The chemistry of contrast agents in medical magnetic resonance imaging

The Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging The Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging Second Edition Edited by ANDRE´ MERBACH Ecole Polytechnique F´ed´erale de Lausanne, Lausanne, Switzerland LOTHAR HELM Ecole Polytechnique F´ed´erale de Lausanne, Lausanne, Switzerland ´ ´ EVA TOTH CNRS, Orl´eans, France A John Wiley & Sons, Ltd., Publication This edition first published 2013 c 2013 John Wiley & Sons, Ltd Registered office John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, United Kingdom For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988 All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic books Designations used by companies to distinguish their products are often claimed as trademarks All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners The publisher is not associated with any product or vendor mentioned in this book This publication is designed to provide accurate and authoritative information in regard to the subject matter covered It is sold on the understanding that the publisher is not engaged in rendering professional services If professional advice or other expert assistance 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and precautions The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read No warranty may be created or extended by any promotional statements for this work Neither the publisher nor the author shall be liable for any damages arising herefrom Library of Congress Cataloging-in-Publication Data ´ T´oth The chemistry of contrast agents in medical magnetic resonance imaging – Second edition / edited by Lothar Helm, Andr´e E Merbach, Eva pages cm Includes bibliographical references and index ISBN 978-1-119-99176-2 (hardback) Contrast-enhanced magnetic resonance imaging Magnetic resonance imaging I Helm, Lothar, editor of compilation II Merbach, Andr´e E., ´ editor of compilation III T´oth, Eva, editor of compilation RC78.7.C65C48 2013 616.07 548–dc23 2012037031 A catalogue record for this book is available from the British Library Print ISBN: 978-1-119-99176-2 Set in 10pt/12pt Times by Laserwords Private Limited, Chennai, India Contents List of Contributors Preface 1.1 1.2 1.3 1.4 1.5 1.6 1.7 2.1 2.2 General Principles of MRI Bich-Thuy Doan, Sandra Meme, and Jean-Claude Beloeil Introduction Theoretical basis of NMR 1.2.1 Short description of NMR 1.2.2 Relaxation times 1.2.3 Saturation transfer 1.2.4 Concept of localization by magnetic field gradients Principles of magnetic resonance imaging 1.3.1 Spatial encoding MRI pulse sequences 1.4.1 Definition 1.4.2 k -Space trajectory 1.4.3 Basic pulse sequences Basic image contrast: Tissue characterization without injection of contrast agents (main contrast of an MRI sequence: Proton density (P), T1 and T2 , T2∗ ) 1.5.1 Proton density weighting 1.5.2 T1 weighting 1.5.3 T2 weighting 1.5.4 T2∗ weighting Main contrast agents 1.6.1 Gadolinium (Gd) complex agents 1.6.2 Iron oxide (IO) agents 1.6.3 CEST agents Examples of specialized MRI pulse sequences for angiography (MRA) 1.7.1 Time of flight angiography: No contrast agent 1.7.2 Angiography using intravascular contrast agent (Blood pool CA) injection 1.7.3 DSC DCE MRI References Relaxivity of Gadolinium(III) Complexes: Theory and Mechanism ´ T´oth, Lothar Helm, and Andr´e Merbach Eva Introduction Inner-sphere proton relaxivity 2.2.1 Hydration number and hydration equilibria 2.2.2 Gd–H distance xiii xv 1 1 4 5 11 11 12 13 16 17 17 17 18 18 19 19 20 21 21 21 23 23 25 25 28 31 37 vi 2.3 2.4 2.5 3.1 3.2 3.3 3.4 3.5 3.6 4.1 4.2 4.3 Contents 2.2.3 Proton/water exchange 2.2.4 Rotation Second- and outer-sphere relaxation Relaxivity and NMRD profiles 2.4.1 Fitting of NMRD profiles 2.4.2 Relaxivity of low-molecular-weight Gd(III) complexes 2.4.3 Relaxivity of macromolecular MRI contrast agents 2.4.4 Contrast agents optimized for application at high magnetic field Design of high relaxivity agents: Summary References Synthesis and Characterization of Ligands and their Gadolinium(III) Complexes Jan Kotek, Vojtˇech Kub´ıcˇ ek, Petr Hermann, and Ivan Lukeˇs Introduction – general requirements for the ligands and complexes Contrast agents employing linear polyamine scaffold 3.2.1 Synthesis of linear polyamine backbone 3.2.2 N -functionalization of linear polyamine scaffold Contrast agents employing cyclen scaffold 3.3.1 Synthesis of the macrocyclic skeleton 3.3.2 N -functionalization of macrocyclic scaffold Other types of ligands 3.4.1 H4 TRITA and related ligands 3.4.2 H3 PCTA and related ligands 3.4.3 TACN derivatives 3.4.4 Ligands with HOPO coordinating arms and related groups 3.4.5 H4 AAZTA and related ligands Bifunctional ligands and their conjugations Synthesis and characterization of the Ln(III) complexes 3.6.1 General synthetic remarks 3.6.2 Characterization of the complexes List of Abbreviations References Stability and Toxicity of Contrast Agents Erno Brăucher, Gyula Tircso, Zsolt Baranyai, Zolt´an Kov´acs, and A Dean Sherry Introduction Equilibrium calculations 4.2.1 Constants that characterize metal ligand interactions (protonation constants of the ligands, stability constants of the complexes, conditional stability constants, ligand selectivity, and concentration of free Gd3+ : pM ) 4.2.2 A brief overview of the programs used in equilibrium calculations (calculation of protonation constants, stability constants, and equilibrium speciation diagrams) Stability of metal–ligand complexes 4.3.1 Stability of complexes of open chain ligands (EDTA, DTPA, EGTA, and TTHA) 4.3.2 Stability of complexes of tripodal and AAZTA ligands 4.3.3 Stability of complexes of macrocyclic ligands 39 57 64 66 66 68 69 73 75 76 83 83 84 85 89 103 103 106 123 123 123 126 130 133 134 138 138 139 144 146 157 157 158 158 159 160 160 165 168 Contents 4.4 4.5 4.6 4.7 4.3.4 Ternary complexes formed between the Ln(L) complexes and various bio-ligands 4.3.5 Mn2+ -based contrast agents Kinetics of M(L) complex formation 4.4.1 Formation kinetics of DOTA complexes 4.4.2 Formation kinetics of complexes of simple DOTA-tetraamides Dissociation of M(L) complexes 4.5.1 Inertness of complexes of open chain ligands (EDTA, DTPA, and AAZTA) 4.5.2 Decomplexation of DOTA complexes 4.5.3 Decomplexation of DOTA-tetraamide complexes Biodistribution and in vivo toxicity of Gd3+ -based MRI contrast agents 4.6.1 Osmolality and hydrophobicity of Gd3+ -based MRI contrast agents 4.6.2 Biodistribution 4.6.3 In vivo toxicity 4.6.4 Predicting in vivo toxicity of Gd3+ -based contrast agents using thermodynamic conditional stability constants 4.6.5 The role of kinetic inertness in determining in vivo toxicity 4.6.6 Kinetic inertness combined with thermodynamic stability is the best predictor of in vivo toxicity 4.6.7 Nephrogenic systemic fibrosis (NSF) Concluding remarks Acknowledgements References Structure, Dynamics, and Computational Studies of Lanthanide-Based Contrast Agents Joop A Peters, Kristina Djanashvili, Carlos F.G.C Geraldes, and Carlos Platas-Iglesias 5.1 Introduction 5.2 Computational methods 5.3 Lanthanide-induced NMR shifts 5.3.1 Bulk magnetic susceptibility shifts 5.3.2 Diamagnetic shifts 5.3.3 Contact shifts 5.3.4 Pseudocontact shifts 5.3.5 Evaluation of bound shifts 5.3.6 Separation of shift contributions 5.4 Lanthanide-induced relaxation rate enhancements 5.4.1 Evaluation of bound relaxation rates 5.4.2 Inner-sphere relaxation 5.4.3 Outer-sphere relaxation 5.5 Anisotropic hyperfine interactions on the first coordination sphere water molecules 5.6 Evaluation of geometries by fitting NMR parameters 5.7 Two-dimensional NMR 139 La and 89 Y NMR 5.8 5.9 Water hydration numbers 5.10 Chirality of lanthanide complexes of polyaminocarboxylates 5.11 Complexes of non-macrocyclic polyaminocarboxylates 5.11.1 DTPA and derivatives vii 176 179 184 184 186 186 187 190 192 193 193 194 195 195 196 197 199 201 201 201 209 209 210 213 213 213 214 215 216 217 219 219 219 221 221 222 224 224 225 227 227 227 viii 5.12 5.13 Contents 5.11.2 TTHA 5.11.3 EGTA 5.11.4 DTTA 5.11.5 Tripodal complexes Complexes of macrocyclic ligands 5.12.1 DOTA and derivatives 5.12.2 DO3A and derivatives 5.12.3 PCTA and derivatives 5.12.4 TETA 5.12.5 DOTP 5.12.6 Phosphinates and phosphonate esters 5.12.7 Cationic macrocyclic lanthanide complexes 5.12.8 AAZTA Fullerenes References Electronic Spin Relaxation and Outer-Sphere Dynamics of Gadolinium-Based Contrast Agents Pascal H Fries and Elie Belorizky 6.1 Introduction 6.2 Theory of electronic spin relaxation of Gd3+ ions 6.2.1 Classical approach: Bloch equations 6.2.2 Quantum approach: Electronic time correlation functions 6.2.3 The zero-field splitting Hamiltonian 6.2.4 The density matrix formalism 6.2.5 The Redfield approximation 6.2.6 The Swedish super-operator approaches 6.2.7 Monte-Carlo simulation of the Gd3+ electronic relaxation: The Grenoble method 6.3 Outer-sphere dynamics 6.3.1 Standard theory neglecting the electronic relaxation 6.3.2 Analytical hard-sphere models 6.3.3 The general case of anisotropic polyatomic molecules 6.3.4 Experimental determination of the dipolar time correlation function 6.4 Relaxivity quenching by the electronic spin relaxation 6.4.1 The various field regimes 6.4.2 Outer-sphere relaxivity 6.4.3 Inner- and second-sphere relaxivities 6.4.4 Application to a cyclodecapeptide Gd3+ complex 6.5 Various experimental approaches of the electronic spin relaxation 6.5.1 Outer-sphere relaxivity profiles 6.5.2 EPR spectroscopy 6.6 Conclusion and perspectives 6.A Appendix: Similar evolutions of the macroscopic magnetization of the electronic spin and of its correlation functions References 236 238 239 240 244 244 250 252 253 254 257 260 264 265 267 277 277 279 279 281 281 284 285 287 288 289 289 291 292 292 295 295 295 297 299 301 301 302 306 307 308 Contents 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 7.10 7.11 7.12 7.13 7.14 7.15 7.16 7.17 7.18 7.19 7.20 8.1 8.2 8.3 9.1 9.2 Targeted MRI Contrast Agents Peter Caravan and Zhaoda Zhang Introduction Serum albumin Fibrin Type I collagen Elastin Sialic acid αV β3 integrin Folate receptor Matrix metalloproteinases (MMP) E-selectin Fibrin-fibronectin complex Alanine aminopeptidase (CD13) Carbonic anhydrase Interleukin receptor Estrogen and progesterone receptors Contrast agents based on natural products Messenger RNA (mRNA) Myelin DNA Conclusions References ix 311 311 313 319 325 326 327 328 329 330 331 332 332 333 334 335 336 337 338 338 340 340 Responsive Probes ´ T´oth C´elia S Bonnet, Lorenzo Tei, Mauro Botta, and Eva Introduction Probes responsive to physiological parameters 8.2.1 Temperature responsive probes 8.2.2 pH sensing 8.2.3 Redox responsive probes 8.2.4 Sensing of biologically relevant ions 8.2.5 Enzyme responsive probes Conclusions References 343 Paramagnetic CEST MRI Contrast Agents Enzo Terreno, Daniela Delli Castelli, and Silvio Aime Introduction Theoretical and practical considerations on CEST response 9.2.1 NMR/chemical properties of CEST site(s) 9.2.2 NMR properties of the wat site 9.2.3 Instrumental variables 9.2.4 Variables dependent on the sample 9.2.5 Spectroscopic versus imaging detection of CEST response 9.2.6 Characterization of a CEST agent and its quantification 387 343 344 344 349 360 364 373 381 382 387 388 391 394 395 397 399 400 x Contents 9.3 9.4 9.5 9.6 10 10.1 10.2 10.3 10.4 10.5 10.6 10.7 11 11.1 11.2 11.3 11.4 Diamagnetic versus paramagnetic CEST agents Paramagnetic CEST agents 9.4.1 ParaCEST agents 9.4.2 SupraCEST agents 9.4.3 NanoCEST agents Other exchange-mediated contrast modes accessible for paramagnetic CEST agents Concluding remarks References Superparamagnetic Iron Oxide Nanoparticles for MRI Sophie Laurent, Luce Vander Elst, and Robert N Muller Introduction Synthesis of iron oxide nanoparticles 10.2.1 Coprecipitation in aqueous medium 10.2.2 Reverse micro-emulsions 10.2.3 Sol gel methods 10.2.4 Polyol methods 10.2.5 Hydrothermal methods 10.2.6 Sonochemistry methods 10.2.7 Pyrolytic methods Stabilization 10.3.1 Steric stabilization: Natural or synthetic polymeric matrices 10.3.2 Electrostatical stabilization Methods of vectorization for molecular imaging Characterization 10.5.1 Relaxivity and NMRD profiles Applications 10.6.1 Tissue labelling with iron oxide particles 10.6.2 Cellular and molecular labelling with iron oxide particles 10.6.3 Iron oxide nanoparticles as molecular MRI probes Conclusions Acknowledgements References Gd-Containing Nanoparticles as MRI Contrast Agents Klaas Nicolay, Gustav Strijkers, and Holger Grăull Introduction Length scales and excretion pathways Preparation of Gd-containing nanoparticles 11.3.1 Lipid aggregates 11.3.2 Liposomes 11.3.3 Micelles 11.3.4 Other lipid-containing nanoparticles 11.3.5 Chemical structures of Gd-containing lipids Methods for nanoparticle characterization 11.4.1 Morphology 400 401 402 411 413 419 421 421 427 427 428 429 430 430 430 430 431 431 431 431 432 432 436 436 440 441 442 442 444 444 444 449 449 452 454 455 456 457 458 458 460 461 Contents 11.5 11.6 11.7 Index 11.4.2 Particle composition 11.4.3 Magnetic properties 11.4.4 Chelate stability 11.4.5 Miscellaneous techniques In vitro applications 11.5.1 Target specificity 11.5.2 Cellular interactions, internalization, and compartmentation 11.5.3 Biological effects In vivo applications 11.6.1 Target-specific imaging 11.6.2 Image-guided drug delivery Conclusions and future perspectives Acknowledgements References xi 462 464 467 468 468 468 470 475 475 476 478 481 483 483 489 Gd-Containing Nanoparticles as MRI Contrast Agents 481 ΔT ΔT O OH O OH H O O H O O OH O O N OH O Gd N N O H2N heating e.g high-intensity focused ultrasound (HIFU) N O O O O OH drug e.g doxorubicin contrast agent e.g Mn2+ Gd(HPDO3A)(H2O) Figure 11.16 Schematic representation of temperature-induced release from a temperature-sensitive liposome (TSL) containing drug (red dots) and contrast agent (yellow dots) Local hyperthermia can be achieved noninvasively with HIFU under MRI guidance, which induces the concurrent release of drug and contrast agent in the tumor vasculature Reprinted from de Smet, M., Heijman, E., Langereis, S et al., Journal of Controlled Release, 150, 102–110 Copyright 2011, with permission from John Wiley & Sons, Ltd the intact liposomal drug carriers In order to circumvent this problem, Langereis et al combined the approach of LipoCEST [171] and fluorine MR imaging encapsulating Tm-HPDO3A and a fluorinated model compound in temperature sensitive liposomes [172] As long as both compounds reside inside the liposome, a shortening of T2 leads to line broadening of the fluorine signal, rendering it “invisible” with MRI, while a clear CEST signal can be observed Upon release, the CEST signal disappears, while upon dilution, the fluorine signal becomes observable This concept could potentially be exploited to image the release of fluorinated drugs such as gemcitabine from temperature sensitive carriers, though fairly high field strength may be required As liposomes can be made responsive to a variety of stimuli, for example, redox potential, presence of enzymes, or pH change, the concept can be broadened to visualize triggered drug release tailored to special applications Recently, Torres et al demonstrated this for pH-triggered release of Gd-HPDO3A from liposomes [173] 11.7 Conclusions and future perspectives Over the past decade, an extensive library of nanoparticulate paramagnetic contrast agents has been developed for molecular and cellular MRI Many examples of their successful use for the in vivo visualization 482 The Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging HIFU (rat 1) muscle tumor HIFU (rat 2) muscle No HIFU (rat 4) muscle tumor tumor cm before TSL injection T1(ms) 1200 960 t = 20 t = 40 720 480 240 120 t = 70 Figure 11.17 In vivo MRI-guided HIFU for monitoring local drug release Anatomical MR images of tumor bearing rats in the small animal HIFU setup (upper row) and T1 maps of the tumor and leg overlaid on the anatomical images at different time points: before injection of thermo-sensitive liposomes, after the first hyperthermia period (t = 20 min, after the second hyperthermia period (t = 40 min) and 70 after liposome injection (Left column) HIFU-treated tumor showing a large T1 change (rat 1); (middle column) HIFU-treated tumor showing a more localized T1 response (rat 2); and (right column) untreated tumor (no HIFU, rat 4) Reprinted from de Smet, M., Heijman, E., Langereis, S et al., Journal of Controlled Release, 150, 102–110 Copyright 2011, with permission from John Wiley & Sons, Ltd of molecular markers of disease processes have been reported The most fruitful applications involve the detection of cell-surface receptors, in particular on vascular endothelium, and imaging of components in the extracellular matrix The low tissue concentrations of many important disease biomarkers, however, continue to challenge the intrinsically low detection sensitivity of MRI Under certain conditions, the effective H-relaxivity of Gd-containing contrast agents is modulated by compartmentation effects We anticipate that this provides exciting opportunities for monitoring the biological fate of the contrast material This particularly applies when multimodal agents are employed, such that another imaging technique can be used for absolute quantification Nanoparticles that are assembled from lipid molecules have virtues because of their excellent biocompatibility Moreover, many lipid-based nanoparticles are in clinical use as drug carriers and a broad range of novel therapeutic formulations are in clinical trials We expect that MRI in combination with nanoparticles equipped with Gd-contrast agents, will increasingly be used to provide guidance for drug delivery and drug release and thus will make important contributions to the optimization of therapeutic interventions In such studies, MRI will play many different roles, including target identification and characterization, as well as monitoring of the intervention and therapy follow-up Gd-Containing Nanoparticles as MRI Contrast Agents 483 Many Gd-containing nanoparticles have relatively long in vivo residence times and this obviously raises safety concerns Apart from toxicity issues, there are major economic and regulatory hurdles for clinical translation of paramagnetic nanoparticulate probes To date, no single target-specific paramagnetic contrast agent has been FDA or EMA approved Even the low-molecular weight fibrin-targeting agent EP-2104R that showed very promising results in explorative patient studies [174], has not yet been approved for clinical use It seems therefore likely that paramagnetic nanoparticles for the time being will be mainly employed for preclinical imaging studies in animal models With the rapid advancement of hybrid imaging systems, multimodal nanoparticles will play a progressively important role In particular, imaging instruments in which MRI is integrated with one of the nuclear imaging techniques, and in parallel therefore combined MRI/radiolabeled contrast agents will experience increasing interest in the coming years Acknowledgements The work in the authors’ laboratories related to the topic of this chapter was financially supported by the BSIK project entitled Molecular Imaging of Ischemic Heart Disease (project number BSIK03033), the European Union Network of Excellence Diagnostic Molecular Imaging (DIMI, LSHB-CT-2005-512146), the European Union project MEDITRANS (FP6-2004-NMP-NI-4/IP 026668-2), the European Union project SonoDrugs (NMP4-LA-2008-213706), the Netherlands Technology Foundation STW (grant number 07952), a Netherlands Heart Foundation program grant (grant number 2006T106) and was partly performed in the framework of the European Cooperation in Science and 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Spuentrup, E., Botnar, R.M., Wiethoff, A.J et al (2008) Eur Radiol., 18, 1995–2005 487 Index AAZTA 133–4, 143–4 ABLAVAR 84, see also MS-325 activation volume(s) 41–4, 53 alanine aminopeptidase 332–3 albumin binding 54, 72 alkaline phosphatase 377 amphiphilic 454–8, 460, 465–7 angiogenesis 476–7, 479 angiography 14, 21 annexin A5 469, 471, 476 apoptosis 469–71, 476 arginine-alanine-aspartate (RAD) 477–8 arginine-glycine-aspartate (RGD) 471–8 Arrhenius law 303 atherosclerosis 476, 479 atomic emission spectrometry (AES) 463 avidin 478 avidin/biotin 380 Ayant, Belorizky, Hwang, Freed (ABHF) model 279, 291 B22956 313, 315 B3LYP 211, 246, 247–51, 256, 264 bandwidth 6–7 BAPTA 366 biocompatibility 453, 458, 482 biodistribution 167, 183, 194–5, 197, 452, 458, 460 bioluminescence imaging 449 Bleaney’s constant 215 Bloch equations 279–80 Bloembergen-Morgan theory 29–31, 75 blood pool agent 313–5 BOPTA 96 bound relaxivity, rbd 312, 315, 319 bovine serum albumin (BSA) 54, 61 BSA 319 bulk magnetic susceptibility (BMS) 414 calcium 366 cancer 476–8, 480–482 capped square antiprism (SA) 228, 244, 246 carbon template 104–5 carbonic anhydrase 333–4 caspase 380 cellular labeling 442 CEST agents 347, 359 CEST 4, 20, 21 chemical exchange saturation transfer (CEST) 387–421, 481 chemical exchange chemical shift 12 chirality 314 cholesterol 457, 463 circulation half-life 452, 457, 478 click chemistry 435 CNA-35 461, 463–4, 469–70 colchicine 336–7 collagen 461, 469–70 compartmentation 472–4, 478, 482 complexes characterization 139–44 isomerism 139–42 synthesis 138–9 comprehensive plasma model 196 computed tomography (CT) 453–4 conditional stability 158–9, 179, 196, 198 conductor-like screening model (COSMO) 212–13 contrast agent 18, 19, 21, 23 157, 160, 165, 167, 178, 187, 190, 198, 200, 201 biodistribution of 194–5, 197 clinically approved 193 dendrimer-based 70 dose 179, 185, 187, 193–4, 197, 200–201 high relaxivity 72, 75 in vivo toxicity of 195 The Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging, Second Edition ´ T´oth Edited by Andr´e Merbach, Lothar Helm and Eva c 2013 John Wiley & Sons, Ltd Published 2013 by John Wiley & Sons, Ltd 490 Index contrast agent (continued) macromolecular 51, 59, 69 Mn2+ -based 179 osmolality of 193 pharmacokinetics of 193–4 responsive 178, 343–82 smart 343 contrast 14, 19 contrast-enhanced (CE) MRI 451, 456–8, 466, 479 contrast-to-noise ratio (CNR) 473 coordination sphere first 214, 221, 225, 227–8, 236, 238, 239–42, 257, 263 second 222, 226 coprecipitation 429, 432 correlation time 467 rotational 282 translational 277, 291 critical aggregation concentration (CAC) 455–7 critical micelle concentration (CMC) 457, 466 cryogenic transmission electron microscopy (cryo-TEM) 461–2 crystal structures 140–144 crystalline phase 456 cyclen aminal 104–5, 107 monoacetic acid (DO1A) 108–9 protection 106–9 synthesis 103–6 DCE MRI 23 Debye-Stokes equation 58 decomposition approximation 296–7 defatted HSA 315 dendrimers 93–5, 108, 111–12, 114, 121–2, 133, 138, 452 density functional theory (DFT) 211–12, 214, 228, 246–7, 251–2, 256, 260, 264, 266 density matrix 284–5 deuterium 58 diethylenetriaminepentaacetic acid, see DTPA diffusion coefficient 462 rotational 289 translational 291 dimers, rotation of 59 dioxane 299–300 dipolar field 297–8 dipolar intermolecular interaction 64 dipole-dipole (DD) mechanism 26, 29 dissociation 186 acid catalyzed 192–3, 197 half-life of (t1/2 ) 183–4, 195 metal assisted (catalyzed) 183 spontaneous 183, 188, 191, 193 DNA 338–9 DO2A 109, 115, 120 DO2A2P 120 DO3A 109–11, 115, 120, 142 DO3A and DO3A-like 354, 363, 376 DO3AM-like ligand 353 DO3AP 120, 142 DO3A-sulfonamide 351, 353–5 DOTA 28, 34–5, 39, 43–4, 47, 50, 55, 60, 68, 75, 316–19, 454, 460 amides 110, 112–17, 137 bifunctional derivatives 113–18, 134–7 esters 108, 113, 116–17, 122, 134–6 monoamides 110–117 DOTAGA 135, 324, 326 DOTAM 110–112 DOTAM-Gly-Phe 347 DOTA-monoamide derivatives 351, 363, 373, 376–8 Dotarem 84 DOTASA 135 DOTMA 345, 346 DOTP 119, 142 Douglas-Kroll-Hess (DKH) 212, 214 doxorubicin 479–80 DPA 368 drug delivery 475, 478–82 DSC MRI 23 DTPA amides 92–4, 140 anhydride 92–4, 122, 134–6, bifunctional derivatives 94, 134–7 esters 92–4, 97, 134–5 DTPA 34–5, 39, 44, 47, 49–50, 54, 57, 60, 68–9, 454, 460 DTPA-bisamides 374 DTPA-BMA 35, 40–41, 44, 47, 49–50, 60, 68 DTTA 94, 99–102 DTTAP 99 dual probes 344, 355, 357 Dy(III) complexes 34 Dy-DOTAM 347 dynamic contrast enhanced MRI 364 dynamic light scattering (DLS) 461–2 dynamic nuclear polarization 350–351 echo time, See TE EDTA 98, 102 effective core potentials 212, 228, 243–4, 246, 251, 264 Index EGTA 89, 90, 96, 98 elastin 326–7 electron paramagnetic resonance (EPR) 41, 59, 61, 67, 278, 281, 288, 302–6 electron spin relaxation 29–31, 40, 64 electron spin resonance 374 electron Zeeman interaction 30 electronic relaxation 30–31, 42, 55, 63, 66–8, 316–18 electronic relaxation time 287, 298, 301–5 electronic spin relaxation 277–309 ellipsometry 469 emulsion 455, 458, 466, 472–6, 479 endocytosis 471–3 endothelial cells 471–7 enhanced permeability and retention (EPR) effect 451, 453, 476 enzyme responsive agents 373–81 Eovist 84 EP-1873 324 EP-2104R 324 EP-3533 325–6 EP-647 313, 315 EPTA 100 equilibrium calculation 158 computer programs for 159 E-selectin 331–2 ESMA 326–7 estrogen and progesterone receptors 335–6 Eu-(2.2.2)cryptand 362 Eu(III) complexes 33–6 Eu2+ /Eu3+ system 362 Eu-DOTAM-Gly 347, 359 evolution operator 281, 288–9, 307–8 excretion 452 extracellular space 452 extravasation 452 Eyring equation 40 F.I.D 2–3, 10 fast exchange region 40–41, 43, fast field cycling (FFC) 66–7 fast local motion 61–2 Fe2+ /Fe3+ 361 fibrin 319–24, 375, 483 fibrin-fibronectin complex 332 fibrinogen 320 fibrosis 325 fluorescence microscopy 468, 470–471, 473, 477–9 19 F-MR 458, 473, 481 19 F NMR/MRI 345, 349–51, 355, 379–80 folate receptor 329–30 Fourier pair Fourier space 9–10 Fourier transforms 2–3, 11 free induction decay, see F.I.D frequency encoding frequential space 10 FTBA 345 fullerene 73–4 gadobenate 315–16 gadocoletic acid 313, 315 gadofosveset, see MS-325 gadofullerene 360 gadolinium 19 gadonanotubes 360 Gadovist 84, 117 β-galactosidase 373, 376–7 Gd(III) 30–31, 34, 37 based contrast agent 27 chelate(s) 27, 44–5, 53, 72 complex 28, 34, 39, 50–51, 68, 75 ions 31 Gd3+ aqua 302–3 cyclodecapeptide 299–302 DOTA 303–5 Gd-AAZTA 466 Gd-AAZTA-C17 315–6 Gd-AAZTA derivatives 363 Gd-based contrast agents: theory 277–309 Gd-(BOM)4 DOTA 315–6 Gd-BOPTA 315–6 Gd-CLT1-DTPA 332 Gd-DO3A-squarate 353, 356 Gd-DOTA 449, 452, 465–8, 473–5, 478 Gd-DOTA-4AMP 253, 357–8 Gd-DOTP 357, 362 Gd-DTPA 311–12, 314, 449, 451–2, 460, 466–8 Gd-DTPA-B(sLex )A 331–2 Gd-DTPA-BMA 349, 449, 452, 467 Gd-DTPA-BSA 458, 466, 468, 475 Gd-DTPA-DOA 467 Gd-DTPA(ENPBA)2 327–8 Gd-DTPA(PBA)2 327–8 Gd-EOB-DTPA 311–12 Gd-H distance 31, 34, 37–9, 61 Gd-HPDO3A 349, 449, 452, 466, 468, 473, 479, 481 Gd-O distance 37, 39, 58, 61 generalized gradient approximation (GGA) 211 g-factor 305–6 491 492 Index glomerular filtration 452 glycerol 295–6 Grenoble method 288–9 hard-sphere models 291 Hartree-Fock (HF) 211–12, 228, 243, 246, 248 high relaxivity 72, 75–6 high-density lipoprotein (HDL) 458, 476 high-intensity focused ultrasound (HIFU) 479, 481–2 Ho3+ complexes 351–2, 355 HOPO 130–133, 142–3 HSA 359, 376 human serum albumin (HSA) 34, 37, 61, 73, 314–16, 319–20, 466 ligands binding to 51, 92, 94, 95, 111–12, 114 hybrid imaging 451 hydration equilibria 31–6, 51 hydration number (q) 28, 31–6, 50, 67 hydrodynamic radius 462 hyperfine coupling constant 214, 222 hyperthermia 479–80 IEPA 350 image-guided therapy 451, 460 in vivo stability 196–7 in vivo toxicity 183, 195–6 and kinetic inertness 196–8 and thermodynamic stability 195, 197–8 models to predict 195 inductively coupled plasma (ICP) 463, 471, 474–5, 478 inner sphere relaxation 27–29 relaxivity(ies) 32–3, 37, 63, 65, 76 water molecules 34–5, 37, 40, 47, 50, 68–9 αv β3 integrin 328–9 integrin 328–9, 470, 475–6, 478–9 interleukin receptor 334 internal motion 315, 324 iopamidol 360 iron oxide 19 isomers square antiprism (SA) 139–41 trigonal prism, 140 twisted square antiprism (TSA) 139–41 K space 9–13 kinetic inertness 184, 187, 196, 198 of AZTAA complexes 178, 190 of macrocyclic complexes 186–7, 190–193, 196 of Mn2+ -based contrast agents 180, 183 of open chain complexes 160, 187, 189 of tripodal complexes 167, 178 kinetic stability 467 lanthanide induced NMR shifts (LIS) 139, 213 bound shift 216 bulk magnetic susceptibility shift (BMS) 213, 225–6 contact shift 213–14, 219, 260 diamagnetic shift 213, 217 paramagnetic shift 217, 243, 246, 252, 264 pseudocontact shift 213, 215, 226, 228, 243 separation of 217, 223 lanthanide ion size 50 Larmor frequency 2, 5, 29, 31–3, 67, 75 ligands with acetylene 102, 111, 113, 115, 137 alcohol group 87, 95, 100, 105–6, 114, 117–19, 127, 134, 136, 142 amine group 95–7, 98–9, 106, 110–116, 118, 120, 122, 124, 129, 136–7 azide group 100, 113, 137 carboxylic group in side chain 97, 115, 117–18, 123, 135 isothiocyanate group 95–7, 108, 112, 125, 129, 136 pyridine ring 89, 93, 99–103, 111, 122–3, 125–8, 135, 142 thiol group 93, 96, 100, 114, 110, 116, 137 Lipari-Szabo 60–63, 71, 72 lipids 455 LipoCEST 363 liposomes 413–19, 450–458, 460–466, 468–78, 481–2 liquid-crystalline phase 456–7 liquid-ordered phase 456–7 Ln(III) 31, 33–4, 37, 55 aqua ions 42–3, 47 induced shift 33 local density approximation (LDA) 211 localization 4–6 longitudinal relaxation 29, 40, 58–61, 64 electron spin 29, 64, 66 longitudinal relaxation rate R1 463, 467, 469–75, 478 longitudinal relaxation time T1 464, 466–7, 470, 478–80, 482 longitudinally detected EPR (LODEPR) 303–5 low molecular weight 39, 57, 68 low-density lipoprotein (HDL) 458, 476 luminescence 33–6 macromolecular agent(s) 51–5, 59, 69, 74, 76 magnetic field gradients 4–6, 12 magnetic field 29–31, 41, 65–7 Index high magnetic field 30, 57, 73–4 magnetic resonance angiography, see MRA magnetic resonance imaging, see MRI magnetic resonance spectroscopy 345, 350–352 magnetization transfer contrast 391, 397–8 magnetization 2–4 Magnevist 84, 92 manganese 479–80 mass spectrometry 463 matrix metalloproteinases (MMP) 330–331 McGarvey’s equation 215 McLachlan 287 MEMRI (Mn2+ -based MRI) 179 metabolic stability 323 metallostar 74–6 micelle 53, 63, 68–9, 452, 455, 457–8, 460, 466, 469, 471, 475–6, 478 microcirculation 453 micro-emulsion 430, 432 microviscosity 282 MIP 21 MMPs 377–9 Mn(II) 25, 30, 37 Mn2+ complexes 361, 374 Mn-EDTA 319, 321 Mn-EDTA(BOM)2 319, 321 molecular dynamics (MD) 210–211, 226, 229, 238, 254, 266 molecular dynamics (MD) simulation 28, 65 molecular imaging 442–3, 450–451, 457–8, 473, 475–8, 481–2 molecular mechanics (MM) 210–211, 242, 249, 254, 256–7, 262 monomer, monomeric 27, 43, 51–3, 57, 59, 68 Monte-Carlo simulation 288–9 MP-2269 46, 54, 60, 72, 313, 315 MRA 21–3, 313–5 MRI 5–23 MRI/PET 357 MRI/SPECT 355 mRNA 337–8 MS-325 84, 95, 313–15 MultiHance 84, 96, 315–16 multimeric contrast agents 319–26 multimodal imaging 451, 458, 462, 473–4, 482–3 multi-photon microscopy 449 myelin 338 myocardial infarction 326, 478 nanoparticles 93, 110, 111, 113–16, 410–411, 449–83 nanostructure 307 493 nanotechnology 450 near infrared probes 376 nephrogenic systemic fibrosis (NSF) 157, 179, 194, 199, 453, 467 and DTPA-derived contrast agents 200 and kinetic inertness 200 and macrocyclic contrast agents 200 and Omniscan 200 and renal failure 200 diagnosis of 200 pathophysiology of 200 treatment of 200 NMR 1, 160–161, 168, 171, 177, 184, 190 NMR relaxation dispersion (NMRD) 465, 467 NMRD profiles 436, 439, 440 NOTA 128–9 NTA 103 nuclear magnetic relaxation dispersion (NMRD) 27, 57, 66, 316, 324, 339 fitting 66 profiles 54, 57, 62–3, 65, 68 nuclear magnetic resonance, see NMR nuclear relaxation 26, 58 312, 317, 319 observed relaxivity, robs Omniscan 84 17 O NMR 34, 39–41, 51–3, 55–6, 61, 67–8, 72, 306, 316–17 relaxation rates 39–41, 58, 62 variable pressure 41–2 variable temperature 39, 51 opening angle 140–143 OptiMARK 84 oscillating electromagnetic field, B1 outer sphere 26–8, 39–40, 56, 64–5, 73 outer-sphere dynamics 277–309 P866 329–30 P947 330–331 packing parameter (PP) 455–7 paclitaxel 336–7 PAMAM (polyamidoamine) 51, 61, 70–72, 357 PAMAM dendrimer 95, 108, 122 PARACEST 4, 21, 110, 112, 114, 344, 347, 379–81 paramagnetic 452–6, 458, 460–462, 464–8, 470–475, 478–9, 483 paramagnetic liposomes 349 paramagnetic relaxation enhancement (PRE) 277–309 paramagnetic shift reagent (SR) 402 partial oxygen pressure (pO2 ) 360–361 PCTA 123, 125–6 494 Index PCTP 125, 143–4 peptide Gd-chelate conjugates 321–6, 328–9, 332–4 perfluorocarbon 455, 458, 463, 466, 472–4, 476, 479 permeability 454, 457, 465 peroxidases 373, 374 PET 344, 358 pH dependence 56–7 pH sensing 349 phage display 320, 325 phase encoding phosphatidylcholine (PC) 455, 463 phosphatidylethanolamine (PE) 455, 457, 463, 465, 467–9, 471, 473–5, 477 phosphatidylserine (PS) 469, 471, 476–7 phosphinic acids 98–9, 111, 119–21, 128–9, 135–6, 142, 144 phospholipids 455 phosphonic acids 98–100, 102, 111–12, 114–16, 119–23, 125–8, 142–4 photochemical activation (PCA) 473 pH-potentiometry 171, 189 31 P NMR 349 polarizable continuum model (PCM) 212–13, 232, 243 poly β-cyclodextrin 355 poly(ethyleneglycol) (PEG) 451, 457, 460, 463, 478 polyatomic molecules 292 polymeric coating 432–3 polymers 53, 59, 70, 71 copolymers 53, 63, 70 linear 59–60, 63, 70 porphyrin 361 positron emission tomography (PET) 449, 479 Primovist 84 Pr-MOE-DO3A 346 probe solute 292–7, 299–302 ProHance 84, 117 protein binding affinity 314–5, 319–21, 323–6, 328, 336 protein bound 54, 61, 70, 72–3 protein concentration 313, 320, 325 proton density (ρ) 13, 14, 16–19 proton density weighting 16–17, 19 proton exchange 29–31, 39, 55–6, 73 versus water exchange 56 proton relaxation enhancement (PRE) effect 314 proton relaxivity 26, 28–31, 37, 56–7, 66, 69, 75 proton resonance frequency (PRF) 344 pseudo-rotation 283, 288–9 pulse sequences 11–15, 21–23 pyclene 123–7, 143–4 pyridine 37, 51 pyrolysis 431–2 pyrophosphate anions 372 q = complex 315, 336, 339 quantum dots 458, 472, 475 q-values See hydration number radiofrequency pulse 2, 12 ratiometric method 344, 357, 359 reaction carbon template 103–6, 107, 123–4 click 100, 102, 137 crab-like 103, 105–6 Kabachnik-Fields 98 Mannich 89, 96, 98, 109, 119, 121, 125, 127–8, 133 Moedritzer-Irani 98 Richman-Atkins 103–5, 123, 125–7 Redfield approximation 285–7 relativistic effects 211–12 relaxation Curie mechanism 216, 220, 228, 244, 258 dipolar mechanism 221 electronic 220–221, 242 hyperfine (scalar) mechanism 220 inner-sphere 219 longitudinal 216, 218–21, 236 outer-sphere 219, 221 transverse 219–21 relaxation rate 29, 39, 40, 42, 48, 72 relaxation theory 30 relaxation times relaxivity 26–7, 454–5, 460, 464–7, 472–4, 478–9, 482 inner-sphere 297–8 outer-sphere 289–7, 299–302 profile 299–300 quenching 295–300 second-sphere 297–300 relaxometry 463, 465–8, 470 repetition time, see TR responsive agents 405–6 reticulo-endothelial system (RES) 452, 478 RGD peptide 328–9 RIME effect 333 rotating frame rotation of dimers 59 rotation of monomers 59 rotational correlation time 27, 29, 31, 33, 57–60 Index saturation transfer (ST) 4–5, 348 scalar (SC) relaxation 29 second sphere 28, 64–6, 71, 76 second-sphere relaxivity 318 selective pulse 6–7, 21 selectivity 164, 167, 169, 179–80, 182, 196 semiempirical methods 211, 234 sensing 349, 361, 364–5, 368, 370–372 serum albumin 313–9 sialic acid 327–8 signal-to-noise ratio (SNR) 466 single-photon emission computed tomography (SPECT) 449, 453–4, 474, 478 slice selection 6, slow kinetic region 40, 43 slow rotation 63, 70, 76 sol-gel 430, 432 Solomon-Bloembergen equations 30, 220–221, 226 Solomon-Bloembergen-Morgan (SBM) theory 29–30, 75 sparkle model 211, 234 spatial encoding 4, 12 spatial frequencies 10 speciation diagram 160, 177, 196 SPECT 344 spectra luminiscence, 139 mass spectometry 139 NMR 139–40 spin spin echo 13 spin echo sequence 12, 14 static magnetic field, B0 2, 13 Stokes formula 282 super-operator approaches 287–8 superparamagnetic iron oxide (SPIO) 427, 429 surface plasmon resonance 469 Swedish approaches 287–8 T1 26–30, 58, 66, 73 T1 longitudinal relaxation time T1 weighting 14, 17 T2 26–30, 58 T2 transverse relaxation time T2 weighting 17 T2 * T2 * weighting 18 TACN 126–30 TAM 130–132 targeting 451, 460, 462–3, 468–9, 471–2, 475–8, 482 Tb(III) 31, 33–4 TE 12, 19 temperature sensitive liposomes 349 temporal frequencies 10 temporal space 10 ternary complexes 177, 372 tert-butanol 295–6 theranostics 451, 478–9 thermodynamic stability 157–8, 195–6, 198 of AZTAA complexes 165, 167 of macrocyclic complexes 168, 172 of Mn2+ -based contrast agents 180, 182 of open-chain complexes 160, 164–5 of ternary complexes formed with bio-ligands 176–9 of tripodal complexes 165, 167–8, 178 thiol/disulfide redox couple 362–3 thrombosis 319, 324 thyroxine 336–7 time correlation function: dipolar 292–5 electronic 281 time of flight, See TOF tissue labeling 441 Tm-DOTA 346, 380 Tm-DOTP 346 TOF 21–2 TR 12, 21 transglutaminases 375 transmetallation 161, 165, 178–9, 187–90, 196–7, 467–8 transverse relaxation rate R2 465, 467, 472, 474–5 transverse relaxation time T2 464, 466, 472, 481 TREN 130, 131–3 tricapped trigonal prism (TTP) 228, 231, 236–7, 246 TRITA 123–4 type I collagen 325–6 tyrosinase 374–5 ultrasmall superparamagnetic iron oxide (USPIO) 427–8 UV-vis 34–6, 160, 171 variable pressure 41–2 Vasovist , see MS-325 Vistarem (P792) 115, 118 VSOP 427 495 496 Index water exchange 29, 39, 41–3, 44, 50–57, 76 water exchange rate 314–9 water hydration number 216, 225, 233, 238, 244, 251–2, 254–5, 258, 264 water residence time 219, 226, 232, 236 Yb-DOTAM-Gly 359 Yb-DOTMA 345 Yb-DOTP 351–2 Yb-HPDO3A 359 zero order regular approximation (ZORA) 212, 214 zero-field-splitting (ZFS) 218, 220, 281–3 zinc 367 Z-spectrum 390, 392 ... T1 weighting of the contrast (the higher the angle, the higher the T1 weighting); The TE allows a T2 * weighting of the contrast (the longer the TE, the higher the T2 * weighting); These sequences... Universitaire of Tours, France 16 1.5 The Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging Basic image contrast: Tissue characterization without injection of contrast agents (main contrast. .. clinical and preclinical experiments, and for advanced applications including the use of contrast agents 12 The Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging 180° 90° RF pulses,