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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

With 66 Figures and 29 Tables

12 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

This work is subject to copyright. All rights are reserved, whether the whole or part of the material is con- cerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproducti- on on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current versi- on, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. Springer is a part of Springer Science+Business Media springer.com ° Springer Berlin Heidelberg 2007 The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about the application of operative techniques and contained in this book. In every individual case the user must check such information by consulting the relevant literature. Editor: Dr. Ute Heilmann Desk Editor: Wilma McHugh Production: LE-TEX Jelonek, Schmidt & Væckler GbR, Leipzig Typesetting: K + V Fotosatz, Beerfelden, Germany Cover: Frido Steinen-Broo, eStudio Calamar, Spain Printed on acid-free paper 21/3100/YL 5 4 3 2 1 0 Foreword

Some persons have thought that the increasing emphasis and development of - emitting radiotracers in nuclear medicine would result in a decrease in the develop- ment and use of single -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 , rather than or negative beta that increase the exposure of the patient and limit the doses of the tracers that can be administered with acceptable . Also, the range of positrons in tissue before they encounter an 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 . 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. VI 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

Viewpoint of the Clinician

Radiopharmaceuticals labeled with 99mTc are commercially available and are employed in more than 80% of all nuclear medicine investigations. Among the , 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 on 99mTc-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 the 99mTc 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 of 99mTc-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 using 99mTc-labeled pharmaceuti- cals in daily practice.

Wçrzburg, July 2006 Christoph Reiners Preface

99mTc pharmaceuticals mark the beginning of diagnostic nuclear medicine and have contributed to patient care worldwide. Since the short-lived was intro- duced for 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- obtained by the 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 of 99mTc 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) for 99mTc 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 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 on 99mTc pharma- ceuticals for daily practice in nuclear medicine, serving as a reference source as well as a teaching tool. Acknowledgments

Dr. Ferenc Raki—s, 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 of 99mTc-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. Raki—s 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. Contents

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 Tricarbonyl Core ...... 27 R. Schibli

2.2.1 Bioconjugates Comprising the M(CO)3 Core ...... 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-Specific 99mTc Pharmaceuticals ...... 42 2.3.4 Search for Novel Tc Pharmaceuticals ...... 46

3 Stannous Chloride in the Preparation of 99mTc Pharmaceuticals ..... 59 H. Spies, H.-J. Pietzsch 3.1 Introduction ...... 59 3.2 Stannous Chloride: the Preferred Reducing Agent for Tc Pharmaceuticals ...... 61 XIV 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 the 99Mo/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 the 99Mo/99mTc generator system ...... 81 5.2.1 Elution Efficiency ...... 81 5.2.2 The Kinetics of Decay and Growth of the 99Mo/99mTc Generator .. 82 5.2.3 Factors Affecting the Elution Yield ...... 85 5.2.4 Elution of Carrier 99Tc ...... 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 the 99Mo 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 Technetium 99mTc 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 XV

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 with 99mTc 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 of 99mTc 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. Raki—s, J. Imre 9.1.3 Electrophoresis ...... 143 J. Imre 9.2 Determination of Tin(II) ...... 144 F. Raki—s 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 XVI Contents

10 Other Tc : 94mTc as a Potential Substitute in Tomography Investigations ...... 151 Z. Kov—cs 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 of 99mTc 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. J—noki 12.2.2 99mTc-Albumin Macroaggregates (MAA) ...... 187 I. Zolle and Gy. J—noki 12.2.3 99mTc-Albumin Microspheres (HAM) ...... 194 I. Zolle Contents XVII

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 12.3.2.2 99mTc-Albumin Nanocolloid ...... 230 I. Zolle 12.4 99mTc-Labeled Myocardial Agents ...... 237 12.4.1 99mTc-MIBI (Methoxyisobutyl Isonitrile) ...... 237 F. Raki—s 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. Raki—s 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. J—noki 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 () ...... 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 99m 12.8.4 Tc-MAG3 (Mercaptoacetyltriglycine) ...... 308 F. Raki—s and I. Zolle XVIII Contents

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. Raki—s 12.11.2 99mTc-Sulesomab ...... 333 F. Raki—s

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 List of Contributors

Andreas G. Bratouss Gyæzæ A. J—noki Nuklearmedizinische Klinik Department of Applied Radioisotopes Klinikum Buch Frederic Joliot- National Research Helios Kliniken Berlin Institute of Wiltbergstraûe 50 and Radiohygiene 13125 Berlin, Germany 1221 Budapest, Hungary

Per Oscar Bremer Silvester Kladnik Radioformulation Development Department of Nuclear Medicine GE Healthcare University Medical Centre Ljubljana Instituttveien 18 1525 Ljubljana, Slovenia PO Box 65 2027 Kjeller, Norway Zolt—n Kov—cs Radiochemistry Group Trygve Bringhammar Institute of Nuclear Research Medical Products Agency Hungarian Academy of Sciences Radiopharmaceuticals 4001 Debrecen, DOB 51, Hungary 75103 Uppsala, Sweden JÕzsef Kærnyei Efstratios Chiotellis Research and Development Dept. of Pharmaceutical Chemistry Radiopharmaceutical Business Line School of Pharmacy Institute of Isotopes Co., Ltd. Aristotelian University of Thessaloniki Konkoly Thege M. Street, 29±33 G-54124 Thessaloniki, Greece 1121 Budapest, Hungary

Clemens Decristoforo Jens-Uwe Kçnstler Medical Department of Nuclear Medicine Research Centre Rossendorf Medical University Innsbruck Institute of Radiopharmacy Anichstraûe 35 PF 510 119 6020 Innsbruck, Austria 01314 Dresden, Germany

Stuart R. Hesslewood Jesus Mallol Escobar Department of Physics Universidad de La Laguna, Tenerife and Nuclear Medicine Schering Espaµa, SA City Hospital NHS Trust 28045 Madrid, Spain Birmingham B18 7QH United Kingdom Ulderico Mazzi Professor of Pharmaceutical Sciences J—nos Imre University of Padova National Institute of Pharmacy Via F. Marzolo, 5 Radiochemistry Section 35131 Padova, Italy 1051 Budapest, Hungary XX List of Contributors

Hans-Juergen Pietzsch Helmut Sinzinger Research Centre Rossendorf Department of Nuclear Medicine Institute of Radiopharmacy Medical University Vienna PF 510 119 1090 Vienna, Austria 01314 Dresden, Germany Hartmut Spies Ferenc Raki—s Research Centre Rossendorf Drug Quality Department Institute of Radiopharmacy National Institute of Pharmacy PF 510119 1051 Budapest, Hungary 01314 Dresden, Germany

Margardia Rodrigues Alfons Verbruggen Department of Nuclear Medicine Professor of Radiopharmaceutical Medical University Vienna Chemistry 1090 Vienna, Austria Onderwijs en Navorsing 2, Box 821 Herestraat 49 Roger Schibli 3000 Leuven, Belgium Center for Radiopharmaceutical Science, OIPA Ilse Zolle Paul Scherrer Institute Department of Medicinal/ ETH Zçrich Pharmaceutical Chemistry 5232 Villigen PSI, Switzerland University of Vienna Althanstraûe 14 1090 Vienna, Austria