Radiopharmaceuticals for Positron Emission Tomography, Volume 1 E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Serie: Wiley Series on Radiochemical Syntheses
• Sprache: Englisch

Seitenzahl: 453

Veröffentlichungsjahr: 2011

Beschreibung

The ultimate reference guide to the synthesis of radiopharmaceuticals

The Radiochemical Syntheses series provides scientists and professionals with a comprehensive reference to proven synthetic methods for radiochemical reactions, along with step-by-step guidance on how to replicate these syntheses in the laboratory.

Volume 1 in the series focuses on the synthesis and purification of radiopharmaceuticals in clinical use today. It brings together in one complete, self-contained volume a collection of monographs containing a wealth of practical information from across the literature, demonstrating in meticulous detail how to prepare radiopharmaceuticals for positron emission tomography (PET) imaging, especially in tumor studies, cardiology, and neuroscience.

Readers have key experimental details culled from the literature at their fingertips, greatly simplifying the process of qualifying a site for the clinical production of new radiopharmaceuticals.

Leseprobe

Table of Contents

Title Page

Series Page

Copyright

Contributors

Foreword

Preface

Abbreviations

Part I: Fluorine-18 Labeled Radiopharmaceuticals

Chapter 1: Synthesis of [18F]-Fluorodeoxyglucose ([18F]FDG)

1.1 Introduction

1.2 Synthesis Procedures

1.3 Quality Control Procedures

1.4 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Chapter 2: Synthesis of Sodium [18F]Fluoride (Na[18F]F)

2.1 Introduction

2.2 Synthesis Procedures

2.3 Quality Control Procedures

2.4 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Chapter 3: Radiosynthesis of 3′-Deoxy-3′-[18F]Fluorothymidine ([18F]FLT)

3.1 Introduction

3.2 Synthesis Procedures

3.3 Quality Control Procedures

3.4 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Chapter 4: Synthesis of [18F]Fluoroazomycin Arabinoside ([18F]FAZA)

4.1 Introduction

4.2 Synthesis Procedures

4.3 Quality Control Procedures

4.4 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Chapter 5: Synthesis of [18F]Fluoromisonidazole (1-(2-Hydroxy-3-[18F]Fluoropropyl)-2-Nitroimidazole, [18F]FMISO)

5.1 Introduction

5.2 Synthesis Procedure

5.3 Quality Control (QC) Procedures

5.4 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Chapter 6: Synthesis of [18F]FPPRGD2

6.1 Introduction

6.2 Synthesis Procedures

6.3 Quality Control Procedures

6.4 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Chapter 7: Synthesis of [18F]Fluorocholine ([18F]FCH)

7.1 Introduction

7.2 Synthesis Procedures

7.3 Quality Control Procedures

7.4 Acknowledgment

7.5 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Chapter 8: Clinical Manufacturing of [18F]-16-α-Fluoroestradiol ([18F]FES)

8.1 Introduction

8.2 Synthesis Procedures

8.3 Stability of [18F]FES Radiopharmaceutical

8.4 Quality Control Procedures

8.5 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Chapter 9: Synthesis of N-Succinimidyl 4-[18F]Fluorobenzoate ([18F]SFB)

9.1 Introduction

9.2 Synthesis Procedures

9.3 Quality Control Procedures

9.4 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Chapter 10: Synthesis of 4-(2′-Methoxyphenyl)-1-[2′-(N-2″″Pyridinyl)-p-[18F]Fluorobenzamido]Ethylpiperazine [18F]MPPF

10.1 Introduction

10.2 Synthesis Procedures

10.3 Quality Control Procedures

10.4 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Chapter 11: Synthesis of [18F]-Fallypride

11.1 Introduction

11.2 Synthesis Procedures

11.3 Quality Control Procedures

11.4 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Chapter 12: Synthesis of [18F]Fluoroethyltyrosine (18F-FET)

12.1 Introduction

12.2 Synthesis Procedure

12.3 Quality Control Procedures

12.4 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Chapter 13: Synthesis of [18F]Flumazenil ([18F]FZ)

13.1 Introduction

13.2 Synthesis Procedures

13.3 Quality Control Procedures

13.4 Chemical Abstracts Nomenclature (Registry Number)

13.5 Appendix

References and Notes

Chapter 14: Synthesis of 6-[18F]Fluorodopamine (6-[18F]FDA)

14.1 Introduction

14.2 Synthesis Procedures

14.3 Quality Control Procedures

14.4 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Chapter 15: Synthesis of 2-([18F]Fluoro)-3-[(2S)-2-Azetidinylmethoxy]Pyridine ([18F]2FA)

15.1 Introduction

15.2 Synthesis Procedures

15.3 Quality Control Procedures

15.4 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Chapter 16: Synthesis of [18F]-Substance-P Antagonist-Receptor Quantifier ([18F]SPA-RQ)

16.1 Introduction

16.2 Synthesis Procedures

16.3 Quality Control Procedures

16.4 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Part 2: Carbon-11 Labeled Radiopharmaceuticals

Chapter 17: Synthesis of [11C]Choline Chloride ([11C]CHL)

17.1 Introduction

17.2 Synthesis Procedures

17.3 Quality Control Procedures

17.4 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Chapter 18: Synthesis of 2-(4-N-[11C]Methylaminophenyl)-6-Hydroxybenzothiazole ([11C]6-OH-BTA-1; [11C]PIB)

18.1 Introduction

18.2 Synthesis Procedures

18.3 Quality Control Procedures

18.4 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Chapter 19: Synthesis of [11C]-meta-Hydroxyephedrine ([11C]MHED)

19.1 Introduction

19.2 Synthesis Procedures

19.3 Quality Control Procedures

19.4 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Chapter 20: Synthesis of -[-11C]Methionine ([11C]MET)

20.1 Introduction

20.2 Synthesis Procedures

20.3 Synthesis of -[-11C]Methionine

20.4 Preparation of -[-11C]Methionine for Injection

20.5 Quality Control Procedures

20.6 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Chapter 21: Synthesis of (+)-α-[11C]Dihydrotetrabenazine ([11C]DTBZ)

21.1 Introduction

21.2 Synthesis Procedures

21.3 Quality Control Procedures

21.4 Discussion

21.5 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Chapter 22: Synthesis of [11C]Flumazenil([11C]FMZ)

22.1 Introduction

22.2 Synthesis Procedure

22.3 Quality Control (QC) Procedures

22.4 Chemical Abstracts Nomenclature (Registry Number)

References

Chapter 23: Synthesis of [11C]Hexadecanoic Acid ([11C]Palmitic Acid)

23.1 Introduction

23.2 Synthesis Procedures

23.3 Quality Control Procedures

23.4 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Chapter 24: Synthesis of O-methyl-11C]Metomidate ([11C]-MTO)

24.1 Introduction

24.2 Synthesis Procedure

24.3 Quality Control Procedures

24.4 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Chapter 25: Synthesis of [11C]Carfentanil ([11C]CFN)

25.1 Introduction

25.2 Synthesis Procedures

25.3 Quality Control Procedures

25.4 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Chapter 26: Synthesis of [carbonyl-11C]Way-100635

26.1 Introduction

26.2 Synthesis Procedures

26.3 Quality Control Procedures

26.4 Acknowledgments

26.5 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Chapter 27: Synthesis of [11C]Raclopride

27.1 Introduction

27.2 Synthesis Procedures

27.3 Quality Control Procedures

27.4 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Chapter 28: Synthesis of 3-Amino-4-[2-(N-Methyl-N-[11C]Methyl-Amino-Methyl)Phenylsulfanyl]-Benzonitrile ([11C]Dasb)

28.1 Introduction

28.2 Synthesis Procedures

28.3 Quality Control Procedures

28.4 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Chapter 29: Synthesis of [11C]Acetate

29.1 Introduction

29.2 Synthesis Procedures

29.3 Quality Control Procedures

29.4 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Chapter 30: Synthesis of N-(2-[11C]Methoxybenzyl)-N-(4-Phenoxypyridin-3-yl)Acetamide ([11C]PBR28)

30.1 Introduction

30.2 Synthesis Procedures

30.3 Quality Control Procedures

30.4 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Part 3: Other Radiopharmaceuticals

Chapter 31: Synthesis of [13N]Ammonia ([13N]NH3)

31.1 Introduction

31.2 Synthesis Procedures

31.3 Quality Control Procedures

31.4 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Chapter 32: Synthesis of [68Ga]Gallium Dota-(Tyr3)-Octreotide Acetate ([68Ga]-Dotatoc)

32.1 Introduction

32.2 Synthesis Procedures

32.3 Quality Control Procedures

32.4 Chemical Abstracts Nomenclature (Registry Number)

References and Notes

Supplier Information

Index

For further information visit: the book web page http://www.openmodelica.org, the Modelica Association web page http://www.modelica.org, the authors research page http://www.ida.liu.se/labs/pelab/modelica, or home page http://www.ida.liu.se/~petfr/, or email the author at [email protected]. Certain material from the Modelica Tutorial and the Modelica Language Specification available at http://www.modelica.org has been reproduced in this book with permission from the Modelica Association under the Modelica License 2 Copyright © 1998–2011, Modelica Association, see the license conditions (including the disclaimer of warranty) at http://www.modelica.org/modelica-legal-documents/ModelicaLicense2.html. Licensed by Modelica Association under the Modelica License 2.

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Copyright © 2011 by the Institute of Electrical and Electronics Engineers, Inc.

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Library of Congress Cataloging-in-Publication Data:

Radiopharmaceuticals for positron emission tomography / edited by Peter J.H. Scott, Brian G. Hockley.

p. ; cm.—(Radiochemical Syntheses ; v.1)

Includes bibliographical references and index.

ISBN 978-0-470-58895-6 (cloth)

1. Radiopharmaceuticals—Synthesis. 2. Tomography, Emission.

I. Scott, Peter J. H. II. Hockley, Brian G. III. Series: Radiochemical syntheses ; v.

[DNLM: 1. Radiopharmaceuticals—chemical synthesis. 2. Positron-Emission Tomography.

3. Radiopharmaceuticals—diagnostic use. WN 415]

RS431.R34R325 2011

616.07'575–dc23

2011019940

Contributors

Franklin I. Aigbirhio Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK

Amar Alfteimi Clinic of Nuclear Medicine, Molecular Imaging and Therapy, University Hospital Schleswig-Holstein Campus Kiel, UKSH, Kiel, Germany

Marion Alvarez CERMEP-Imagerie du Vivant, Hospices Civils de Lyon, ICBMS UMR, Université Lyon 1, Bron (Lyon), France

Jan D. Andersson Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Stockholm, Sweden

Robert Bielik Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK

Guy Bormans Laboratory for Radiopharmacy, Faculty of Pharmaceutical Sciences, K.U. Leuven, Leuven, Belgium

István Boros Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK

Stefano Boschi PET Radiopharmacy, Nuclear Medicine Unit, Policlinico S. Orsola-Malpighi, Bologna, Italy

Laurent Brichard Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK

Roberto Canales-Candela Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK

Assunta Carpinelli IBFM-CNR, Nuclear Medicine Department, University of Milan Bicocca, San Raffaele Scientific Institute, Milano, Italy

Sofie Celen Laboratory for Radiopharmacy, Faculty of Pharmaceutical Sciences, K.U. Leuven, Leuven, Belgium

Michael A. Channing National Institutes of Health, PET Department, Clinical Center, Bethesda, Maryland

Xiaoyuan Chen Molecular Imaging Program, Department of Radiology, Stanford University School of Medicine, Stanford, California; Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland

Zhen Cheng Molecular Imaging Program, Department of Radiology, Stanford University School of Medicine, Stanford, California

Frederick T. Chin Molecular Imaging Program, Department of Radiology, Stanford University School of Medicine, Stanford, California

Robert F. Dannals The Johns Hopkins University School of Medicine, Baltimore, Maryland

Harald Eidherr Department of Nuclear Medicine, Medical University of Vienna, Vienna, Austria

Valentina Ferrari Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK

Umesh B. Gangadharmath Siemens Molecular Imaging Biomarker Research, Culver City, California

Friedrich Girschele Department of Nuclear Medicine, Medical University of Vienna, Vienna, Austria

Tjibbe de Groot Department of Nuclear Medicine, K.U. Leuven, Leuven, Belgium

Daniela Haeusler Department of Nuclear Medicine, Medical University of Vienna, Vienna, Austria; Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Vienna, Austria

Christer Halldin Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Stockholm, Sweden

Terence G. Hamill Discovery Imaging, Merck Research Laboratories, West Point, Pennsylvania

Bradford Henderson University of Michigan School of Medicine, Ann Arbor, Michigan

Brian G. Hockley Department of Radiology, University of Michigan School of Medicine, Ann Arbor, Michigan

Daniel P. Holt The Johns Hopkins University School of Medicine, Baltimore, Maryland

Michael R. Kilbourn Department of Radiology, University of Michigan School of Medicine, Ann Arbor, Michigan

Hartmuth C. Kolb Siemens Molecular Imaging Biomarker Research, Culver City, California

Alexey Kostikov McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada

Miriam Kovacevic McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada

Raisa N. Krasikova Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Stockholm, Sweden; Institute of Human Brain, Russian Academy of Sciences, St. Petersburg, Russia

David Kryza ISPB, Faculté de Pharmacie, Université Claude Bernard Lyon 1; Hospices Civils de Lyon, Hôpital E Herriot, Radiopharmacie; LPCML, UMR5620 CNRS, Villeurbanne, Lyon, France

Piyush Kumar Department of Oncology, University of Alberta, Edmonton, Alberta, Canada

Jozef J. Kusmierz National Institutes of Health, PET Department, Clinical Center, Bethesda, Maryland

Didier Le Bars CERMEP-Imagerie du Vivant, Hospices Civils de Lyon, ICBMS UMR, Université Lyon 1, Bron (Lyon), France

Shuanglong Liu Molecular Imaging Program, Department of Radiology, Stanford University School of Medicine, Stanford, California

Filippo Lodi PET Radiopharmacy, Nuclear Medicine Unit, Policlinico S. Orsola-Malpighi, Bologna, Italy

Claudio Malizia PET Radiopharmacy, Nuclear Medicine Unit, Policlinico S. Orsola-Malpighi, Bologna, Italy

Gassan Massaweh McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada; Canada Imaging & Research Centre, Department of Radiology, Queen Elizabeth II Health Sciences Centre, Capital Health/Dalhousie University, Halifax, Nova Scotia, Canada

John R. Mercer Department of Oncology, University of Alberta, Edmonton, Alberta, Canada

Markus Mitterhauser Department of Nuclear Medicine, Medical University of Vienna, Vienna, Austria; Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Vienna, Austria

Vani P. Mocharla Siemens Molecular Imaging Biomarker Research, Culver City, California

Bruce H. Mock Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana

Fanrong Mu Siemens Molecular Imaging Biomarker Research, Culver City, California

John L. Musachio National Institutes of Health, PET Department, Clinical Center, Bethesda, Maryland

Sangram Nag Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Stockholm, Sweden

Henry C. Padgett Siemens Molecular Imaging Biomarker Research, Culver City, California

Jim Patanella Siemens Molecular Imaging Biomarker Research, Culver City, California

Cécile Philippe Department of Nuclear Medicine, Medical University of Vienna, Vienna, Austria; Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Vienna, Austria

Victor W. Pike Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland

Hayden T. Ravert The Johns Hopkins University School of Medicine, Baltimore, Maryland

Michelle L. Richards Department of Radiology, University of Michigan School of Medicine, Ann Arbor, Michigan

Patrick J. Riss Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK

Adam C. Runkle Department of Radiology, University of Michigan School of Medicine, Ann Arbor, Michigan

Peter J. H. Scott Department of Radiology, University of Michigan School of Medicine, Ann Arbor, Michigan

Ralf Schirrmacher McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada; Lady Davis Institute for Medical Research, Montreal, Quebec, Canada

Kim Serdons Department of Nuclear Medicine, K.U. Leuven, Leuven, Belgium

Xia Shao Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor, Michigan

Rob Smith Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK

Scott E. Snyder Division of Nuclear Medicine, Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee

Alexander Thiel Lady Davis Institute for Medical Research, Montreal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada

Louis Tluczek Division of Nuclear Medicine, Department of Radiology, University of Michigan, School of Medicine, Ann Arbor, Michigan

Amy L. Vavere Division of Nuclear Medicine, Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee

Wolfgang Wadsak Department of Nuclear Medicine, Medical University of Vienna, Vienna, Austria; Department of Inorganic Chemistry, University of Vienna, Vienna, Austria

Joseph C. Walsh Siemens Molecular Imaging Biomarker Research, Culver City, California

Min Wang Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana

Carmen Wängler McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada

Yi Zhao Clinic of Nuclear Medicine, Molecular Imaging and Therapy, University Hospital Schleswig-Holstein Campus Kiel, UKSH, Kiel, Germany

Qi-Huang Zheng Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana

Steve Zigler Siemens Molecular Imaging Biomarker Research, Culver City, California

Maaz Zuhayra Clinic of Nuclear Medicine, Molecular Imaging and Therapy, University Hospital Schleswig-Holstein Campus Kiel, UKSH, Kiel, Germany

Foreword

Thirty years ago, the synthesis of radiolabeled compounds for positron emission tom ography (PET) was practiced by a relatively small band of dedicated chemists, alternatively challenged by the unusual requirements of synthetic speed, stochiometry, and specific activity, yet excited by the ground-breaking visualization of in vivo biochemistry in the living human subject. Twenty years ago, the number of chemists was growing rapidly, biochemical targets were increasing in complexity and scope, and the chemical and physiochemical approaches to radiopharmaceutical synthesis were becoming more numerous. Ten years ago, the technology associated with PET radiochemistry was well advanced, with an ever-widening group of chemists producing new techniques and new radiotracers at a quickening pace.

Today, PET radiochemistry has greatly matured: synthetic techniques are readily available for many structural classes of compounds, synthetic equipment can be purchased and quickly brought into use, and analytical methods have become standardized. PET is part of the clinical medicine arena, and numerous pharmaceutical companies are actively pursuing development of new radiopharmaceuticals. Research using PET imaging is now undertaken at just about every major medical center in countries around the world.

Radiochemical Syntheses: Volume 1, Radiopharmaceuticals for Positron Emission Tomography is a welcome and much-needed addition to the PET radiopharmaceutical literature, offering for the first time a description of established, reliable synthetic methods for a large number of PET radiopharmaceuticals that are routinely prepared in multiple institutions. New users of PET can rapidly find details of peer-reviewed methods suitable for syntheses of valuable PET radiopharmaceuticals, and established users may find that the methods described herein provide better or easier synthetic methods. Whether an experienced PET radiochemist, or a chemist new to this unusual field, this first volume of Radiochemical Syntheses will be a valuable guide to the exciting and challenging area of PET radiopharmaceutical chemistry.

Michael R. Kilbourn, Ph.D

Professor of Radiology

University of Michigan Medical School

Ann Arbor, Michigan

Preface

With feelings of excitement and anticipation, we present the first volume of Radiochemical Syntheses to the field, offering reliable and robust procedures for the preparation of many common radiopharmaceuticals utilized in positron emission tomographic (PET) imaging.

It is extremely likely that all of us are familiar with organic syntheses, either through the complimentary volume we receive every year from the American Chemical Society Organic Chemistry Division or through the equally powerful online edition. Certainly we are thankful when a given procedure we are trying to replicate has been published in Organic Syntheses, as it provides us with a high degree of confidence, from the outset, that the protocol will actually work in our hands! What we observed, through talking to many of our colleagues in the radiochemistry field, was that an equivalent product was in demand for the increasing numbers of radiochemical reactions and radiopharmaceutical syntheses reported in the literature. To address this need, we have established Radiochemical Syntheses (Rad. Syn.). The goal of this series is to present monographs dealing specifically with radiochemical reactions that report many of the details that are required for successful replication, but that are frequently omitted from the mainstream radiochemistry literature. Owing to the frequently very busy radiopharmaceutical production schedules for PET radiochemistry facilities, and the associated costs of laboratory operations, it is not feasible to put the monographs through the same rigorous checking that Organic Syntheses is noted for. However, to ensure reliability of the included procedures, we have adopted the common regulatory practice of requiring inclusion of complete quality control data for three successive process verification runs.

We are deeply indebted to the authors and editorial board that have made this first volume a reality. These experts from the global field of radiochemistry have responded to this series with energy and enthusiasm, whether by preparing the excellent series of monographs found herein, or through their diligent reviewing and checking of the reported synthetic procedures. Moreover, the support of the editorial team at Wiley has been invaluable. In particular, thanks are due to Jonathan Rose who has enthusiastically backed this project from the very earliest idea and patiently seen it through to publication.

Finally, this is the first volume of Radiochemical Syntheses. It is anticipated that Volume 2 will focus on new methods for preparing radiopharmaceuticals for PET imaging and Volume 3 will focus on radiopharmaceuticals for SPECT imaging. Potential authors and guest volume editors are encouraged to obtain information about preparing monographs or future volumes from the Radiochemical Syntheses Editorial Office ([email protected]).

Peter J. H. Scott, Ph.D

Michael R. Kilbourn, Ph.D

The University of Michigan

Ann Arbor, Michigan

October 2010

Abbreviations

AcAcetateAcOHAcetic acidASUAutomated synthesis unitBETBacterial endotoxin testBnBenzylBoctert-ButoxycarbonylBqBecquerelBTABenzothiazoleBzBenzoylCFNCarfentanilCHLCholineCiCurieCMSU.S. Centers for Medicare and Medicaid ServicesCROContract research organizationDAADiacetone alcoholDASB3-amino-4-[2-(N-methyl-N-methyl-amino-methyl)phenylsulfanyl]-benzonitrileDATDopamine transporterDMAEDimethylamino ethanolDMFN,N-dimethyl formamideDMSODimethyl sulfoxideDMTDimethoxy tritylDOTATOCDOTA-(Tyr3)-octreotide acetateDTBZ(+)-α-DihydrotetrabenazineECEndothelial cellsEDTAEthylenediaminetetraacetic acidEtOHEthanolEUEndotoxin unitsEu. Ph.European PharmacopeiaFA2-(Fluoro)-3-[(2S)-2-azetidinylmethoxy]pyridineFAZAFluoroazomycin arabinosideFCHFluorocholine (or fluoromethylcholine)FDA6-FluorodopamineFDAU.S. Food and Drug AdministrationFDGFluorodeoxyglucoseFES16-α-FluoroestradiolFETFluoroethyltyrosineFIDFlame ionization detectorFLTFluorothymidineFMISOFluoromisonidazole (1-(2-hydroxy-3-fluoropropyl)-2-nitroimidazole)FMZFlumazenilFTMFluid thioglycolate mediaFZFlumazenilGABAγ-Aminobutyric acidGBqGigabecquerelGCGas chromatographyGEMSGeneral electric medical systemsGluTGlucose transportersHPLCHigh-performance liquid chromatography5-HT5-Hydroxytryptamine (5-HT))ICHThe International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human UseICP-MSInductively coupled plasma mass spectrometryIUInternational unitsK-2.2.2Kryptofix-2.2.2 (4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane)keVKilo electron voltLC-MSLiquid chromatography-mass spectrometryLALLimulus amebocyte lysateLODLimits of detectionMBqMegabecquerelmCiMillicurieMETMethionineMeCNAcetonitrileMeIIodomethane (methyl iodide)MeOHMethanolMeOTfMethyl triflateMeVMega electron voltMHEDmeta-HydroxyephedrineMinMinuteMPPF4-(2′-Methoxyphenyl)-1-[2′-(N-2′′-pyridinyl)-p-fluorobenzamido]ethylpiperazineMPPI4-(2′-Methoxyphenyl)-1-[2′-[N-(2′′-pyridinyl)-p-iodobenzamido]ethyl]piperazineMTO[O-Methyl]metomidateNaFSodium fluorideNETNorepinephrine transporterNFP4-Nitrophenyl 2-[18F]-fluoropropionateNKTachykinin receptorsNosNosylnNeutronNITTP1-(2-nitro-1-imidazolyl)-2-O-tetrahydropyranyl-3-O-toluenesulfonylpropanediolOTfTriflatepProtonPETPositron emission tomographyPIBPittsburgh compound BPBR28N-(2-Methoxybenzyl)-N-(4-phenoxypyridin-3-yl)acetamideppmParts per millionPsiPounds per square inchQCQuality controlQMAQuaternary methyl ammoniumRCPRadiochemical purityRCYRadiochemical yieldRGDArg-Gly-AspRRTRelative retention timeRfRetention factorRSAResidual solvent analysisRxnReactionSERTSerotonin transporterSASpecific activitySFBN-Succinimidyl 4-[18F]fluorobenzoateSCDMSoybean casein digest mediaSPA-RQSubstance-P antagonist-receptor quantifierSPESolid phase extractionSPECTSingle photon emission computed tomographySSRISelective serotonin reuptake inhibitorTBZTetrabenazineTFATrifluoroacetic acidTHFTetrahydrofuranTLCThin layer chromatographyTPAHTetrapropylammonium hydroxideTSTUO-(N-Succinimidyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborateUSPUnited States PharmacopeiaUVUltravioletVMAT2Vesicular monoamine transporter type 2

Part I

FLUORINE-18 LABELED RADIOPHARMACEUTICALS

Chapter 1

Synthesis of [18F]-Fluorodeoxyglucose ([18F]FDG)

Michelle L. Richards Peter J. H. Scott

Department of Radiology, University of Michigan School of Medicine, Ann Arbor, Michigan

1.1 Introduction

Positron emission tomographic (PET) imaging provides a noninvasive, accurate diagnostic method of imaging and detecting possible diseases at a cellular, molecular, and tissue level. PET has a proportional relationship between the tissue intensity on the tomographic image and the actual radiopharmaceutical concentration in tissue [1]. [18F]Fluorodeoxyglucose ([18F]FDG) is a glucose analog and is known as the “work horse” of PET simply because of the multiple modalities for application. The implications of abnormal glucose metabolism are vital in evaluating a variety of diseases, and the applications of this positron emitting radiotracer are great. [18F]FDG is preferentially taken up into cells with high metabolic activity by specific glucose transporters (GluT) and phosphorylated by hexokinase. It becomes metabolically trapped in the cell because [18F]FDG-6-phosphate is not a substrate for glucose-6-phosphate isomerase, the enzyme that metabolizes glucose, and therefore cannot be broken down. During radioactive decay, 18F decays to 18O, allowing the decayed product, 2-18O-deoxyglucose-6-phosphate, to enter the normal glucose metabolic pathway.

The first synthesis of [18F]FDG was based on a direct electrophilic substitution reaction by Wolf et al. in 1976 [2], [3]. This fluorination reaction by electrophilic substitution refers to the addition of fluorine atoms across a double bond, producing a difluoro derivative of the parent compound [4]. However, the synthesis of [18F]FDG by nucleophilic substitution fluorination (Fig. 1.1) proved to be a more efficient method of producing [18F]FDG in higher, more reproducible yields. In 1986, Hamacher et al. utilized mannose triflate, as the precursor, and Kryptofix-[2.2.2] dissolved in acetonitrile, as a catalyst, substituting the trifluoromethane sulfonate leaving group with [18F]fluoride to form [18F]FDG [5]. This method of generating [18F]FDG has allowed for widespread use in clinical imaging [6] in neurology [7]–[8], oncology [9]–[10], and cardiology [11]. It has been significantly studied in numerous oncology studies, including lung cancer, lymphoma, and colorectal cancer [1]. Because [18F]FDG is a marker for hexokinase activity and glucose metabolism, this PET radiotracer has become a valuable tool in tumor detection, staging, and treatment evaluation because most tumors are marked by increased glucose uptake [12]. New innovative applications of [18F]FDG have been applied recently as well. In 2002, Chacko et al. investigated the possible application of [18F]FDG in evaluating infections, such as osteomyelitis, infected orthopedic hardware, and deep-seated soft tissue infections, and concluded that [18F]FDG was an effective imaging modality in the assessment of patients with suspected infections. However numerous the possible uses for [18F]FDG are, it is important to note that [18F]FDG is a nonspecific radiotracer for imaging disease. This chapter provides a brief overview of the radiochemical synthesis and clinical use of [18F]FDG, but because of the enormous body of literature available on [18F]FDG, a detailed discussion is beyond the scope of this chapter.

Figure 1.1 Synthesis of [18F]FDG by nucleophilic aliphatic substitution on tetraacetyl mannosyl-2-triflate.

1.2 Synthesis Procedures

CAUTION: All radiochemical syntheses must be carried out using the appropriate equipment in a facility authorized for the use of radioactive materials. Personal protective equipment must be worn, and all local radiation safety laws followed.

1.2.1 Preliminary Steps

A General Electric Medical Systems (GEMS) TRACERlab MXFDG module [13] was used for the synthesis of [18F]FDG at the University of Michigan Cyclotron and Radiochemistry Facility. The preliminary steps for the [18F]FDG synthesis were performed before the transfer of [18O]H2O into the synthesizer. Initial tests run by the MXFDG module ensured that the heater, syringe actuators, compressed air, vacuum pump, and nitrogen flow were all properly working.

The single-use TRACERlab MXFDG cassette (Fig. 1.2) [14], manufactured by GE Healthcare, was assembled in a Horizontal LAF Hood. The cassette came prepackaged with two tC18 cartridges and one alumina-N cartridge. The cassette was assembled per manufacturer recommendations, which included attaching one Millipore Millex-FG sterilizing filter [15] to the nitrogen inlet connector tubing, a conical column reservoir [16] to collect the [18O]H2O transferred from the cyclotron to the cassette, a QMA Sep-Pak Light Accell Plus cartridge [17], two single-use 30-mL syringes [18], ABX manufactured mannose triflate [19] precursor, and the ABX synthesizer reagent kit [20] containing predispensed volumes of acetonitrile, ethanol, neutralization solution, sodium hydroxide, Kryptofix-[2.2.2]/potassium carbonate solution, and sterile water for injection. The neutralization solution [26], with an approximate pH of 6.4, was a mixture of citrate buffer with hydrochloric acid, resulting in a composition of 23.5 mg of disodium hydrogen citrate-0,5-hydrate (extra pure), 144.4 mg of trisodium citrate-2-hydrate (extra pure), 5 mL of pure water, and 1 mL of HCl 2 N for one synthesis, and was manufactured by ABX.

Figure 1.2 Single-use cassette for manufacture of [18F]FDG.

Once the cassette was mounted to the MXFDG module, additional steps performed included hooking the syringes onto the syringe actuators, dissolving the precursor in 3.5 mL of acetonitrile, pressurizing the reagent vials used during synthesis, and rinsing the single-use cassette with acetonitrile.

1.2.2 Production of [F]Flouride

A GEMS PETtrace cyclotron [19] was used to generate [18F]fluoride by the 18O(p,n)18F nuclear reaction using a [18F]fluoride target [21]. Approximately 2 mL of [18O]H2O [22] was loaded into the [18F]fluoride target and bombarded at 40 μA for 25 min to generate approximately 1 Ci of activity (37 GBq).

1.2.3 Azeotropic Drying of [F]Fluoride

After bombardment, the [18F]fluoride was transferred to a GEMS TRACERlab MXFDG synthesizer [19] in approximately 2 mL of [18O]H2O [28], where it was passed through an anion exchange cartridge [23]. The fluoride ions were trapped on the cartridge and the [18O]H2O was recovered.

Once the [18O]H2O was recovered, the [18F]fluoride ions were eluted from the anion exchange cartridge into the reaction vessel using a 0.6 mL solution [26] containing 7 mg of potassium carbonate, 22 mg of Kryptofix-[2.2.2], 300 μL of water, and 300 μL of acetonitrile. In the reaction vessel, the solvents were evaporated at 95°C for 8.5 min under negative pressure and nitrogen flow. Throughout the evaporation process, 80 μL of acetonitrile was added three times to the reaction vessel during the evaporation stage to maintain the H2O/MeCN azeotrope, totaling 240 μL of acetonitrile.

1.2.4 Synthesis of [F]FDG

During the preliminary steps of preparing the GEMS TRACERlab MXFDG module for synthesis, 40.0 mg of mannose triflate precursor [25] was dissolved in 3.5 mL of acetonitrile [26]. Following drying of the fluoride, the precursor was added to the reactor vessel. A nucleophilic aliphatic substitution reaction occurred, in which the [18F]fluoride ions replaced the trifluoromethane sulfonate leaving group, creating the 2-[18F]fluoro-1,3,4,6-tetra-O-acetyl-d-glucose molecule. This reaction occurred at 85°C for 4 min in a closed reactor vessel.

1.2.5 Purification of [F]FDG

The tC18 cartridges used for hydrolysis and purification were rinsed with 10 mL of sterile water for injection [26]. Afterwards, both tC18 cartridges [20] were conditioned with 3 mL of ethanol and 22 mL of water during synthesis. The labeled solution was then diluted with 26 mL of water and passed through the first tC18 cartridge, which was used for hydrolysis. The 2-[18F]fluoro-1,3,4,6-tetra-O-acetyl-d-glucose molecule was trapped on the cartridge, while all other solvents, unreacted [18F]fluoride ions, and polar byproducts were washed away into the external waste bottle. Kryptofix was trapped on this cartridge as well. The hydrolysis cartridge was washed three times with water; the first rinse was with 10 mL of water, the second with 10 mL of water, and the final with 23 mL of water.

Alkaline hydrolysis of the labeled compound occurred at room temperature, using 800 μL of 2 N sodium hydroxide. The sodium hydroxide passed through the tC18 cartridge, removing the four acetyl-protecting groups. [18F]FDG was collected from the tC18 cartridge in water and pulled into a 30-mL syringe [24]. The neutralization solution [26] was added to the alkaline [18F]FDG solution (10.8 mL) in order to provide a solution of physiological pH suitable for injection. The final formulation (16.8 mL) was further purified using a second tC18 cartridge [20] and an alumina-N cartridge [20], and passed through a sterile Millex-GS 0.22-µm filter [23] into a sterile dose vial [24], typically generating 500–600 mCi (18.5–22.2 GBq) of [18F]FDG. The solution was then released for quality control (QC) testing. After the synthesis was complete, the cassette was rinsed with the remaining sterile water to reduce residual radioactivity in the single-use cassette before removal and disposal.

1.3 Quality Control Procedures

CAUTION: All radiopharmaceuticals produced for clinical use must have local regulatory approval before use in humans. Trained personnel must carry out quality control procedures, and each dose must meet all established quality control criteria before release to the clinic.

QC tests at the University of Michigan Cyclotron and Radiochemistry Facility for [18F]FDG were carried out in accordance with the current US Pharmacopeia [25], [26] and are summarized below. Data from QC testing for three repeat batches of [18F]FDG are summarized in Table 1.1. Each of the three doses of [18F]FDG met all established QC criteria.

Table 1.1 QC Data for Three Repeat Runs of [18F]FDG

* Release criteria not available.

1.3.1 Visual Inspection

The [F]FDG dose must be clear, colorless, and free of particulate matter. This must be inspected behind proper shielding. A PET L-block barrier system was used.

1.3.2 Radiochemical Identity and Purity

Radiochemical purity was determined by thin layer chromatography (TLC) using silica gel chromatography plates [27] and a Bioscan AR-2000 TLC scanner [28]. The plate was spotted with approximately 10 μg of FDG reference standard solution [29] and then spotted with a sample of [18F]FDG dose. The FDG reference standard solution was prepared by dissolving 10 mg of 2-fluoro-2-deoxy-d-glucose [35] in 50 μL of acetonitrile and 50 μL of water. The developing solution [30], or mobile phase, contained 95% acetonitrile and 5% water. The plate was developed in this solvent system, dried using a warm laboratory hot plate [31] (temperature setting 5), and placed on the TLC scanner for analysis. The Bioscan TLC Scanner measured the radiochemical purity, which must be greater than or equal to 90%.

Radiochemical identity was determined by TLC and analysis of the retention factor (Rf). The retention factor of the standard was compared to the [18F]FDG dose sample placed on the TLC plate. One plate was developed and dried, as described above, for both radiochemical purity and identity analysis. Once the standard became visibly brown after heating, the plate was removed and placed on the TLC scanner for analysis. The Rf was calculated for the hot [18F]FDG sample. The “cold” FDG standard retention factor was calculated manually and compared with the [18F]FDG sample, the radioactivity distribution of which is determined by use of the Bioscan AR-2000 TLC scanner [34]. The Rf value of the [18F]FDG, free [18F]fluoride, and acetylated [18F]FDG are about 0.45, 0.0, and 0.85, respectively [4].

1.3.3 Radionuclidic Identity

A Capintec CRC®-15R Radioisotope Dose Calibrator [32] was used to measure activities. A sample of the [18F]FDG product was placed in the Capintec Dose Calibrator located behind an L-block lead shield and measured, noting both the time and activity. After a period of at least 15 min, time and activity was noted again. The half-life was calculated using Equation 1.1, which must be within the range of 105–115 min for the dose to be released to the clinic.

1.1

1.3.4 Residual Solvent Analysis

Residual solvent analysis of [18F]FDG was performed on a Shimadzu GC-2010 Gas Chromatograph [33]. Acetonitrile and ethanol were tested for concentration levels and compared with a standard solution in accordance with the US Pharmacopeia [31]. The standard solution contained known concentrations of acetonitrile and ethanol, 0.01% and 0.1%, respectively. A Restek Stabliwax with Integra-Guard 30 m × 0.25 mm GC column [34] was used with helium as the carrier gas. Concentration percentages were calculated, and no more than 0.5% ethanol and 0.04% acetonitrile can be found in the dose, according to the US Pharmacopeia [31]. Acetonitrile, a class 2 solvent, has a limit on concentrations of <410 ppm per patient per day, imposed by the ICH Harmonised Tripartite Guidelines [35]. Ethanol, a class 3 solvent, has a limit of <5000 ppm/day.

1.3.5 Dose pH

ColorpHast® nonbleeding pH strips [36] were used to analyze a small amount of [18F]FDG dose. The specification range of the colorpHast nonbleeding pH strips used were 2.0–9.0, and the determination of pH was done by visual comparison of the pH strip with the reference card supplied with the strips. The pH must be within the range of 4.5–7.5 to meet the release criteria.

1.3.6 Residual Kryptofix-[2.2.2] Analysis

Kryptofix-[2.2.2] is a phase transfer agent used to facilitate the nucleophilic fluorination reaction for [18F]FDG, and because of its toxicity, verification of the absence of Kryptofix-[2.2.2] in the dose must take place before its release [37]. Residual Kryptofix-[2.2.2] levels in [18F]FDG were analyzed using the established spot test. Kryptofix standards [38] were prepared by serial dilution of a 1.0 mg/mL stock solution using deionized water. Both water (negative control) and a 50-μg/mL standard (positive control) were used in this test. Stock iodoplatinate reagent was prepared to create iodoplatinate indicator strips used in spot testing. This reagent was generated using 5 mL of water mixed with 0.26 g of chloroplatinic acid [39]. This solution was then mixed with 45 mL of water and 5 g of potassium iodide [40] and diluted with an additional 100 mL of water. Precut strips of thin-layer silica gel [41] were immersed in the iodoplatinate reagent for 5–10 s. Once the strips had been completely saturated by the reagent, they were dried overnight and then stored at room temperature in a vented glass jar.

A sample of the [18F]FDG dose was applied to the indicator strip using a single droplet. On the same strip, both the negative water control and the Kryptofix standard [44] (50 μg/mL) were applied and allowed to dry for 5–10 min. The three spots were analyzed, and a visual determination of the relative concentration of Kryptofix-[2.2.2] was made for the [18F]FDG dose.

The presence of Kryptofix-[2.2.2] in the dose is confirmed by the appearance of a blue-black ring around a white circle of silica surrounded by a pink ring of unreacted reagent. At very low or no concentrations of Kryptofix, a faint pink core remains in the center of the white circle, with no visible blue-black ring. The dose must contain < 50 μg/mL for the dose to be acceptable for release.

1.3.7 Sterile Filter Integrity Test

Validation of the integrity of the sterile filter going into the dose vial must also be performed before the release of the dose to the clinic. The filter integrity test is essential in testing [18F]FDG product sterility, as the actual sterility testing results will not be available until 14 days later [4]. The Millex-GS sterile filter [29] from the [18F]FDG synthesis was attached to the nitrogen supply through a calibrated regulator. The tip of the filter was submerged in water. The nitrogen flow was gradually turned on to increase the nitrogen pressure on the filter. The pressure was increased to greater than 50 psi, which is the acceptance criterion for the Millipore-GS filter. If the pressure reaches 50 psi or more without resulting in a stream of bubbles in the water, the filter is considered intact. If a steady stream of bubbles is seen before the minimum bubble point pressure is reached, the test fails and the dose is rejected.

1.3.8 Endotoxin Analysis

The Charles River Portable Testing System [42], [43] was used to determine the endotoxin content in the [18F]FDG doses. Limulus Amebocyte Lysate (LAL) test cartridges [44], purchased from Charles River, were used in this test. A volume of 3.9 mL of Endosafe LAL Reagent water [45] was pipetted into a test tube. A volume of 0.1 mL of the [18F]FDG dose was then added to this tube, mixed for 10 s using a vortex [46], and 25 μL of the diluted [18F]FDG sample was added to each well on the Charles River test cartridge. This was performed in accordance with the US Pharmacopeia [47]. The dose must contain ≤ 175 Endotoxin Units (EU) per dose.

1.3.9 Sterility Testing

Sterility testing must also be performed on all doses of [18F]FDG produced to verify that the process by which each PET radiopharmaceutical is produced is consistently sterile and suitable for human use. Sterility testing was performed by inoculating samples of [18F]FDG into a fluid thioglycolate media (FTM) [48] and a soybean casein digest media (SCDM) [49]. SCDM is used for the detection of aerobic bacteria and fungi, while the general purpose of FTM is to detect common aerobic, facultative, and anaerobic microorganisms.

The [18F]FDG medium was incubated along with positive and negative controls for 14 days. Incubation temperatures were 32°C and 22°C for FTM and SCDM, respectively, according to current USP guidelines [50] for sterility testing. The media was visually inspected on the third, eigth, and fourteenth days of the incubation test period and compared to the positive and negative controls. The positive control must show growth (cloudiness or turbidity) in the medium, and the [18F]FDG samples and negative control must show no growth after 14 days of incubation in order to be considered sterile.

1.4 Chemical Abstracts Nomenclature (Registry Number)

Mannose triflate (92051-23-5)

[18F]Fluorodeoxyglucose ([18F]FDG) (128441-61-2)

Carabonic acid, potassium salt (1:2) (584-08-7)

Sodium hydroxide (1310-73-2)

Acetonitrile (75-05-8)

Ethanol (64-17-5)

2-Fluoro-2-deoxy-d-glucose (29702-43-0)

Kryptofix-[2.2.2] (23978-09-8)

Chloroplatinic acid (16941-12-1)

Potassium iodide (7681-11-0)

References and Notes

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19. GE Healthcare, USA.

20. TRACERlab MXFDG Cassettes were purchased from General Electric Healthcare (part no. P5150ME), and used as received. The cassettes came prepackaged and assembled with two tC18 cartridges and one alumina-N cartridge.

21. Millex-FG sterile 0.20 μm filters were purchased from Millipore (part no. SLFG025LS) and used as received.

22. Conical Column 10mL Reservoir was purchased from ABX (part no. 9180) and used as received.

23. QMA-Light Sep-Pak® preconditioned cartridges (part no. K-920) were purchased from Advanced Biochemical Compounds (ABX) and used as received.

24. 30mL syringes were purchased from Fischer Scientific (part no. 309650) and used as received.

25. Mannose triflate ultrapure precursor was purchased from ABX (part no. 101.0040) and used as received.

26. Coincidence FDG18 Synthesizer Reagent Kit was purchased from ABX (part no. K-153TM) and used as received.

27. GEMS silver high-yield [18F]fluoride target.

28. Virgin [18O]H2O was purchased from ABX, Amic, Rotem, or Medical Isotopes, and used as received.

29. Millex-GS sterile 0.22-µm filters were purchased from Millipore (part no. SLGSV255F) and used as received.

30. Sterile 30-mL dose vial was purchased from Hospira (part no. 5829-30), and used as received.

31. U.S. Pharmacopeia <823> Radiopharmaceuticals for positron emission tomography compounding. USP 32-NF 27; 2009.

32. U.S. Pharmacopeia Official Monographs/Fludeoxyglucose. USP 29-NF 24; 2006.

33. Whatman Thin Layer Chromatography Plates (part no. 4861-110) MK6F Silica Gel 60 A, Dimensions 2.5 × 7.5 cm, layer thickness 250 μm.

34. Bioscan, Inc., USA.

35. The FDG reference standard solution contained both 2-fluoro-2-deoxy-d-glucose reference standard, purchased from Sigma Aldrich (part no. F5006) and used as received, and anhydrous acetonitrile, purchased from Acros (part no. 61096-1000) and used as received.

36. The TLC developing solution contained anhydrous acetonitrile, purchased from Acros (part no. 61096-1000) and used as received and MilliQ water, in concentrations of 95% and 5%, respectively.

37. Laboratory Hot Plate, manufactured by Corning, Model no. PC-200, and used at temperature setting 5.

38. Capintec, Inc., USA.

39. Shimadzu Corporation, USA.

40. GC Column: Restek Stabliwax with Integra-Guard; 30 m × 0.25 mm, purchased from Restek (part no. 10623-124).

41. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).

42. EMD Chemicals Inc., USA (part no. 9578-3).

43. Mock BH, Winkle W, Vavrek MT. Nucl Med Biol 1997; 24:193–195.

44. Kryptofix–[2.2.2] was purchased from Acros (part no. 29195-0010) and used as received for preparation of reference standard.

45. Chloroplatinic acid was purchased from Acros (part no. 363590010) and used as received.

46. Potassium iodide was purchased from Acros (part no. 19379-0500) and used as received.

47. Thin-layer silica gel sheets were purchased from EMD Chemicals (part no. 57487), 20 × 20 cm sheets, silica gel 60 A, and cut into squares 4 × 5 cm.

48. Charles River Laboratories, USA.

49. Endosafe Portable Testing System (model no. PTS 100), purchased and calibrated according to manufacture guidelines by Charles River Laboratories, USA.

50. Limulus Amebocyte Lysate (LAL) Test Cartridges (part no. PTS20F) purchased from Charles River Laboratories and used as received.

51. Endosafe Limulus Amebocyte Lysate (LAL) Reagent water (part no. W110) purchased from Charles River Laboratories and used as received.

52. VWR Vortexer 2 (model no. G-560), vortex speed setting 8.

53. US Pharmacopeia <85>. Bacterial endotoxins test. USP 32-NF 27, 2009.

54. Fluid Thioglycolate Media (part no. 220889) purchased from Beckon, Dickson and Company, USA, and used as received.

55. Soybean Casein Digest Media (part no. 221823) purchased from Beckon, Dickson and Company, USA, and used as received.

55. US Pharmacopeia <71> Sterility tests. USP 32-NF 27, 2009.