Ust 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, T2*) ...... 16
1.5.1 Proton density weighting ........................ 17
1.5.2 T1 weighting .................................... 17
1.5.3 T2 weighting .................................... 17
1.5.4 T2* 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 GadoIinium(III) Complexes: Theory and
Mechanism ................................................... 25
Éva Tóth, Lothar Helm, and André 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, Vojtěch Kubíček, Petr Hermann, and Ivan Lukeš
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
Ernõ Brücher, Gyula Tircsó, Zsolt Baranyai, Zoltan
Kovács, 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.
Geraides, 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
6.7 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 αηβ3 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
Célia S. Bonnet, Lorenzo Tei, Mauro Botta, and Éva Tóth
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 Delii 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 Eist, 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 Grüll
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
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