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Book Details
Abstract
As a practical reference guide for designing and performing experiments, this book focuses on the five most common classes of contrast agents for MRI namely gadolinium complexes, chemical exchange saturation transfer agents, iron oxide nanoparticles, manganese complexes and fluorine contrast agents. It describes how to characterize and evaluate them and for each class, a description of the theory behind their mechanisms is discussed briefly to orient the new reader. Detailed subchapters discuss the different physical chemistry methods used to characterize them in terms of their efficacy, safety and in vivo behavior. Important consideration is also given to the different physical properties that affect the performance of the contrast agents.
The editors and contributors are at the forefront of research in the field of MRI contrast agents and this unique, cutting edge book is a timely addition to the literature in this area.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Cover | Cover | ||
| Preface | v | ||
| Contents | vii | ||
| Chapter 1 General Synthetic and Physical Methods | 1 | ||
| 1.1 Ligand Synthesis and Characterization | 1 | ||
| 1.1.1 Relationships between Ligand Structure and Complex Properties | 1 | ||
| 1.1.2 Ligand Design for MRI Contrast Agents | 5 | ||
| 1.1.3 Synthetic Methods | 15 | ||
| 1.1.4 Purification and Characterization of Ligands | 27 | ||
| 1.2 Synthesis and Characterization of Metal Complexes | 32 | ||
| 1.2.1 Preparation of Metal Complexes | 32 | ||
| 1.2.2 Characterization of Metal Complexes | 34 | ||
| 1.3 Stability of Metal Complexes | 40 | ||
| 1.3.1 Introduction | 40 | ||
| 1.3.2 Equilibrium Constants Used to Characterize Metal-Ligand Interactions | 41 | ||
| 1.3.3 Equilibrium Models | 46 | ||
| 1.3.4 Physicochemical Methods for Characterizing Metal-Ligand Interactions | 51 | ||
| 1.3.5 Stabilities of Gadolinium Complexes: Selected Examples | 69 | ||
| 1.3.6 Acknowledgements | 74 | ||
| 1.4 Lability of Metal Complexes | 75 | ||
| 1.4.1 Introduction | 75 | ||
| 1.4.2 Dissociation Kinetics of Metal Chelates | 76 | ||
| 1.4.3 Methods for Kinetic Studies | 81 | ||
| 1.4.4 Decomplexation Reactions near Physiological Conditions | 82 | ||
| 1.4.5 Effect of Ligand Structure on the Inertness of Gadolinium Complexes | 88 | ||
| 1.4.6 Acknowledgements | 95 | ||
| Notes and References | 95 | ||
| Chapter 2 Gadolinium-based Contrast Agents | 121 | ||
| 2.1 General Theory of the Relaxivity of Gadolinium-based Contrast Agents | 122 | ||
| 2.1.1 Definition of Relaxivity | 122 | ||
| 2.1.2 Theory of Inner-sphere Relaxivity | 124 | ||
| 2.1.3 Theory of Outer-sphere Relaxivity | 127 | ||
| 2.2 Measuring Longitudinal (T1) and Transverse (T2) Relaxation Times | 128 | ||
| 2.2.1 General Experimental Method to Measure T1 | 128 | ||
| 2.2.2 General Experimental Method to Measure T2 | 132 | ||
| 2.3 NMRD Profiles: Theory, Acquisition, and Interpretation | 135 | ||
| 2.3.1 Acquisition of NMRD Profiles | 135 | ||
| 2.3.2 Theory and Interpretation of NMRD Profiles | 136 | ||
| 2.4 Measuring Water Coordination Numbers (q) | 139 | ||
| 2.4.1 Hydration: Inner- Versus Outer-Sphere Water Ligands | 139 | ||
| 2.4.2 Oxygen-17 NMR Spectroscopy | 139 | ||
| 2.4.3 Luminescence Spectroscopy | 142 | ||
| 2.4.4 Electron Nuclear Double Resonance | 149 | ||
| 2.4.5 Single Crystal X-ray Diffraction | 151 | ||
| 2.4.6 Extended X-ray Absorbance Fine Structure Spectroscopy | 151 | ||
| 2.5 Measuring Rotational Correlation Times (τR) | 153 | ||
| 2.5.1 Fit of NMRD Profiles | 154 | ||
| 2.5.2 Debye-Stokes Equation | 156 | ||
| 2.5.3 Oxygen-17 1/T1 NMR Spectroscopy | 156 | ||
| 2.5.4 Deuterium-NMR Spectroscopy | 157 | ||
| 2.5.5 Carbon-13-NMR Spectroscopy | 158 | ||
| 2.5.6 Hydrogen-NMR Longitudinal Relaxation Rates (Curie Mechanism) | 161 | ||
| 2.6 Measuring Water Residence Times (τM) | 164 | ||
| 2.6.1 Variable Temperature Oxygen-17-NMR Spectroscopy | 164 | ||
| 2.6.2 Variable Temperature Hydrogen-NMR Spectroscopy | 169 | ||
| 2.6.3 1/T1 Hydrogen-NMRD Profiles | 170 | ||
| 2.6.4 Temperature Dependence of Proton Relaxivity | 171 | ||
| 2.7 Measuring the Concentration of Gadolinium | 174 | ||
| 2.7.1 Importance of Accurate Measurements | 174 | ||
| 2.7.2 Mineralization Monitored by NMR Relaxometry | 175 | ||
| 2.7.3 Metal Analysis with Plasma Techniques | 177 | ||
| 2.7.4 High-Resolution NMR Technique: Bulk Magnetic Susceptibility | 180 | ||
| 2.7.5 Complexometry | 182 | ||
| 2.8 Relaxometric Titrations | 187 | ||
| 2.8.1 Determination of the Binding Parameters: E- and M-titrations | 188 | ||
| 2.8.2 The Enhancement Factor ε* | 192 | ||
| 2.8.3 Experimental Procedure | 194 | ||
| 2.9 Computational Methods | 196 | ||
| 2.9.1 Molecular Mechanics and Molecular Dynamics Simulations | 196 | ||
| 2.9.2 Semi-empirical Calculations | 198 | ||
| 2.9.3 Density Functional Theory and Ab Initio Methods | 198 | ||
| 2.9.4 Basis Sets and Relativistic Effects | 203 | ||
| 2.9.5 Solvent Effects | 205 | ||
| 2.9.6 Practical Aspects and Selected Examples | 207 | ||
| 2.9.7 Software | 214 | ||
| 2.9.8 Acknowledgements | 214 | ||
| 2.10 Acquiring Phantom Images | 215 | ||
| 2.10.1 Image Formation in MRI | 215 | ||
| 2.10.2 MRI Pulse Sequences | 222 | ||
| 2.10.3 Effect of T1 and T2 on Image Contrast | 224 | ||
| 2.10.4 Measurement of T1 and T2 Time Constants by MRI | 225 | ||
| 2.10.5 Field-strength Dependencies | 228 | ||
| References | 229 | ||
| Chapter 3 Chemical Exchange Saturation Transfer (CEST) Contrast Agents | 243 | ||
| 3.1 General Theory of CEST Agents | 244 | ||
| 3.1.1 General Introduction to CEST Contrast | 244 | ||
| 3.1.2 Theoretical and Practical Considerations about CEST Agents | 247 | ||
| 3.1.3 Practical Considerations for CEST Experiments | 251 | ||
| 3.1.4 Classification of CEST Agents | 253 | ||
| 3.1.5 Selected Applications of CEST and PARACEST Agents | 257 | ||
| 3.2 Acquisition of CEST Spectra | 263 | ||
| 3.2.1 Instrumentation and Sample Conditions for Collecting Z-Spectra to Characterize CEST Contrast | 263 | ||
| 3.2.2 Pulse Sequences Utilized for Collecting Z-Spectra | 263 | ||
| 3.2.3 Data Post-processing and Analysis | 265 | ||
| 3.2.4 Acknowledgements | 266 | ||
| 3.3 Determining q for CEST Complexes | 267 | ||
| 3.3.1 Oxygen-17 NMR Spectroscopy for CEST Agents | 267 | ||
| 3.3.2 Other Techniques for Gadolinium-based Complexes That Also Apply to CEST Agents | 269 | ||
| 3.4 Determining Proton Exchange Rates (kex) | 274 | ||
| 3.4.1 Introduction to Proton Exchange | 274 | ||
| 3.4.2 Linewidth Measurement for Assessing Exchange Rate | 274 | ||
| 3.4.3 WEX Experiments for Assessing Exchange Rate | 275 | ||
| 3.4.4 QUEST and QUESP Experiments for Assessing Exchange Rate | 275 | ||
| 3.4.5 Acknowledgements | 279 | ||
| 3.5 Preparation and Characterization of Paramagnetic Micelles and Liposomes | 280 | ||
| 3.5.1 Routes to Enhance the Sensitivity of CEST Agents | 280 | ||
| 3.5.2 Preparation and Characterization of Paramagnetic CEST Micelles | 281 | ||
| 3.5.3 Preparation and Characterization of Paramagnetic CEST Liposomes | 286 | ||
| 3.5.4 Preparation and Characterization of Other Paramagnetic CEST Nanosystems | 293 | ||
| 3.5.5 Preparation and Characterization of Cell-based Paramagnetic CEST Agents | 296 | ||
| 3.5.6 CEST Readout of Binding Interactions | 302 | ||
| 3.6 Acquiring CEST MR Phantom Images | 304 | ||
| 3.6.1 B0 Field Correction | 304 | ||
| 3.6.2 B1 Field Corrections | 306 | ||
| 3.6.3 Continuous Wave Saturation | 306 | ||
| 3.6.4 Practical Considerations | 306 | ||
| 3.6.5 Field-strength Dependencies | 309 | ||
| References | 309 | ||
| Chapter 4 Iron-oxide Nanoparticle-based Contrast Agents | 318 | ||
| 4.1 General Theory of the Relaxivity of Particulate Contrast Agents | 319 | ||
| 4.1.1 General Introduction to Iron Oxide Nanoparticles | 319 | ||
| 4.1.2 Mechanisms of Relaxation of Iron Oxide Nanoparticles | 322 | ||
| 4.1.3 Acknowledgements | 330 | ||
| 4.2 Synthesis of Iron Oxide Nanoparticles | 331 | ||
| 4.2.1 Mechanism of Formation | 331 | ||
| 4.2.2 Methods for the Preparation of Magnetic Nanoparticles | 332 | ||
| 4.2.3 Acknowledgements | 338 | ||
| 4.3 Coatings for Iron Oxide Nanoparticles | 339 | ||
| 4.3.1 Standard Coatings for Iron Oxide Nanoparticles | 339 | ||
| 4.3.2 Effects of Coatings and Anchoring Groups on Magnetic Properties of Nanoparticles | 353 | ||
| 4.3.3 Effects of Coatings on Relaxivity | 356 | ||
| 4.4 Characterizing Functionalized Iron Oxide Nanoparticles | 362 | ||
| 4.4.1 Characterization of the Iron Oxide Core of Functionalized Nanoparticles | 363 | ||
| 4.4.2 Characterization Techniques for Nanoparticle Coatings | 383 | ||
| 4.5 Magnetic Characterization | 391 | ||
| 4.5.1 Magnetic Parameters of Iron Oxide Nanoparticles of Interest to MRI | 391 | ||
| 4.5.2 Magnetism at the Nanoscale with Applications to Iron Oxide Nanoparticles | 394 | ||
| 4.5.3 Characterization Techniques of Iron Oxide Nanoparticles for MRI | 401 | ||
| 4.5.4 Acknowledgements | 426 | ||
| 4.6 Acquiring Phantom Images with Nanoparticles | 427 | ||
| 4.6.1 Contrast in T2- and T2*-weighted MRI | 427 | ||
| 4.6.2 Contrast in T1-weighted MRI and Magnetic-field-strength Dependencies | 429 | ||
| Notes and References | 430 | ||
| Chapter 5 Transition Metal-based T1 Contrast Agents | 448 | ||
| 5.1 Differences and Similarities Between GdIII and Transition Metal Complexes | 448 | ||
| 5.1.1 Historical Perspective | 448 | ||
| 5.1.2 Similarities and Differences between the Coordination Chemistry of GdIII, MnII, and FeIII | 449 | ||
| 5.1.3 Contributions to 1H Relaxivity and Interpretation of NMRD Profiles | 453 | ||
| 5.1.4 Characterizing Manganese and Iron Complexes | 461 | ||
| 5.1.5 Computational Methods | 463 | ||
| 5.2 Determining Effective Magnetic Moment (μeff) | 465 | ||
| 5.2.1 Bulk Magnetic Susceptibility (BMS) Shifts | 468 | ||
| 5.2.2 Superconducting Quantum Interference Device (SQUID) Measurements | 469 | ||
| 5.3 Measuring q for Transition Metal Complexes | 471 | ||
| 5.4 Acknowledgements | 473 | ||
| Notes and References | 473 | ||
| Chapter 6 Fluorine-based Contrast Agents | 479 | ||
| 6.1 Compositions for Fluorine-19 MRI Molecular Imaging Applications | 479 | ||
| 6.1.1 Fluorine-19 MRI Probes | 479 | ||
| 6.1.2 Perfluorocarbons (PFCs) | 481 | ||
| 6.1.3 Emulsion Formulations for Imaging | 487 | ||
| 6.1.4 Acknowledgements | 490 | ||
| 6.2 Acquiring Fluorine-19 Phantom Images | 491 | ||
| 6.2.1 Fluorine-19 Imaging | 491 | ||
| 6.2.2 Complications of 19F Imaging: Chemical Shift Dispersion and Multiple Peaks | 492 | ||
| Notes and References | 493 | ||
| Chapter 7 Standard Biological and in vivo Methods | 499 | ||
| 7.1 Cell Toxicity, Binding, and Uptake | 499 | ||
| 7.1.1 Introduction and Biological Characterization of Molecular Imaging Agents | 499 | ||
| 7.1.2 Cytotoxicity | 501 | ||
| 7.1.3 Cell Binding | 518 | ||
| 7.1.4 Cell Uptake | 527 | ||
| 7.2 Distribution, Metabolism, Pharmacokinetics, and Toxicity | 536 | ||
| 7.2.1 Rationale for Measuring Distribution, Metabolism, Pharmacokinetics, and Toxicity | 536 | ||
| 7.2.2 Routes of Administration | 537 | ||
| 7.2.3 Dose and Exposure | 539 | ||
| 7.2.4 Distribution in Tissue | 539 | ||
| 7.2.5 Pharmacokinetics and Elimination | 544 | ||
| 7.2.6 Metabolism | 552 | ||
| 7.2.7 Toxicity | 553 | ||
| 7.3 Practical Aspects of Contrast-enhanced Preclinical MRI | 559 | ||
| 7.3.1 When to Image: Molecular Probe Clearance | 559 | ||
| 7.3.2 How to Image: MRI Methods for Probe Quantification | 561 | ||
| 7.3.3 Where to Image: Magnetic Field Strength and Contrast Agent Relaxivity | 565 | ||
| 7.3.4 Physiological Monitoring and Image Gating | 565 | ||
| 7.3.5 Image Reconstruction and Probe Quantification | 567 | ||
| 7.3.6 MRI Radio-frequency Coils | 568 | ||
| Notes and References | 575 | ||
| Subject Index | 585 |