Magnetic Resonance Imaging (MRI) is one of the most important tools in clinical diagnostics and biomedical research. The number of MRI scanners operating around the world is estimated to be approximately 20,000, and the development of contrast agents, currently used in about a third of the 50 million clinical MRI examinations performed every year, has largely contributed to this significant achievement.
This completely revised and extended second edition:
- Includes new chapters on targeted, responsive, PARACEST and nanoparticle MRI contrast agents.
- Covers the basic chemistries, MR physics and the most important techniques used by chemists in the characterization of MRI agents from every angle from synthesis to safety considerations.
- Is written for all of those involved in the development and application of contrast agents in MRI.
- Presented in colour, it provides readers with true representation and easy interpretation of the images.
A word from the Authors:
Twelve years after the first edition published, we are convinced that the chemistry of MRI agents has a bright future. By assembling all important information on the design principles and functioning of magnetic resonance imaging probes, this book intends to be a useful tool for both experts and newcomers in the field. We hope that it helps inspire further work in order to create more efficient and specific imaging probes that will allow materializing the dream of seeing even deeper and better inside the living organisms.
Reviews of the First Edition:
"...attempts, for the first time, to review the whole spectrum of involved chemical disciplines in this technique..." - Journal of the American Chemical Society
"...well balanced in its scope and attention to detail...a valuable addition to the library of MR scientists..." - NMR in BiomedicineTable of Contents
List of Contributors xiii
Preface xv
1 General Principles of MRI 1
Bich-Thuy Doan, Sandra Meme, and Jean-Claude Beloeil
1.1 Introduction 1
1.2 Theoretical basis of NMR 1
1.2.1 Short description of NMR 1
1.2.2 Relaxation times 4
1.2.3 Saturation transfer 4
1.2.4 Concept of localization by magnetic field gradients 4
1.3 Principles of magnetic resonance imaging 5
1.3.1 Spatial encoding 5
1.4 MRI pulse sequences 11
1.4.1 Definition 11
1.4.2 k-Space trajectory 12
1.4.3 Basic pulse sequences 13
1.5 Basic image contrast: Tissue characterization without injection of contrast agents (main contrast of an MRI sequence: Proton density (P), T1 and T2, T∗ 2) 16
1.5.1 Proton density weighting 17
1.5.2 T1 weighting 17
1.5.3 T2 weighting 17
1.5.4 T∗
2 weighting 18
1.6 Main contrast agents 18
1.6.1 Gadolinium (Gd) complex agents 19
1.6.2 Iron oxide (IO) agents 19
1.6.3 CEST agents 20
1.7 Examples of specialized MRI pulse sequences for angiography (MRA) 21
1.7.1 Time of flight angiography: No contrast agent 21
1.7.2 Angiography using intravascular contrast agent (Blood pool CA) injection 21
1.7.3 DSC DCE MRI 23
References 23
2 Relaxivity of Gadolinium(III) Complexes: Theory and Mechanism 25
E´va To´th, Lothar Helm, and Andre´ Merbach
2.1 Introduction 25
2.2 Inner-sphere proton relaxivity 28
2.2.1 Hydration number and hydration equilibria 31
2.2.2 Gd–H distance 37
2.2.3 Proton/water exchange 39
2.2.4 Rotation 57
2.3 Second- and outer-sphere relaxation 64
2.4 Relaxivity and NMRD profiles 66
2.4.1 Fitting of NMRD profiles 66
2.4.2 Relaxivity of low-molecular-weight Gd(III) complexes 68
2.4.3 Relaxivity of macromolecular MRI contrast agents 69
2.4.4 Contrast agents optimized for application at high magnetic field 73
2.5 Design of high relaxivity agents: Summary 75
References 76
3 Synthesis and Characterization of Ligands and their Gadolinium(III) Complexes 83
Jan Kotek, Vojt¢§ech Kub´©¥¢§cek, Petr Hermann, and Ivan Luke¢§s
3.1 Introduction – general requirements for the ligands and complexes 83
3.2 Contrast agents employing linear polyamine scaffold 84
3.2.1 Synthesis of linear polyamine backbone 85
3.2.2 N-functionalization of linear polyamine scaffold 89
3.3 Contrast agents employing cyclen scaffold 103
3.3.1 Synthesis of the macrocyclic skeleton 103
3.3.2 N-functionalization of macrocyclic scaffold 106
3.4 Other types of ligands 123
3.4.1 H4TRITA and related ligands 123
3.4.2 H3PCTA and related ligands 123
3.4.3 TACN derivatives 126
3.4.4 Ligands with HOPO coordinating arms and related groups 130
3.4.5 H4AAZTA and related ligands 133
3.5 Bifunctional ligands and their conjugations 134
3.6 Synthesis and characterization of the Ln(III) complexes 138
3.6.1 General synthetic remarks 138
3.6.2 Characterization of the complexes 139
List of Abbreviations 144
References 146
4 Stability and Toxicity of Contrast Agents 157
Ern˜o Br¨ucher, Gyula Tircs´o, Zsolt Baranyai, Zolt´an Kov´acs, and A. Dean Sherry
4.1 Introduction 157
4.2 Equilibrium calculations 158
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) 158
4.2.2 A brief overview of the programs used in equilibrium calculations (calculation of protonation constants, stability constants, and equilibrium speciation diagrams) 159
4.3 Stability of metal–ligand complexes 160
4.3.1 Stability of complexes of open chain ligands (EDTA, DTPA, EGTA, and TTHA) 160
4.3.2 Stability of complexes of tripodal and AAZTA ligands 165
4.3.3 Stability of complexes of macrocyclic ligands 168
4.3.4 Ternary complexes formed between the Ln(L) complexes and various bio-ligands 176
4.3.5 Mn2+-based contrast agents 179
4.4 Kinetics of M(L) complex formation 184
4.4.1 Formation kinetics of DOTA complexes 184
4.4.2 Formation kinetics of complexes of simple DOTA-tetraamides 186
4.5 Dissociation of M(L) complexes 186
4.5.1 Inertness of complexes of open chain ligands (EDTA, DTPA, and AAZTA) 187
4.5.2 Decomplexation of DOTA complexes 190
4.5.3 Decomplexation of DOTA-tetraamide complexes 192
4.6 Biodistribution and in vivo toxicity of Gd3+-based MRI contrast agents 193
4.6.1 Osmolality and hydrophobicity of Gd3+-based MRI contrast agents 193
4.6.2 Biodistribution 194
4.6.3 In vivo toxicity 195
4.6.4 Predicting in vivo toxicity of Gd3+-based contrast agents using thermodynamic conditional stability constants 195
4.6.5 The role of kinetic inertness in determining in vivo toxicity 196
4.6.6 Kinetic inertness combined with thermodynamic stability is the best predictor of in vivo toxicity 197
4.6.7 Nephrogenic systemic fibrosis (NSF) 199
4.7 Concluding remarks 201
Acknowledgements 201
References 201
5 Structure, Dynamics, and Computational Studies of Lanthanide-Based Contrast Agents 209
Joop A. Peters, Kristina Djanashvili, Carlos F.G.C. Geraldes, and Carlos Platas-Iglesias
5.1 Introduction 209
5.2 Computational methods 210
5.3 Lanthanide-induced NMR shifts 213
5.3.1 Bulk magnetic susceptibility shifts 213
5.3.2 Diamagnetic shifts 213
5.3.3 Contact shifts 214
5.3.4 Pseudocontact shifts 215
5.3.5 Evaluation of bound shifts 216
5.3.6 Separation of shift contributions 217
5.4 Lanthanide-induced relaxation rate enhancements 219
5.4.1 Evaluation of bound relaxation rates 219
5.4.2 Inner-sphere relaxation 219
5.4.3 Outer-sphere relaxation 221
5.5 Anisotropic hyperfine interactions on the first coordination sphere water molecules 221
5.6 Evaluation of geometries by fitting NMR parameters 222
5.7 Two-dimensional NMR 224
5.8 139La and 89Y NMR 224
5.9 Water hydration numbers 225
5.10 Chirality of lanthanide complexes of polyaminocarboxylates 227
5.11 Complexes of non-macrocyclic polyaminocarboxylates 227
5.11.1 DTPA and derivatives 227
5.11.2 TTHA 236
5.11.3 EGTA 238
5.11.4 DTTA 239
5.11.5 Tripodal complexes 240
5.12 Complexes of macrocyclic ligands 244
5.12.1 DOTA and derivatives 244
5.12.2 DO3A and derivatives 250
5.12.3 PCTA and derivatives 252
5.12.4 TETA 253
5.12.5 DOTP 254
5.12.6 Phosphinates and phosphonate esters 257
5.12.7 Cationic macrocyclic lanthanide complexes 260
5.12.8 AAZTA 264
5.13 Fullerenes 265
References 267
6 Electronic Spin Relaxation and Outer-Sphere Dynamics of Gadolinium-Based Contrast Agents 277
Pascal H. Fries and Elie Belorizky
6.1 Introduction 277
6.2 Theory of electronic spin relaxation of Gd3+ ions 279
6.2.1 Classical approach: Bloch equations 279
6.2.2 Quantum approach: Electronic time correlation functions 281
6.2.3 The zero-field splitting Hamiltonian 281
6.2.4 The density matrix formalism 284
6.2.5 The Redfield approximation 285
6.2.6 The Swedish super-operator approaches 287
6.2.7 Monte-Carlo simulation of the Gd3+ electronic relaxation: The Grenoble method 288
6.3 Outer-sphere dynamics 289
6.3.1 Standard theory neglecting the electronic relaxation 289
6.3.2 Analytical hard-sphere models 291
6.3.3 The general case of anisotropic polyatomic molecules 292
6.3.4 Experimental determination of the dipolar time correlation function 292
6.4 Relaxivity quenching by the electronic spin relaxation 295
6.4.1 The various field regimes 295
6.4.2 Outer-sphere relaxivity 295
6.4.3 Inner- and second-sphere relaxivities 297
6.4.4 Application to a cyclodecapeptide Gd3+ complex 299
6.5 Various experimental approaches of the electronic spin relaxation 301
6.5.1 Outer-sphere relaxivity profiles 301
6.5.2 EPR spectroscopy 302
6.6 Conclusion and perspectives 306
6.A Appendix: Similar evolutions of the macroscopic magnetization of the electronic spin and of its correlation functions 307
References 308
7 Targeted MRI Contrast Agents 311
Peter Caravan and Zhaoda Zhang
7.1 Introduction 311
7.2 Serum albumin 313
7.3 Fibrin 319
7.4 Type I collagen 325
7.5 Elastin 326
7.6 Sialic acid 327
7.7 αVβ3 integrin 328
7.8 Folate receptor 329
7.9 Matrix metalloproteinases (MMP) 330
7.10 E-selectin 331
7.11 Fibrin-fibronectin complex 332
7.12 Alanine aminopeptidase (CD13) 332
7.13 Carbonic anhydrase 333
7.14 Interleukin 6 receptor 334
7.15 Estrogen and progesterone receptors 335
7.16 Contrast agents based on natural products 336
7.17 Messenger RNA (mRNA) 337
7.18 Myelin 338
7.19 DNA 338
7.20 Conclusions 340
References 340
8 Responsive Probes 343
Ce´lia S. Bonnet, Lorenzo Tei, Mauro Botta, and E´va To´th
8.1 Introduction 343
8.2 Probes responsive to physiological parameters 344
8.2.1 Temperature responsive probes 344
8.2.2 pH sensing 349
8.2.3 Redox responsive probes 360
8.2.4 Sensing of biologically relevant ions 364
8.2.5 Enzyme responsive probes 373
8.3 Conclusions 381
References 382
9 Paramagnetic CEST MRI Contrast Agents 387
Enzo Terreno, Daniela Delli Castelli, and Silvio Aime
9.1 Introduction 387
9.2 Theoretical and practical considerations on CEST response 388
9.2.1 NMR/chemical properties of CEST site(s) 391
9.2.2 NMR properties of the wat site 394
9.2.3 Instrumental variables 395
9.2.4 Variables dependent on the sample 397
9.2.5 Spectroscopic versus imaging detection of CEST response 399
9.2.6 Characterization of a CEST agent and its quantification 400
9.3 Diamagnetic versus paramagnetic CEST agents 400
9.4 Paramagnetic CEST agents 401
9.4.1 ParaCEST agents 402
9.4.2 SupraCEST agents 411
9.4.3 NanoCEST agents 413
9.5 Other exchange-mediated contrast modes accessible for paramagnetic CEST agents 419
9.6 Concluding remarks 421
References 421
10 Superparamagnetic Iron Oxide Nanoparticles for MRI 427
Sophie Laurent, Luce Vander Elst, and Robert N. Muller
10.1 Introduction 427
10.2 Synthesis of iron oxide nanoparticles 428
10.2.1 Coprecipitation in aqueous medium 429
10.2.2 Reverse micro-emulsions 430
10.2.3 Sol gel methods 430
10.2.4 Polyol methods 430
10.2.5 Hydrothermal methods 430
10.2.6 Sonochemistry methods 431
10.2.7 Pyrolytic methods 431
10.3 Stabilization 431
10.3.1 Steric stabilization: Natural or synthetic polymeric matrices 431
10.3.2 Electrostatical stabilization 432
10.4 Methods of vectorization for molecular imaging 432
10.5 Characterization 436
10.5.1 Relaxivity and NMRD profiles 436
10.6 Applications 440
10.6.1 Tissue labelling with iron oxide particles 441
10.6.2 Cellular and molecular labelling with iron oxide particles 442
10.6.3 Iron oxide nanoparticles as molecular MRI probes 442
10.7 Conclusions 444
Acknowledgements 444
References 444
11 Gd-Containing Nanoparticles as MRI Contrast Agents 449
Klaas Nicolay, Gustav Strijkers, and Holger Gr¨ull
11.1 Introduction 449
11.2 Length scales and excretion pathways 452
11.3 Preparation of Gd-containing nanoparticles 454
11.3.1 Lipid aggregates 455
11.3.2 Liposomes 456
11.3.3 Micelles 457
11.3.4 Other lipid-containing nanoparticles 458
11.3.5 Chemical structures of Gd-containing lipids 458
11.4 Methods for nanoparticle characterization 460
11.4.1 Morphology 461
11.4.2 Particle composition 462
11.4.3 Magnetic properties 464
11.4.4 Chelate stability 467
11.4.5 Miscellaneous techniques 468
11.5 In vitro applications 468
11.5.1 Target specificity 468
11.5.2 Cellular interactions, internalization, and compartmentation 470
11.5.3 Biological effects 475
11.6 In vivo applications 475
11.6.1 Target-specific imaging 476
11.6.2 Image-guided drug delivery 478
11.7 Conclusions and future perspectives 481
Acknowledgements 483
References 483
Index 489
