Biomedical imaging the chemistry of labels probes and contrast agents

RSC Drug Discovery Edited by Martin Braddock Biomedical Imaging The Chemistry of Labels, Probes and Contrast Agents Biomedical Imaging The Chemistry of Labels, Probes and Contrast Agents RSC Drug Discovery Series Editor-in-Chief: Professor David Thurston, London School of Pharmacy, UK Series Editors: Dr David Fox, Pfizer Global Research and Development, Sandwich, UK Professor Salvatore Guccione, University of Catania, Italy Professor Ana Martinez, Instituto de Quimica Medica-CSIC, Spain Dr David Rotella, Montclair State University, USA Advisor to the Board: Professor Robin Ganellin, University College London, UK Titles in the Series: 1: Metabolism, Pharmacokinetics and Toxicity of Functional Groups: Impact of Chemical Building Blocks on ADMET 2: Emerging Drugs and Targets for Alzheimer’s Disease; Volume 1: BetaAmyloid, Tau Protein and Glucose Metabolism 3: Emerging Drugs and Targets for Alzheimer’s Disease; Volume 2: Neuronal Plasticity, Neuronal Protection and Other Miscellaneous Strategies 4: Accounts in Drug Discovery: Case Studies in Medicinal Chemistry 5: New Frontiers in Chemical Biology: Enabling Drug Discovery 6: Animal Models for Neurodegenerative Disease 7: Neurodegeneration: Metallostasis and Proteostasis 8: G Protein-Coupled Receptors: From Structure to Function 9: Pharmaceutical Process Development: Current Chemical and Engineering Challenges 10: Extracellular and Intracellular Signaling 11: New Synthetic Technologies in Medicinal Chemistry 12: New Horizons in Predictive Toxicology: Current Status and Application 13: Drug Design Strategies: Quantitative Approaches 14: Neglected Diseases and Drug Discovery 15: Biomedical Imaging: The Chemistry of Labels, Probes and Contrast Agents How to obtain future titles on publication: A standing order plan is available for this series A standing order will bring delivery of each new volume immediately on publication For further information please contact: Book Sales Department, Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge, CB4 0WF, UK Telephone: +44 (0)1223 420066, Fax: +44 (0)1223 420247, Email: books@rsc.org Visit our website at http://www.rsc.org/Shop/Books/ Biomedical Imaging The Chemistry of Labels, Probes and Contrast Agents Edited by Martin Braddock AstraZeneca, Loughborough, UK RSC Drug Discovery Series No 15 ISBN: 978-1-84973-014-3 ISSN: 2041-3203 A catalogue record for this book is available from the British Library r Royal Society of Chemistry 2012 All rights reserved Apart from fair dealing for the purposes of research for non-commercial purposes or for private study, criticism or review, as permitted under the Copyright, Designs and Patents Act 1988 and the Copyright and Related Rights Regulations 2003, this publication may not be reproduced, stored or transmitted, in any form or by any means, without the prior permission in writing of The Royal Society of Chemistry or the copyright owner, or in the case of reproduction in accordance with the terms of licences issued by the Copyright Licensing Agency in the UK, or in accordance with the terms of the licences issued by the appropriate Reproduction Rights Organization outside the UK Enquiries concerning reproduction outside the terms stated here should be sent to The Royal Society of Chemistry at the address printed on this page The RSC is not responsible for individual opinions expressed in this work Published by The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 0WF, UK Registered Charity Number 207890 For further information see our web site at www.rsc.org Preface The concept of medical imaging is one of the cornerstones of modern medicine Although its origins can be found in 19th century photography, the field only properly emerged in 1895 following W C Roăntgens discovery of Xrays Since then, insights from across physics and chemistry have devised many more modalities, such as magnetic resonance imaging (MRI), optical imaging (including fluorescence), X-ray imaging (including X-ray Computed Tomography, CT), gamma imaging (including Single Photon Emission Computed Tomography, SPECT), positron emission tomography (PET) and ultrasound techniques In this exemplary new book a distinguished group of experts from both industry and academia present a comprehensive review on how medical imaging is being used in screening, diagnosis, patient management, clinical research and to assist in the development of new therapeutic drugs Biomedical Imaging: The Chemistry of Labels, Probes and Contrast Agents begins with a comprehensive introduction to endogenous and exogenous contrast in medical imaging The book is then broken down into four sections Section one presents a review of some of the more important advances in recent years such as the development of radiotracers and radiopharmaceuticals as biomedical imaging tools, recent developments in imaging agents for selected brain targets that are of clinical relevance in psychiatry and neurology and of pharmacological interest in drug discovery and development and the synthesis of radiopharmaceuticals for application in SPECT imaging Section two focuses on the design and synthesis of contrast agents, MRI and X-ray modalities Topics covered include the synthesis and applications of MRI contrast agents, synthetic methods used for the preparation of DTPA and DOTA derivative ligands, MRI contrast agents based on metallofullerenes, applications of MRI in radiotherapy treatment and the use of autoradiography in the pharmaceutical discovery and development of RSC Drug Discovery Series No 15 Biomedical Imaging: The Chemistry of Labels, Probes and Contrast Agents Edited by Martin Braddock r Royal Society of Chemistry 2012 Published by the Royal Society of Chemistry, www.rsc.org v vi Preface xenobiotics Section three concentrates on optical imaging techniques and the value of fluorescence optical imaging in pharmacological research and drug development There are also chapters on fluorescence lifetime imaging applied to microviscosity mapping and fluorescence modification studies in cells and the design and use of contrast agents for ultrasound imaging The final section focuses on physical techniques and application, with a review of recent advances in brain imaging that provide opportunities to develop biomarkers for diseases of the central nervous system (CNS) and current progress and future prospects of using MRI to assist in the drug discovery and development process The final chapter brings the book to a close peering into the future of MRI contrast agents This book will be essential reading for medicinal and physical scientists working in both industry and academia in the fields of chemistry, physics, radiology, biochemistry and pharmaceutical sciences Contents Chapter Medical Imaging: Overview and the Importance of Contrast John C Waterton 1.1 1.2 Introduction Medical Imaging Modalities 1.2.1 Some General Ideas 1.2.2 Imaging and the Electromagnetic Spectrum 1.2.3 Radio Frequencies and Below 1.2.4 Magnetic Resonance 1.2.5 Microwaves 1.2.6 Optical Imaging 1.2.7 Ultraviolet 1.2.8 X-Ray 1.2.9 Gamma Rays and Nuclear Medicine 1.2.10 Single Photon Emission Computed Tomography 1.2.11 Positron Emission Tomography 1.2.12 Ultrasound 1.2.13 Multimodal Techniques 1.3 How is Medical Imaging Used? 1.3.1 Prognostic or Diagnostic Biomarkers 1.3.2 Predictive Biomarkers or Companion Diagnostics 1.3.3 Monitoring Biomarkers 1.3.4 Response Biomarkers 1.4 Regulatory and Cost Issues 1.5 Conclusion References RSC Drug Discovery Series No 15 Biomedical Imaging: The Chemistry of Labels, Probes and Contrast Agents Edited by Martin Braddock r Royal Society of Chemistry 2012 Published by the Royal Society of Chemistry, www.rsc.org vii 1 4 6 10 10 11 12 13 13 14 15 16 16 17 17 17 18 18 19 20 viii Chapter Contents Biomedical Imaging: Advances in Radiotracer and Radiopharmaceutical Chemistry Robert N Hanson 21 2.1 21 Background 2.1.1 Factors in Radiopharmaceutical Design and Synthesis 2.2 Recent Examples of Integrated Radiotracer and Radiopharmaceutical Development 2.2.1 b-Amyloid Targeted Agents for Imaging in Alzheimer’s Disease 2.2.2 PSMA Targeting for Imaging Prostate Cancer 2.2.3 Integrin Receptor Targeted Agents for Imaging Cancer 2.3 Conclusions Acknowledgments References Chapter Recent Developments in PET and SPECT Radioligands for CNS Imaging David Alagille, Ronald M Baldwin and Gilles D Tamagnan 3.1 Introduction 3.2 Amyloid Plaque 3.2.1 2-(4-([11C]Methyl amino)phenyl)benzo[d] thiazol-6-ol ([11C]PIB) 3.2.2 2-(1-(6-((2-[18F]fluoroethyl)(methyl)amino)-2naphthyl)ethylidene)malononitrile ([18F]FDDNP) 3.2.3 6-[123I]iodo-2-(4’-dimethylamino)phenylimidazo[1,2-a]pyridine ([123I]IMPY) 3.2.4 2-(2-(2-Dimethylaminothiazol-5-yl)ethenyl)6-(2([18F]fluoro)ethoxy)benzoxazole ([18F]BF227) and 2-(2-(2-N-methyl-N[11C]methyl-aminothiazol-5-yl)ethenyl)-6(2(fluoro)ethoxy)benzoxazole ([11C]BF-227) 3.2.5 trans-4-(N-Methylamino)-4’-(2-(2-(2-[18F] fluoroethoxy)ethoxy)stilbene ([18F]BAY94– 9172 or [18F]florbetaben) 3.3 Metabotropic Glutamate Receptors 3.3.1 mGluR1 3.3.2 Metabotropic Glutamate Type (mGluR5) Receptor 3.4 Monoamine Transporter Targets 3.4.1 Dopamine Transporter (DAT) 3.4.2 Norepinephrine Transporter (NET) 3.4.3 Serotonin Transporter (SERT or 5-HTT) 22 25 27 30 35 38 39 39 49 49 50 51 54 55 56 57 58 58 60 64 64 71 75 ix Contents 3.5 3.6 3.7 3.8 3.9 3.10 Vesicular Monoamine Transporter Type (VMAT2) 3.5.1 [11C]-Tetrabenazine ([11C]TBZ) 3.5.2 [11C]-Methoxytetrabenazine ([11C]MTBZ) 3.5.3 [125I]-Iodovinyltetrabenazine ([123I]IV-TBZOH) 3.5.4 [11C]Dihydrotetrabenazine ([11C]TBZOH) 3.5.5 Fluoroalkyl dihydrotetrabenazine ([18F]FE-DTBZ and [18F]FP-DTBZ) Post-Synaptic Dopamine Receptor D3 (D3r) 3.6.1 [11C](ỵ)-4-Propyl-3,4,4a,5,6,10bhexahydro-2H-naphto-[1,2-b][1,4]oxazin9-ol ([11C](ỵ)-PHNO) (Figure 3.8) Post-Synaptic Serotonin Receptor Targets 3.7.1 Serotonin Receptor Subtype (5-HT4) 3.7.2 Serotonin Receptor Subtype (5-HT6) Peripheral Benzodiazepine Receptor, PBR (Translocator Protein 18kD, TSPO) 3.8.1 1-(2-Chlorophenyl)-N-[11C]methyl-N(1-methylpropyl)-3-isoquinoline carboxamide ([11C]PK11195) 3.8.2 N-[18F]Fluoroacetyl-N-(2,5-dimethoxybenzyl)2-phenoxyaniline ([18F]PBR06) and N-acetylN-(2-[11C]methoxybenzyl)-2-phenoxy-5pyridinamine ([11C]PBR28) 3.8.3 N-Acetyl-N-(2-[11C]methoxybenzyl)-2phenoxy-5-pyridinamide ([11C]PBR06) Phosphodiesterase Inhibitors 3.9.1 PDE4 3.9.2 PDE10 Adenosine Receptor A1 and A2A 3.10.1 8-Dicyclopropylmethyl-1-[11C]methyl-3propylxantine ([11C]MPDX) 3.10.2 8-cyclopentyl-3-[(E)-3-iodoprop-2-en-1-yl]1-propylxanthine ([131I]CPIPX) 3.10.3 8-Cyclopentyl-3-(3-[18F]fluoropropyl)-1propylxanthine ([18F]CPFPX) 3.10.4 [11C]2-(1-Methyl-4-piperidinyl)-6-(2phenylpyrazolo[1,5-a]pyridine-3-yl)3(2H)-pyridazinone ([11C]FR194921) 3.10.5 (E)-8-(3,4-Dimethoxystyryl)-1,3-dipropyl-7[11C]methylxanthine ([11C]KF17837) 3.10.6 [7-Methyl-11C]-(E)-8-(3,4,5-trimethoxystyryl)1,3,7-trimethylxanthine ([11C]KF18446 or [11C]TMSX) 80 81 82 83 83 85 85 86 88 89 90 91 93 94 95 95 97 98 99 100 101 102 103 104 104 520 Chapter 8.4 160 J Zheng, C Allen and D Jaffray, Med Phys., 2005, 32, 2054–2054 161 H Ai, C Flask, B Weinberg, X T Shuai, M D Pagel, D Farrell, J Duerk and J Gao, Adv Mater., 2005, 17, 1949–1952 162 J A Kaufman, E T Ahrens, D H Laidlaw, S Zhang and J M Allman, Am J Phys Anthropol., 2006, 112 163 A Obenaus, M Robbins, G Blanco, N R Galloway, E Snissarenko, E Gillard, S Lee and M Curras-Collazo, J Neurotraum., 2007, 24, 1147– 1160 164 A M Tang, D F Kacher, E Y Lam, M Brodsky, F A Jolesz and E S Yang, Multi-modal imaging: Simultaneous MRI and ultrasound imaging for carotid arteries visualization, in Engineering in Medicine and Biology Society, EMBS 2007: 29th Annual International Conference of the IEEE Lyon, France, August 23-26, 2007, pp 2603–2606 165 J R McCarthy, F A Jaffer and R Weissleder, Small, 2006, 2, 983–987 166 J R McCarthy, P Patel, I Botnaru, P Haghayeghi, R Weissleder and F A Jaffer, Bioconjugate Chem., 2009, 20, 1251–1255 167 D Pan, S D Caruthers, G Hu, A Senpan, M J Scott, P J Gaffney, S A Wickline and G M Lanza, J Am Chem Soc., 2008, 130, 9186 168 A H Schmieder, S D Caruthers, H Zhang, T A Williams, J D Robertson, S A Wickline and G M Lanza, FASEB J., 2008, 22, 4179– 4189 169 B Sumer and J M Gao, Nanomedicine, 2008, 3, 137–140 170 H S Chong, H A Song, X Ma, D E Milenic, E D Brady, S Lim, H Lee, K Baidoo, D Cheng and M W Brechbiel, Bioconjugate Chem., 2008, 19, 1439–1447 171 M Johannsen, U Gneueckow, B Thiesen, K Taymoorian, C H Cho, N Waldofner, R Scholz, A Jordan, S A Loening and P Wust, Eur Urol., 2007, 52, 1653–1662 172 C G Hadjipanayis, M J Bonder, S Balakrishnan, X Wang, H Mao and G C Hadjipanayis, Small, 2008, 4, 1925–9 173 A T Tatham, H Nakamura, E C Wiener and Y Yamamoto, Magn Reson Med., 1999, 42, 32–36 Subject Index As ligands and contrast agents have very long, complex chemical names they are indexed under their standard abbreviated form Elements are indexed under their full name AAZTA 187 abdominal cancers contrast enhanced ultrasound imaging 402–5 [11C]ABP688 60–1 [123I]ADAM 79–80 adenosine receptors (ARs) 99–106 ADHD 71 Alberto, R., guidelines for preparing 99m Tc radiopharmaceuticals 149–50 allergic airway inflammation optical imaging of 361–3 Alzheimer’s disease (AD) Alzheimer’s Disease Neuroimaging Initiative (ADNI) 420–1, 429 amyloid plaque targeted agents 27–30, 50–7 gray matter volume change monitoring 429 vascularization studies 93 in vivo cerebral plaque imaging 360–1, 362 [123I]AM251 107–9 [123I]AM281 109 AMPA antagonists 447 amyloid plaque 50–7 amyloid precursor protein (APP) 50–1 b-amyloid targeted agents 27–30, 50–1 amyotrophic lateral sclerosis (ALS) 94 anatomic MRI 293–4 animal models 471, 475 anti-HIV drug discovery and development using QWBA 328–31 apparent diffusion coefficient (ADC) mapping 444 autism and SERT density 76 autoradiography (ARG) definitions 311–12 macro-autoradiography 310, 311 micro-autoradiography (MARG) 310–11, 312, 333–9 quantitative whole-body autoradiography (QWBA) 310, 311–33 whole-body autoradiography (WBA) 310, 311, 313–33 whole-body autoradioluminography (WBAL) 311–12 xenobiotics 309 [18F]BAY94 57 [123I]b-CIT 67–9 [11C]BF227 56–7 [18F]BF227 56–7 bifunctional chelating agents (BFC) 217–25 biologics see biopolymers 522 bioluminescence imaging 11 biomarkers anatomical CNS biomarkers 420–2 chemical CNS biomarkers 423–4 classification of 16–18 CNS biomarker development and the FDA 429–30 current and potential 414–19 for dopamine dysfunction in PD 428 for drug development 427–8 functional brain diseases, biomarker targets 424, 425 for migraine 428–9 potential neuroimaging 428–9 predictive 17 prognostic 17 response 18 selection and validation 426–7 biomedical imaging definition principles and properties of significant modalities 3–6 biopolymers labelling of 354–7, 501 Translational Biologics Imaging Platform 355 blood oxygen level dependence (BOLD) effect BOLD fMRI 422, 448–9 blood–brain barrier (BBB), targeting problems 23, 332 BODIPY fluorescent molecular rotors 378–83 bone tissues 266 BOPTA 213 brachytherapy 285 brain imaging 2, 23, 49, 146, 271–5, 294–6 toxicity of drugs to 483 brain diseases (functional) anatomical CNS biomarkers 420–2 basic technological approaches 419–20 Subject Index brain state and biomarker targets 424, 425 chemical CNS biomarkers 423–4 CNS biomarker development and the FDA 429–30 criteria for biomarkers 419 current and potential biomarkers 414–19 drug development biomarkers 427–8 functional CNS biomarkers 422–3 imaging as a biomarker 411–13 incidence of (USA) 412 neuroimaging biomarkers (potential) 428–9 neuro-psychiatric clinical practice 425–6 subjective measures 413–14 see also CNS imaging bronchoscopy 11 calcium, assessment in tissues 192–3 cancer contrast enhanced ultrasound imaging 402–5 drug development using MRI 448–50 integrin receptor targeted agents 35–8 optical imaging techniques 358–9 radiotherapy 285–92 see also specific cancers cannabinoid receptors 107–14 CB1 107–13 CB2 107, 113–14 carbon-11 [11C]ABP688 60–1 [11C]BF227 56–7 clinical relevant radionuclides 24 [11C]DASB 77–9 [11C]FMePPEP 111–12 [11C]FR194921 103–4 [11C]GSK-215083 90–1 [11C]KF17837 104 [11C]KF18446 104–5 [11C]KW6002 105–6 Subject Index 11 [ C]McN 75–6 [11C]MeNER 72–3 [11C]MePEP 110 [11C]MPDX 100–1 [11C]MTBZ 82–3 [N-11C]nisoxetine 71–2 [O-11C]nisoxetine 71–2 [11C]PBR06 95 [11C]PBR28 94–5 [11C]PE21 567 [11C](ỵ)-PHNO 868 [11C]PIB 514 [11C]PK11195 934 [11C]SB207145 8990 [11C]SCH225336 113–14 [11C]SCH442416 106 [11C]TBZ 81–2 [11C]TBZOH 83–4 [11C]TMSX 104–5 cardiovascular disorders cardiotoxicity of drugs 482–3 drug development using MRI 450–2 FMT imaging 363–4 ultrasound imaging 406–7 cell therapy MRI applications to 453–4 cerebral amyloid angiopathy [11C]PIB assessment 54 CEST (Chemical Exchange Saturation Transfer) agents 201–2 chemical exchange saturation transfer (CEST) agents 10 chemoradiation 291–2 chronic fatigue syndrome 76 CIT [123I]b-CIT 67–9 CALM- PD-CIT trial 68 [123I]FP-CIT (ioflupane) 65–7 CNS imaging adenosine receptors (ARs) 99–106 amyloid plaque 50–7 blood–brain barrier (BBB), targeting problems 23, 332 brain imaging 2, 23, 49, 146, 271–5, 294–6 523 brain toxicity of drugs 483 cannabinoid receptors 107–14 glioma, monitoring chemoradiation of 303–5 head and neck cancers 296–8 melanin binding 332–3 metabotropic glutamate receptors 58–63 monoamine transporter targets 64–80 peripheral benzodiazepine receptor, PBR 91–5 PET and SPECT imaging 49–50 phosphodiesterase inhibitors 95–9 post-synaptic dopamine receptor D3 (D3r) 85–8 post-synaptic serotonin receptor targets 88–91 vesicular monoamine transporter type (VMAT2) 80–5 see also brain diseases (functional) CNS receptor occupancy and mapping 423–4 companion diagnostics see predictive biomarkers complexation equilibria, DOTA and DTPA 236–9 computer programs equilibrium constant calculation 230–1 contrast endogenous contrast 7–9 endogenous vs exogenous exogenous contrast 9–10 importance of see also specific techniques contrast agents for MRI agents for innovative approaches 201–2 applications 182–3 clinically used Gd31 agents 210 complexes available 175–6 future trends and developments 186–90, 490–511 general properties 179–82, 495–7 524 contrast agents for MRI (continued) history 173–4 multimodal 16, 346–7, 456–8, 509–11 nanosized contrast agents 195–202 responsive contrast agents 190–5 superparamagnetic particles 184–5 synthesis of complexes 177–9 targeting groups 454–6, 497–8 toxicology 18, 181–2, 239, 262, 482, 496 see also DOTA; DTPA contrast agents for ultrasound imaging 391–409 corticobasal degeneration 94 corticobasal degeneration (CBD) 68–9 cost issues 18–19 [18F]CPFPX 102–3 [131I]CPIPX 67–9 CT (computed tomography) principles and energies 12–13 [11C]DASB 77–9 dendrimers 196–7, 498–501 depressive disorders 429 diagnostic biomarkers see prognostic biomarkers diffusion tensor imaging (DTI) in drug development 444 functional brain disease monitoring 421–2 tumor cell identification 294, 295 diffusion weighted imaging (DWI) 294, 295, 302–3 in drug development 444 digitally reconstructed radiographs (DRRs) 289 Discovery Based Biomarker Definition, CNS 424, 425 DO3A, Gd complexes 175, 210, 216–17 dopamine receptor D3 (D3r) 85–8 dopamine transporter DAT 64–71 DOPA-responsive dystonia (DRD) 84 Subject Index DOTA bifunctional ligands 217–25 complexation equilibria 236–9 equilibrium properties 227–40 formation rate constants 242 kinetic properties 240–4, 247–9 macrocyclic ligands 214–17, 235 metal chelates (general) 208–11 novel Gd complexes 186–7, 195, 196 PAMAM (polyamidoamine) dendrimers 197, 498–501 protonation constants and sequence 227–36 rate constants for decomplexation 248 stability constants of derivatives 238 synthesis of complexes and derivatives 225–7 transmetallation reactions, equilibria of 239–40 see also gadolinium Dy-DOTAM ligands 201 Tb-DOTAMGly ligands 201 DOTATOC 164–6 Tm-DOTP chelates 201 drug development anti-HIV drugs using QWBA 328–31 cell therapy 453–4 clinical evaluation 442–3 drug development cycle 441–2 MRI technologies for 443–5 multimodal imaging 456–8 specific conditions 445–52 target specific MRI 454–6 see also drug discovery drug discovery anti-HIV drugs using QWBA 328–31 attrition rates 468 background 465–6 clinical trials 467 drug-release mechanisms, analysis of 480–1 imaging technologies 468–70 MRI applications 474–83 Subject Index MRI technology 472–4, 484–5 preclinical investigations 467 regulatory considerations 467 screening 466–7 small animal imaging technologies 471, 475 target identification and validation 466, 477–9 toxicology 481–3 translational applicability 483–4 see also drug development DTPA bifunctional ligands 217–25 complexation equilibria 236–9 EOB-DTPA 213–14 equilibrium properties 227–40 Gd complexes 9, 175, 177, 181, 189–92, 444–5, 448–50, 502 kinetic properties 240–7, 249 ligand structure 234 metal chelates (general) 208–11 PAMAM (polyamidoamine) dendrimers 197, 498–501 protonation constants and sequence 212–13, 227–36 rate constants for decomplexation 246 stability constants of derivatives 237 synthesis of complexes and derivatives 211–14, 225–7 transmetallation reactions, equilibria of 239–40 see also gadolinium DTTA 186–7 dynamic contrast-enhanced (DCE) MRI 301–3 dynamic imaging 4–5 dysprosium Dy-DOTAM ligands 201 ECG (electrocardiography) 6, 450 echistatin 404 EDTA bifunctional ligands 219 Tc derivatives 148–9 525 EEG (electroencephalography) EIT (electrical impedance tomography) electromagnetic radiation and imaging modalities 5–6 encapsulated systems as nanosized contrast agents 199–201 endohedral metallofullerenes (EMFs) see metallofullerenes endoscopy 11 enzyme responsive agents 190–3 EOB-DTPA 213–14 [99mTc]exametazime 152 extracellular fluid (ECF) agents 261–2 [18F]FDDNP 54–5 FDG (fludeoxyglucose) 14–15 [18F]FE-DABP688 61–2 [18F]FE-DTBZ 85 [18F]FEPEP 111–12 ferrite nanocrystals (grains) 184–5, 494–5, 508–9 [18F]florbetaben see [18F]BAY94 fluid-attenuated-inversion-recovery (FLAIR) image 293–4, 303–5 fluorescence decay analysis 376–7 fluorescence lifetime imaging (FLIM) anisotropy measurements 382–3 diffusion studies 377–82 fluorescence lifetime modifications, metal-induced 376, 383–5 historical background 371–3 instrumentation 377 theoretical background 373–7 time-resolved fluorescence anisotropy imaging (TR-FAIM) 374–5 fluorescence molecular tomography (FMT) airway inflammation imaging 360–1 basic technique 345–6 cancer imaging 358–9 cardiological applications 360–1 in vivo cerebral plaque imaging 360–1, 362 526 fluorescence optical imaging background 10–11, 343–4 clinical applications 357–64 dye-doped nanoparticles for 348–52 in multimodal systems 346–7 probe design 352–4 small organic dyes for 348, 349, 350 in vivo techniques 344–6 fluorescent molecular rotors 375 fluorine-18 18 F-AV-45 (Florbetapir F-18) 30 [18F]BAY94 57 [18F]BF227 56–7 [18F]CPFPX 102–3 emission characteristics 23–4 [18F]FDDNP 54–5 [18F]FE-DABP688 61–2 [18F]FE-DTBZ 85 [18F]FEPEP 111–12 [18F]FMeNER 73–4 [18F]FMPEP 111–12 [18F]FMPEP-d2 111–12 [18F]F-MTEB 63 [18F]FP-DTBZ 85 [18F]FPEB 62 [18F]FPECMO 61–2 [18F]FTIDC 60 [18F]MK-1312 59 [18F]MK-4908 59 [18F]MK-9470 112–13 [18F]PBR06 94–5 [18F]SP203 63 Food and Drug Administration (FDA), USA clinical evaluation of drug development 442–3 CNS biomarker development and 429–30 SPECT agents 14 formation rate constants DOTA complexes 242 formats 3, Foărster Resonance Energy Transfer (FRET) 372 [123I]FP-CIT (ioupane) 65–7 Subject Index 18 [ F]FP-DTBZ 85 [18F]FPEB 62 [18F]FPECMO 61–2 [11C]FR194921 103–4 frontotemporal dementia 94 lobar degeneration 57 [18F]FTIDC 60 fullerene encapsulated systems see metallofullerenes functional imaging vs anatomic imaging 3, functional MRI (fMRI) 294–6 gadolinium Gd-AAZTA 187 biopolymers 354–7, 501 chelate borohydrides 510–11 clinically used Gd31 contrast agents 210, 493–5 complexes for MRI 9–10, 175–83, 493–5 dendrimers 498–501 DO3A complexes 175, 210, 216–17 Gd-DTTA 186–7 gadofullerenes 199–201, 261–81, 503–7 gadolinium-enhanced MRI for joint disease 446–7 gadonanotubes and their derivatives 277, 278–80, 507–8 GRID (gadolinium-rhodamine dextran) 453 Gd-HOPO 186 Hydrochalarone series 273, 506–7 Ga-NETA 189 newly developed and future ligands 186–90, 493–508 Gd-PCT2A 187 poly(aminocarboxylate) chelates 261–2 see also DOTA; DTPA gallium-67 162 gamma knife treatment planning 298–301 Gd-DTPA2– (gadopentetate) 9–10 527 Subject Index genes and genetic loci 5-HTTLPR (SERT) 76, 77 5p15.3 (DAT) 64 16q12.2 (NET) 64 17q11 (SERT) 64 glioma, monitoring chemoradiation of 303–5 mGluR1 tracers 58–60 mGluR5 tracers 60–3 glutamate receptors 58–63 gradient echo-echo planar imaging (GE-EPI) 295 green fluorescent protein (GFP) 11 GRID (gadolinium-rhodamine dextran) 453 [11C]GSK-215083 90–1 hard shell microbubbles 394, 395–6 head and neck cancers 296–8 head and neck cancers, MRI evaluation 296–8 HeLa cells 267 helium hyperpolarised 10 herpes encephalitis 94 HOPO 186 5-HTT see serotonin transporter (SERT) Huntington’s disease 93–4, 97 Hydrochalarone series 273, 506–7 5-hydroxy tryptamine, 5HT see serotonin receptors image fusion for radiotherapy 290–1 imaging technology and analysis for QWBA 327–8 [123I]IMPY 51, 55–6 indium-111 162–3 [111In] labeled leukocytes 166–7 123 [ I]INER 74 integrin receptor targeted agents 35–8 intensity modulated radiation therapy (IMRT) 289 Investigational Medicinal Product, IMP (EU) 19 Investigational New Drug, IND (USA) 19 iodination of arenes 157 iodine isotopes [123I]ADAM 79–80 [123I]AM251 107–9 [123I]AM281 109 [123I]b-CIT 67–9 commonly used isotopes 153–4 [131I]CPIPX 67–9 emission characteristics 24 [123I]FP-CIT (ioflupane) 65–7 [123I]IMPY 51, 55–6 [123I]INER 74 [123I]ioflupane 160–2 [123I]IPBM 74 [123I]IV-TBZOH 83 [131I]MIBG 74 [123I]PE21 69–70 production of 154 radiolabeling strategies 154–60 radiopharmaceuticals based on 160–2 radiopharmaceuticals labeled with 153–62 sodium iodide 160 [123I]IPBM 74 iron see ferrite nanocrystals [123I]IV-TBZOH 83 joint diseases, degenerative drug development using MRI 445–7 rheumatoid arthritis (RA), NIRF imaging of 359–60 [11C]KF17837 104 [11C]KF18446 104–5 kidney toxicity of drugs 482 [11C]KW6002 105–6 lanthanides DOTA and DTPA chelates (general) 208–11 kinetic properties of derivatives 240–9 528 lanthanides (continued) lanthanoid endohedral metallofullerenols 265–6, 503–7 within liposomes (LIPOCEST agents) 201–2 paramagnetic chelates (PARACEST agents) 201 Leksell Gamma Knife 298–301 leukocytes, [111In] labeled 166–7 linear accelerators 286–7 liposomes for cell therapies 453 LIPOCEST agents 201–2 SPIO 509 structure and stability 502–3 liver cancer contrast enhanced ultrasound imaging 402–4 liver toxicity of drugs 481–2 luciferin 11 lymph node ultrasound imaging 405–6 macromolecular systems for nanosized contrast agents 195–7 magnesium, assessment in tissues 192–3 magnetic resonance spectroscopic imaging (MRSI) 294, 423 major depression episodes (MDE) 77–8 manganese chelates 9–10, 493–4 Marketing Authorisation Application, MAA (EU) 19 [11C]McN 75–6 MDMA treatment 75–6, 78 [99mTc]MDP 151–2 medical applications 16–18 MEG (magnetoencephalography) melanin binding 332–3 [11C]MeNER 72–3 [11C]MePEP 110 metabotropic glutamate receptors 58–63 Subject Index metal ions DOTA and DTPA chelates (general) 208–11 DOTATOC 164–6 new ligands 186–90 paramagnetic ion complexes for MRI 175–83 radiolabeling strategies with 163–7 radiopharmaceuticals labeled with 162–3 responsive contrast agents 193–5 superparamagnetic particles 184–5 transmetallation reactions, equilibria of 239–40 metal-induced fluorescence lifetime modifications 376, 383–5 metallofullerenes background 261–2 classification and encapsulation 199–201 endohedral metallofullerenols 265–6, 503–7 gadonanotubes and their derivatives 277, 278–80, 507–8 Gd@C60 268–71, 503, 505 Gd@C80 263, 271–8, 503, 505–6 Gd@C82 263–8, 503, 505, 507 relaxivity 262–5 metastasis see integrin receptor targeted agents micro-autoradiography (MARG) applications of 337–9 definitions 310–12, 333–4 history of 333–6 limitations of 336–7 microbubbles as drugs and genes carriers 397–8 enhanced ultrasound imaging 392, 394–8 use-oriented characterisation of 398–400 microwaves, imaging problems 10 middle cerebral artery occlusion (MCAO) 447–8 migraine, biomarkers for 428–9 Subject Index MION (monocrystalline iron oxide nanoparticles) 494 [18F]MK-1312 59 [18F]MK-4908 59 [18F]MK-9470 112–13 molybdenum (Mo) in production of Tc-99m 145–7 supply problems 13 in Tc-99m radiolabeling 147–51 molybedenum-99 see technetium99m monitoring biomarkers 17–18 monoamine transporter targets 64–80 [11C]MPDX 100–1 MPI (magnetic particle imaging) MRI (magnetic resonance imaging) acquiring images 6–7, 491–3 anatomic MRI 293–4 application to radiotherapy 285–305 in drug development 441–59 in drug discovery 465–86 dynamic contrast-enhanced (DCE) MRI 301–3 endogenous contrast in 7–9 exogenous contrast in 9–10 field strengths 6–7 functional imaging vs anatomic imaging 3, functional MRI 294–6 future trends and developments 186–90, 490–511 transverse relaxation times 7–9 see also contrast agents for MRI [11C]MTBZ 82–3 multimodal imaging techniques 16, 346–7, 456–8, 509–11 multiple sclerosis 94 multiple system atrophy (MSA) 68–9 NAALADase derivatives as PSMA agents 31–2 nanoparticles, dye-doped 348–52 nanoparticles and nanospheres for ultrasound contrast 397, 502 529 nanosized contrast agents encapsulated systems 199–201, 348–52 macromolecular systems 195–7, 502 quantum dots 351–2 supramolecular assemblies 197–9 nanotubes, single-walled 200–1 near-infrared fluorescence (NIRF) imaging 344–5 small organic dyes for 348, 349, 350 nephrogenic systemic fibrosis (NSF) 181–2, 239, 262, 496 nephrotoxicity of drugs 18, 482 nephrogenic systemic fibrosis (NSF) 181–2, 239, 262, 496 NETA 189 New Drug Application, NDA (USA) 19 [N-11C]nisoxetine 71–2 [O-11C]nisoxetine 71–2 NMDA antagonists 447 NMR (nuclear magnetic resonance) norepinephrine transporter (NET) 71–4 nuclear magnetic relaxation dispersion (NMRD) profile, Gd@C60 269–70 nuclear medicine 13 obsessive-compulsive disorder 78–9, 97 oncology see cancer optical imaging see fluorescence optical imaging optoacoustic tomography (OAT) 345–6 multispectral (MSOT) 345–6, 360–1, 362 osteoarthritis (OA) drug development using MRI 446–7 pain (chronic), approaches to 421 PAMAM (polyamidoamine) dendrimers 197, 498–501, 510–11 530 PARACEST agents 201 paramagnetic lanthanide chelates (PARACEST) 201 Parkinson’s disease (PD) [123I]b-CIT assessment 67–9 [11C]DASB assessment 77–9 dopamine dysfunction, biomarkers for 428 [123I]FP-CIT assessment 66–7 [11C]McN assessment 75–6 melanin binding 332–3 phosphodiesterase inhibitors 97 [11C]PIB assessment 54 [11C]TBZOH assessment 83–4 [99mTc]TRODAT-1 assessment 70–1 vascular parkinsonism (VP) 69, 71 vascularization studies 93 young onset (YOPD) 70 [11C]PBR06 95 [11C]PBR28 94–5 [18F]PBR06 94–5 PCTA 187 [11C]PE21 56–7 [123I]PE21 69–70 PEP [18F]FEPEP 111–12 [11C]FMePPEP 111–12 [18F]FMPEP-d2 111–12 [11C]MePEP 110 perfusion weighted imaging (PWI) 294–5 in drug development 444–5 peripheral benzodiazepine receptor, PBR 91–5 PET (Positron Emission Tomography) CNS Imaging 49–50 halogen tracers 14–15 pH responsive contrast agents 195 pharmacological MRI (phMRI) 4223 [11C](ỵ)-PHNO 868 phosphodiesterase inhibitors 95–9 PDE4 97–8 PDE10 98–9 physiology 95–7 Subject Index phosphoramidate-based imaging agents 34–5 [11C]PIB 51–4 [11C]PK11195 93–4 post-synaptic receptors 85–8 dopamine receptor D3 (D3r) 85–8 serotonin targets 88–91 predictive biomarkers 17 prognostic biomarkers 17 progressive supranuclear palsy (PSP) 68–9 prostate cancer metallofullerenol and 266–7 monitoring radiation therapy 301–3 PSMA targeting agents 30–5 ultrasound imaging 404–5 protonation constants, calculation of 227–36 sequence, DTPA and DOTA derivatives 212–13, 231–6 Prozac 64 PSMA (prostate-specific membrane antigen) targeting agents 30–5 quantitative whole-body autoradiography (QWBA) applications of 328–33 definition 310, 311–12 history of 315–17 limitations of 319–28 methodology 313–15 strengths of 317–19 quantum dots 351–2 radio frequency techniques radiohalogens for PET 14 as PSMA agents 32–3 radiohalogenation 25–7 in radionuclide selection 23–5 radioiodination of arenes 157 radiolabel stability in QWBA 321–4 531 Subject Index radiopurity in QWBA 320–1 radiotherapy, application of MRI to chemoradiation 291–2 historical perspective 285–6 image fusion 290–1 initial planning 287–9 MRI processes 292–6 target definition 289–91 teletherapy equipment 286–7 radiotracer and radiopharmaceutical chemistry definitions 21–2 design and synthesis for SPECT 144–68 integrated development 25–7 radionuclide selection 23–5 receptor occupancy and mapping, CNS 423–4 regulatory issues 18–19 relaxivity metallofullerenes 262–3, 273, 276 transverse relaxation times in MRI 7–9 renal insufficiency and dysfunction 262 respiratory diseases allergic airway inflammation, optical imaging of 361–3 drug development using MRI 452 inflammatory conditions 361–3 target definition for respiratory tumors 290 response biomarkers 18 responsive contrast agents enzyme responsive agents 190–3 metal ion responsive agents 193–5 pH responsive agents 195 resting state networks (RSN) 422 reticuloendothelial system (RES) 268 retinal angiography 10–11 RGD (arginine-glycine-aspartic) sequence targeting 35–8 rheumatoid arthritis (RA) drug development using MRI 4456 NIRF imaging of 35960 Ritalin 64 Roăntgen, Wilhelm C 1, 12 sample processing variables in QWBA 324–6 [11C]SB207145 89–90 [11C]SB207710 90 [11C]SCH225336 113–14 [11C]SCH442416 106 schizophrenia 94, 97 secretases, APP cleavage 50–1 serotonin receptors physiological effects 88 Subtype (5-HT4) 89–90 Subtype (5-HT6) 90–1 serotonin transporter (SERT) 75–80 [99mTc]sestamibi 152–3 short-lived isotope use in QWBA 324 skin penetration characteristics, cosmetics 338–9 small animal imaging technologies 471, 475 small organic dyes for optical imaging 348, 349, 350 soft shell microbubbles 394, 395 Solomon-Bloembergen-Morgan (SBM) equation 278, 493 [18F]SP203 63 SPECT (single photon emission computed tomography) 13–14 CNS Imaging 49–50 radiopharmaceuticals for 144–68 SPIO (superparamagnetic iron oxide) 184–5, 495, 508–9 stability constants calculation of 228–31 DOTA derivatives 238 DTPA derivatives 237 stem cells, mesenchymal 267 stroke drug development using MRI 447–8 ultrasound microbubbles in diagnosis 407 studies and trials bapineuzumab 53 532 studies and trials (continued) CALM- PD-CIT 68 D3 vs D2 receptors [11C](ỵ)PHNO specicity 878 ELIDOPA 68 paroxetine 67 Tourette’s syndrome multitracer study 76 supramolecular assemblies for nanosized contrast agents 197–9 target definition radiotherapy 289–91 target specific MRI in drug development 454–6, 497–8 [11C]TBZ 81–2 [11C]TBZOH 83–4 technetium-99m (Tc-99m) [99mTc]based radiopharmaceuticals 151–3 chelates for SPECT 13–14 emission characteristics 24–5, 144–5 [99mTc]exametazime 152 [99mTc]MDP 151–2 production of 145–7 in PSMA agents 33–4 radiolabeling strategies using 147–51 [99mTc]sestamibi 152–3 [99mTc]TRODAT-1 70–1 terbium Tb-DOTAMGly ligands 201 texaphyrins 189–90 theranostics 510–11 thioethers 159 Thioflavin-T for b-amyloid targeting 27–30 thulium Tm-DOTP chelates 201 time-resolved fluorescence anisotropy imaging (TR-FAIM) 374–5 [11C]TMSX 104–5 Subject Index tomographic imaging see specific tomographic techniques tositumomab, 131I labelled 17 Tourette’s syndrome 68, 71 multitracer (DAT, D2, SERT, 5-HT2A) study 76 toxicology in drug discovery and development 18, 181–2, 239, 262, 481–3, 496 Translational Biologics Imaging Platform 355 translocator protein 18kD, TSPO see peripheral benzodiazepine receptor, PBR transmetallation reactions, equilibria of 239–40 [99mTc]TRODAT-1 70–1 tumor-associated macrophages (TAMs), targeting 358 ultrasound imaging A-mode images 15 clinical applications 402–7 contrast enhanced images 398–401 future prospects 409 imaging classes 15–16 indications for contrast agents 392–3 microbubble enhanced images 392, 394–8 nanoparticles and nanospheres 397 safety of contrast agents 407–9 ultraviolet, imaging problems 11 USPIO (ultrasmall superparamagnetic iron oxide) 184–5, 494, 510–11 vascular endothelial growth factor (VEGF) 404 vesicular monoamine transporter type (VMAT2) 80–5 volumetric imaging as an anatomical CNS biomarker 420–1 533 Subject Index whole-body autoradiography (WBA) see quantitative wholebody autoradiography (QWBA) whole-body autoradioluminography (WBAL) 311–12 Wilson’s disease 68 X-rays planar imaging techniques 12–13, 490 see also computed tomography (CT) yttrium-90 163 xenon hyperpolarised 10 Xenopus laevis larva 190 zinc, assessment in tissues 192–3 ... research and to assist in the development of new therapeutic drugs Biomedical Imaging: The Chemistry of Labels, Probes and Contrast Agents begins with a comprehensive introduction to endogenous and. .. covered include the synthesis and applications of MRI contrast agents, synthetic methods used for the preparation of DTPA and DOTA derivative ligands, MRI contrast agents based on metallofullerenes,... applications of MRI in radiotherapy treatment and the use of autoradiography in the pharmaceutical discovery and development of RSC Drug Discovery Series No 15 Biomedical Imaging: The Chemistry of Labels,