, S-104 01 STOCKHOLM, Sweden P. Bobillier, Laboratory of Pathological Anatomy, CNRS URA 1195, Rue G. Paradin, F-69372 LYON Cedex 08, France Co-authors: E. Grange, A. Gharib, M. Leclerc, N. Sarda and P. Lepetit H.H. Coenen, Clinic for Nuclear Medicine, University of Essen, Hufelandstrasse 55, DW-4300 ESSEN, Germany D. Comar, EEC Concerted Action on PET, Service Hospitalier Frederic Joliot, Hopital D'Orsay, F-91406 ORSA Y, France J.-M. Derlon, Cyceron, Boulevard Henri Becquerel, P.O. Box 5027, F-14021 CAEN Cedex, France K. Ericson, Department of Neuroradiology, Karolinska Hospital, S-104 01 STOCKHOLM, Sweden, W.-D. Heiss, Max-Planck-Institute for Neucological Research, Gleueler Str 50, DW-5000 COLOGNE, Germany K. Herholz, Max-Planck-Institute, for Neurological Research, University Clinic, Gleueler Str 50, DW-5000 COLOGNE, Germany A. Lajtha, N.S. Kline Institute for Psychiatric Research, Center for Neurochemistry, ORANGEBURG, NY 10962, U.S.A. Co-authors: D. Dunlop and M. Banay-Schwartz C. Lemaire, Liege University, B-30, Cyclotron Research Center, B-4000 LIEGE, Belgium S. Leskinen-Kallio, Department of Oncology and Radiotherapy, Turku University Central Hospital, SF-20520 TURKU, Finland H. Lundqvist, Department of Radiation Sciences, P.O. Box 535, S-751 21 UPPSALA, Sweden B.M. Mazoyer, Groupe d'Imagerie Neuro-fonctionelle, Service Hopitalier Frederic Joliot, CEA-DRIPP , Hopital R. Debre, 45, Boulevard Serrurier, F-75019 PARIS, France G.J. Meyer, Department of Nuclear Medicine and Special Biophysics, DW-3000 HANNOVER 61, Germany Co-authors Chapter 13: J. van den Hoff, W. Burchert and H. Hundeshagen Co-authors Chapter 18: W. Burchert, K.-F. Gratz and H. Hundeshagen K. NAgren, Turku Medical Cyclotron-PET Center, Radiochemistry Laboratory, Turku University, Porthaninkatu 3, SF-20500 TURKU, Finland A.M.J. Paans, PET Center, University Hospital Groningen, P.O. Box 30.001, 9700 RB GRONINGEN, The Netherlands Co-authors: P.H. Elsinga and W. Vaalburg M.-C. Petit-Taboue, Cyceron, Boulevard Henri Becquerel, P.O. Box 5027, F-14021 CAEN Cedex, France Co-authors: F. Dauphin and J.-M. Derlon