Ilse Zolle
Editor
Technetium-99m Pharmaceuticals
Gedruckt mit Unterstçtzung des Bundesministeriums fçr Bildung, Wissenschaft und Kultur in Wien
und der Kulturabteilung der Stadt Wien, Wissenschafts- und Forschungsfærderung
Ilse Zolle Editor
Technetium-99m Pharmaceuticals
Preparation and Quality
Control in Nuclear Medicine
With 66 Figures and 29 Tables
1 2
Ilse Zolle
Department of Medicinal/Pharmaceutical Chemistry University of Vienna
Althanstraûe 14 1090 Vienna Austria
Library of Congress Control Number 2006925440
ISBN-10 3-540-33989-2 Springer Berlin Heidelberg New York ISBN-13 978-3-540-33989-2 Springer Berlin Heidelberg New York
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Some persons have thought that the increasing emphasis and development of positron- emitting radiotracers in nuclear medicine would result in a decrease in the develop- ment and use of single photon-emitting radiotracers. That this is not the case is illu- strated by the fact that there were 302 presentations involving technetium-99m at the June 2006 annual meeting of the Society of Nuclear Medicine in the United States. Io- dine-123 accounted for 88 presentations, and indium-111 for 81.
Among the most recent advances in the fusion of nuclear medicine images with computed tomography (SPECT/CT) and computed tomography angiography (SPECT/
CTA) in basic science studies in small animals, SPECT/CT was the topic of 11 instru- mentation presentations, while PET/CT in small animals accounted for 5 presentations.
The success of molecular imaging in medicine and biomedical research is the result of the diversity of imaging technologies, the integrating and collaboration of imaging and pharmaceutical development experts, and friendly competitition. The advantage of single photon tracers is that many of them, such as technetium-99m, emit only photons, rather than positrons or negative beta particles that increase the radiation exposure of the patient and limit the doses of the tracers that can be administered with acceptable radiation exposure. Also, the range of positrons in tissue before they encounter an electron and emit 511 keV photons limits the spatial resolution that can be obtained in living animals and patients. Theoretically, the spatial resolution of single photon tracer studies is limitless, especially with the use of special pinhole collimation.
Radioactive tracers used in medicine today provide information, and need to be judged by how reliably they provide this information. Some of the safeguards built into the drug review process by the FDA for regulating pharmaceuticals are not needed in the case of the mass of injected material used in radiopharmaceuticals. With radiophar- maceuticals, the criterion should be whether the information provided by the diagnos- tic procedure is valid and valuable.
Today, we need to promote a ªfast trackº regulatory approval process to make diag- nostic procedures more readily available. A major difference between therapeutic and diagnostic drugs is that the efficacy of the diagnostic procedure in providing the re- quired information can be assessed shortly after the performance of the imaging proce- dure. The patients do not need to be followed for longer periods of time to identify any untoward side effects. Multi-institutional randomized control studies can determine whether the procedure provides the diagnostic information provided by the study, as well as identify any untoward side-effects.
Radiotracers, by definition, have no effect on the patients' biochemistry or body functions, which should be a major simplifying factor along the road to their regula- tory approval. There is ever-increasing evidence of their great value in answering the questions: What is wrong? What is going to happen? What can be done about it? How did it happen?
This book covers the past, present and future of single photon tracers in medical practice and biomedical research. It is likely to become a standard textbook for those persons entering the exciting career of a radiopharmacist or researcher in biomedical research using radioactive tracers.
Foreword
The pathway to assuring the safe and effective use of short-lived radiotracers is to place the responsibility for quality assurance in the hands of nuclear pharmacists who fill physician's prescriptions for radiotracers as they do for other drugs under state pharmacy laws. Radiochemists or others working in institutions with radiopharmacies must have the expertise for the preparation of the radiotracers as well as for quality control under good manufacturing practices. This book provides guidance and safety standards applicable to Tc-99m pharmaceuticals.
Baltimore, June 2006 Henry N. Wagner, Jr. M.D.
Foreword VI
Viewpoint of the Clinician
Radiopharmaceuticals labeled with99mTc are commercially available and are employed in more than 80% of all nuclear medicine investigations. Among the radionuclides, technetium-99m is most attractive to the nuclear medicine physician because of its op- timal gamma energy for SPECT, its availability, its relatively low cost, and its easy-to-la- bel kit preparations for in-house use. Another advantage is the low radiation burden to patients, due primarily to its short half-life. The decay within hours also facilitates the handling of waste.
Professor Dr. Ilse Zolle ± together with other leading international radiochemists and radiopharmacists ± made an effort to collect the available data on99mTc-labeled compounds with respect to their chemistry, labeling methods, quality control proce- dures and clinical applications. The comprehensive text is presented in two parts. The first part comprises chapters on technetium compounds in medicine, including ad- vances in labeling biomolecules with technetium, the advantages of sterile kit formula- tions, and analytical methods to verify pharmaceutical quality. Emphasis is given to the rules governing the manufacture of radiopharmaceuticals and the importance of specifications given by the pharmacopoeia, which are obligatory. A special chapter is devoted to the performance of the 99Mo/99mTc generator and to the characteristics of the99mTc eluate.
For the clinician, Part II offers 25 monographs relating to 99mTc-pharmaceuticals, which describe the pharmaceutical particulars of each radiotracer as well as relevant information on its clinical application, concerning the pharmaceutical dosage, contra- indications and interference with other pharmaceuticals, quality control, pharmacoki- netic data, radiation dose and valuable references. In addition, recommendations for storage and criteria of stability are also given.
The multidisciplinary properties of99mTc-pharmaceuticals are presented in the form of a highly structured text with informative tables, which enables the clinician to find clinically relevant data very easily.
The book should therefore not only be recommended for radiochemists and radio- pharmacists, but also for nuclear medicine physicians using99mTc-labeled pharmaceuti- cals in daily practice.
Wçrzburg, July 2006 Christoph Reiners
Foreword
99mTc pharmaceuticals mark the beginning of diagnostic nuclear medicine and have contributed to patient care worldwide. Since the short-lived radionuclide was intro- duced for thyroid imaging in 1964, it has attracted much attention and stimulated clini- cal research. Little was known about element 43, except that it was an artificial radio- nuclide obtained by the radioactive decay of molybdenum-99. No wonder specialists from all fields joined medical institutions in the United States to participate in the ex- ploration of its chemistry.
This textbook gives an account of the accomplishments related to the development of 99mTc pharmaceuticals and their application in diagnostic nuclear medicine. Since radioactive drug development is a multidisciplinary task, experts working in nuclear medicine and research institutions have contributed valuable information concerning the preparation with sterile kits, methods of quality control, and the use of99mTc phar- maceuticals in patients. In addition, the legal aspects governing production and clinical application are also considered.
99mTc pharmaceuticals in nuclear medicine are presented in two parts. Part 1 in- cludes basic principles and methods used for preparation and analysis, in particular the chemistry of technetium-99m and methods described for the synthesis of com- plexes and conjugates of technetium-99m, the characteristics and performance of the
99Mo/99mTc generator system, the importance of kits and formulations for one-step la- beling, and safety aspects for labeling blood cells. Special emphasis is given to analyti- cal methods verifying pharmaceutical quality. The quality standards of good manufac- turing practice (GMP) for99mTc pharmaceuticals and purity standards of the pharma- copeia (European Pharmacopeia and United States Pharmacopeia) have been consider- ed as part of the concept of quality assurance.
Part 2 presents 26 monographs of 99mTc pharmaceuticals, concerning the prepara- tion and safe clinical application. Each monograph provides information on the charac- teristics of the radiotracer based on chemistry, factors affecting the preparation and in vivo stability, pharmacokinetics and elimination properties, as well as details concern- ing the clinical application. For each clinical procedure, the effective radiation dose of the patient has been calculated. Methods recommended for quality control and actual results are included.
Each radiopharmaceutical is listed under the name used in daily practice. The chemical name, the abbreviated name, and the officinal name in the pharmacopeia are also stated. Listing the trade names may facilitate understanding, especially when relat- ing to products in the literature, which over the years have changed manufacturers.
The presentation of 99mTc pharmaceuticals as monographs serves a practical pur- pose: it offers relevant information on kit preparation and clinical application at a glance. These monographs provide a wide spectrum of information on99mTc pharma- ceuticals for daily practice in nuclear medicine, serving as a reference source as well as a teaching tool.
Preface
Dr. Ferenc Rakis, Deputy Chief of Drug Quality, The National Institute of Pharmacy in Budapest, Hungary and Co-ordinator of a European Working Group on the Quality Control of99mTc-Radiopharmaceuticals (COST Action B3) has gained high recognition for major contributions, which resulted from the collective effort of the Working Group. Based on studies of quality control methods, and a collection of manuscripts, Dr. Rakis and his dedicated staff have produced a first version of this book, docu- menting the multidisciplinary nature of the cooperation. The National Institute of Pharmacy in Budapest has also hosted most Working Group meetings, their hospitality is appreciated.
The participation of Austrian scientists in COST Action B3 was supported by:
The Federal Ministry of Education, Science, and Culture, actively promoted by:
Dr. Norbert Rozsenich, Head, Section V, Commerce and Technology
Hofrat Dr. Raoul Kneucker, Head, Section VI, Scientific Research and International Affairs
Ministerialrat Dr. Helga Mieling, National COST Co-ordinator
Dipl. Ing. Otto Zellhofer, Science, Energy and Space Program 'AUSTROMIR' Ministerialrat Alois Sæhn, Presidial Division 4
Hofrat Mag. Anna Kolde, and Regierungsrat Franz Gerersdorfer
The Department of Nuclear Medicine and the Ludwig-Boltzmann-Institute of Nuclear Medicine, Professor Emeritus Dr. Rudolf Hæfer, and
the Department of Biomedical Engineering and Physics, Professor Dr. Helmar Berg- mann, all at the University Hospital AKH, Vienna.
Editorial work was kindly supported by Hofrat Dipl.-Ing. Gerhard Wolf and his team, Mrs. Elisabeth Abromeit and Mrs. Sandra Jama
The assistance of Dr. Yu Jie (Julia) and Mag. pharm. Georg Kropf is gratefully acknowl- edged.
Acknowledgments
Part I
1 Drug Safety . . . . 1
I. Zolle 1.1 Quality Control and COST . . . . 3
1.2 Quality Standards . . . . 4
1.3 Quality Assurance . . . . 4
1.4 Quality Control of Kit Products . . . . 4
1.5 European Economic Community Directives and Regulations . . . . 5
2 Technetium in Medicine . . . . 7
2.1 99mTechnetium Chemistry . . . . 7
U. Mazzi 2.1.1 Technetium Compounds and their Structures . . . . 8
2.1.2 Technetium(V) Complexes . . . . 9
2.1.3 Technetium(IV), (III), and (I) Complexes . . . . 17
2.1.4 99mTc Labeling . . . . 20
2.2 Technetium and Rhenium Tricarbonyl Core . . . . 27
R. Schibli 2.2.1 Bioconjugates Comprising the M(CO)3Core . . . . 32
2.3 Technetium Coupled With Biologically Active Modules . . . . 40
H.-J. Pietzsch, J.-U. Kçnstler and H. Spies 2.3.1 Introduction . . . . 40
2.3.2 Factors Affecting In Vivo Performance . . . . 41
2.3.3 Chelate Units in the Design of Target-Specific99mTc Pharmaceuticals . . . . 42
2.3.4 Search for Novel Tc Pharmaceuticals . . . . 46
3 Stannous Chloride in the Preparation of99mTc Pharmaceuticals . . . . . 59
H. Spies, H.-J. Pietzsch 3.1 Introduction . . . . 59
3.2 Stannous Chloride: the Preferred Reducing Agent for Tc Pharmaceuticals . . . . 61
Contents
4Quality Assurance of Radiopharmaceuticals . . . . 67
T. Bringhammar, I. Zolle 4.1 Introduction . . . . 67
4.2 Definitions . . . . 67
4.2.1 Quality Assurance . . . . 67
4.2.2 Good Manufacturing Practice . . . . 68
4.2.3 Pharmacopeias . . . . 70
4.2.4 Approval for Marketing Authorization of a Radiopharmaceutical . . 71
4.2.5 Quality Control . . . . 71
5 Performance and Quality Control of the99Mo/99mTc Generator . . . . . 77
I. Zolle 5.1 The Equilibrium State . . . . 78
5.1.1 Production of Molybdenum-99 . . . . 79
5.1.2 Separation Methods . . . . 79
5.1.3 Design of the Generator Column . . . . 80
5.1.4 The Generator Eluate . . . . 80
5.2 Performance of the99Mo/99mTc generator system . . . . 81
5.2.1 Elution Efficiency . . . . 81
5.2.2 The Kinetics of Decay and Growth of the99Mo/99mTc Generator . . 82
5.2.3 Factors Affecting the Elution Yield . . . . 85
5.2.4 Elution of Carrier99Tc . . . . 85
5.3 Purity of Generator Eluate (European Pharmacopeia) . . . . 86
5.3.1 Radionuclidic Purity . . . . 86
5.3.2 Radiochemical Purity . . . . 86
5.3.3 Chemical Purity . . . . 87
5.3.4 pH of Eluate . . . . 87
5.4 Methods and Results . . . . 87
5.4.1 Determination of the Elution Efficiency . . . . 87
5.4.2 Determination of the99Mo Content of the Eluate . . . . 87
5.4.3 Determination of the Radiochemical Purity of the Eluate . . . . 89
5.4.4 Determination of the Chemical Purity of the Eluate . . . . 89
5.5 Conclusions . . . . 90
6 Preparation of Technetium99mTc Pharmaceuticals . . . . 95
J. Mallol, I. Zolle 6.1 Introduction . . . . 95
6.1.1 Physical Characteristics . . . . 95
6.1.2 Chemical Characteristics . . . . 95
6.2 Kit Preparation . . . . 95
6.2.1 General Considerations . . . . 96
6.2.2 Cold Kits . . . . 96
6.2.3 99mTc-Pertechnetate . . . . 97
6.2.4 Incubation . . . . 97 Contents
XIV
6.2.5 Quality Control . . . . 97
6.2.6 Dispensing . . . . 98
7 Lyophilization Technique for Preparing Radiopharmaceutical Kits . . . 99
E. Chiotellis 7.1 History of the Lyophilization Technique . . . . 99
7.2 Principles of Lyophilization . . . . 100
7.3 Apparatus for Freeze-Drying . . . . 101
7.3.1 The Drying Chamber . . . . 101
7.3.2 The Ice Condenser . . . . 101
7.3.3 The Refrigeration Unit . . . . 101
7.3.4 The Vacuum Pump . . . . 102
8 Cellular Labeling with99mTc Chelates: Relevance of In Vitro and In Vivo Viability Testing . . . . 103
H. Sinzinger, M. Rodrigues 8.1 Introduction . . . . 103
8.2 Red Blood Cells . . . . 103
8.3 Platelets . . . . 108
8.4 White Blood Cells . . . . 114
8.5 Stem Cells . . . . 118
8.6 Conclusions . . . . 118
9 Quality Control Methods of99mTc Pharmaceuticals . . . . 123
9.1 Determination of Chemical Purity . . . . 123
9.1.1 Thin-Layer Chromatography . . . . 123
C. Decristoforo, I. Zolle 9.1.2 Column Chromatography . . . . 136
F. Rakis, J. Imre 9.1.3 Electrophoresis . . . . 143
J. Imre 9.2 Determination of Tin(II) . . . . 144
F. Rakis 9.3 Sterility Testing of Radiopharmaceuticals . . . . 146
S.R. Hesslewood 9.3.1 Problems in Applying European Pharmacopeia Test to Radiopharmaceuticals . . . . 146
9.3.2 Recommendations for Sterility Testing of Radiopharmaceuticals . . 147
9.3.3 Frequency of Testing . . . . 148
9.4 Pyrogen Testing of Radiopharmaceuticals . . . . 148
S.R. Hesslewood 9.4.1 Recommendations for Endotoxin Determinations of Radiopharmaceuticals . . . . 149
Contents XV
10 Other Tc Isotopes:94mTc as a Potential Substitute in Positron Emission
Tomography Investigations . . . . 151
Z. Kovcs 10.1 Introduction . . . . 151
10.2 Methods of Production . . . . 151
10.3 Methods of Separation . . . . 152
11 The Rules Governing Medicinal Products for Human Use in the European Union . . . . 155
11.1 European Economic Community Directives and Regulations . . . . 155
A. Verbruggen, I. Zolle 11.1.1 Application for Marketing Authorization . . . . 157
11.1.2 Industrial Production . . . . 158
11.1.3 Marketing Authorization . . . . 158
11.1.4 Sales and Distribution . . . . 159
11.1.5 Pharmacovigilance . . . . 159
11.1.6 Other Aspects . . . . 159
11.1.7 SPC for Radiopharmaceutical Products . . . . 160
11.2 The European Pharmacopeia . . . . 161
A. Verbruggen 11.2.1 General . . . . 161
11.2.2 Monographs on Radiopharmaceuticals in the European Pharmacopeia . . . . 162
11.2.3 Elaboration of New European Pharmacopeia Monographs on Radiopharmaceutical Preparations . . . . 163
11.3 European Union Legislation Concerning New Drug Development . . . . 165
A. Verbruggen 11.3.1 European Commission Directives and Guidelines . . . . 165
11.3.2 Clinical Trials . . . . 166
11.3.3 CTA Requirements . . . . 166
Part 2 12 Monographs of99mTc Pharmaceuticals . . . . 173
12.1 99mTc-Pertechnetate . . . . 173
I. Zolle and P.O. Bremer 12.2 99mTc-Labeled Human Serum Albumin . . . . 181
12.2.1 99mTc-Albumin (HSA) . . . . 181
I. Zolle and Gy. Jnoki 12.2.2 99mTc-Albumin Macroaggregates (MAA) . . . . 187
I. Zolle and Gy. Jnoki 12.2.3 99mTc-Albumin Microspheres (HAM) . . . . 194
I. Zolle Contents
XVI
12.3 99mTc-Labeled Colloids . . . . 201 12.3.1 99mTc-Labeled Microcolloids . . . . 201
I. Zolle
12.3.1.1 99mTc-Tin Colloid (Size Range: 0.2±0.8 lm) . . . . 201 I. Zolle
12.3.1.2 99mTc-Rhenium Sulfide Colloid . . . . 207 I. Zolle
12.3.1.3 99mTc-Albumin Microcolloid . . . . 213 I. Zolle
12.3.1.4 99mTc-Albumin Millimicrospheres . . . . 218 I. Zolle
12.3.2 99mTc-Labeled Nanocolloids . . . . 224 12.3.2.1 99mTc-Rhenium Sulfide Nanocolloid . . . . 224
I. Zolle
12.3.2.299mTc-Albumin Nanocolloid . . . . 230 I. Zolle
12.4 99mTc-Labeled Myocardial Perfusion Agents . . . . 237 12.4.1 99mTc-MIBI (Methoxyisobutyl Isonitrile) . . . . 237
F. Rakis and I. Zolle
12.4.2 99mTc-Tetrofosmin . . . . 245 J. Imre and I. Zolle
12.5 99mTc-Labeled Brain Perfusion Agents . . . . 251 12.5.1 99mTc-HMPAO (Hexamethylpropylene Amine Oxime) . . . . 251
F. Rakis and I. Zolle
12.5.2 99mTc-ECD (Ethyl Cysteinate Dimer) . . . . 260 J. Imre and I. Zolle
12.6 99mTc-Labeled Leukocytes . . . . 266 I. Zolle and Gy. Jnoki
12.7 99mTc-Labeled Bone Imaging Agents . . . . 271 12.7.1 99mTc-Pyrophosphate (PYP) . . . . 271
S. Kladnik and I. Zolle
12.7.2 99mTc-Diphosphonates . . . . 280 I. Zolle and S. Kladnik
12.8 99mTc-Labeled Renal Imaging Agents . . . . 291 12.8.1 99mTc-DMSA (Dimercaptosuccinic Acid) . . . . 291
J. Kærnyei and I. Zolle
12.8.2 99mTc-DPTA (Diethylenetriaminepentaacetate) . . . . 297 J. Kærnyei and I. Zolle
12.8.3 99mTc-EC (Ethylene Dicysteine) . . . . 303 J. Kærnyei
12.8.4 99mTc-MAG3(Mercaptoacetyltriglycine) . . . . 308 F. Rakis and I. Zolle
Contents XVII
12.9 99mTc-Labeled Hepatobiliary Agents . . . . 315 12.9.1 99mTc-IDA (Iminodiacetic Acid) Derivatives . . . . 315
I. Zolle and A.G. Bratouss
12.10 99mTc-Labeled Peptides . . . . 322 12.10.1 99mTc-Depreotide . . . . 322
I. Zolle
12.11 99mTc-Labeled Monoclonal Antibodies . . . . 328 12.11.1 99mTc-Arcitumomab . . . . 328
F. Rakis
12.11.2 99mTc-Sulesomab . . . . 333 F. Rakis
Appendix 1
Table A1, Administration of Radioactive Substances Advisory Committee
(ARSAC): radiation doses for children . . . . 339 Table A2, European Association of Nuclear Medicine (EANM): radiation
doses for children (issued by the Pediatric Task Group of the EANM) . . . . 340 Recommended Reading . . . . 340 Appendix 2
Scope of COST B3 . . . . 343 Contents
XVIII
List of Contributors
Andreas G. Bratouss Nuklearmedizinische Klinik Klinikum Buch
Helios Kliniken Berlin Wiltbergstraûe 50 13125 Berlin, Germany Per Oscar Bremer
Radioformulation Development GE Healthcare
Instituttveien 18 PO Box 65
2027 Kjeller, Norway Trygve Bringhammar Medical Products Agency Radiopharmaceuticals 75103 Uppsala, Sweden Efstratios Chiotellis
Dept. of Pharmaceutical Chemistry School of Pharmacy
Aristotelian University of Thessaloniki G-54124 Thessaloniki, Greece
Clemens Decristoforo
Medical Department of Nuclear Medicine Medical University Innsbruck
Anichstraûe 35
6020 Innsbruck, Austria Stuart R. Hesslewood Department of Physics and Nuclear Medicine City Hospital NHS Trust Birmingham B18 7QH United Kingdom Jnos Imre
National Institute of Pharmacy Radiochemistry Section 1051 Budapest, Hungary
Gyæzæ A. Jnoki
Department of Applied Radioisotopes Frederic Joliot-Curie National Research Institute of Radiobiology
and Radiohygiene 1221 Budapest, Hungary Silvester Kladnik
Department of Nuclear Medicine University Medical Centre Ljubljana 1525 Ljubljana, Slovenia
Zoltn Kovcs Radiochemistry Group Institute of Nuclear Research Hungarian Academy of Sciences 4001 Debrecen, DOB 51, Hungary JÕzsef Kærnyei
Research and Development Radiopharmaceutical Business Line Institute of Isotopes Co., Ltd.
Konkoly Thege M. Street, 29±33 1121 Budapest, Hungary Jens-Uwe Kçnstler Research Centre Rossendorf Institute of Radiopharmacy PF 510 119
01314 Dresden, Germany Jesus Mallol Escobar
Universidad de La Laguna, Tenerife Schering Espaµa, SA
28045 Madrid, Spain Ulderico Mazzi
Professor of Pharmaceutical Sciences University of Padova
Via F. Marzolo, 5 35131 Padova, Italy
List of Contributors XX
Hans-Juergen Pietzsch Research Centre Rossendorf Institute of Radiopharmacy PF 510 119
01314 Dresden, Germany Ferenc Rakis
Drug Quality Department National Institute of Pharmacy 1051 Budapest, Hungary Margardia Rodrigues
Department of Nuclear Medicine Medical University Vienna 1090 Vienna, Austria Roger Schibli
Center for Radiopharmaceutical Science, OIPA
Paul Scherrer Institute ETH Zçrich
5232 Villigen PSI, Switzerland
Helmut Sinzinger
Department of Nuclear Medicine Medical University Vienna 1090 Vienna, Austria Hartmut Spies
Research Centre Rossendorf Institute of Radiopharmacy PF 510119
01314 Dresden, Germany Alfons Verbruggen
Professor of Radiopharmaceutical Chemistry
Onderwijs en Navorsing 2, Box 821 Herestraat 49
3000 Leuven, Belgium Ilse Zolle
Department of Medicinal/
Pharmaceutical Chemistry University of Vienna Althanstraûe 14 1090 Vienna, Austria
