Preface | p. ix |
List of Contributors | p. xi |
Color Figures | p. xiii |
Hypoxia: An Introduction | |
Definitions of Hypoxia | p. 1 |
Predictive Assays for Tissue Hypoxia | p. 2 |
The Design of Predictive Assays | p. 2 |
Predictive Assays based on the Measurement of Tissue Hypoxia | p. 3 |
Hypoxia in Selected Pathologies | p. 4 |
Oncology | p. 4 |
Cardiovascular Disease | p. 6 |
Cerebrovascular Disease | p. 7 |
Diabetes | p. 10 |
Infection | p. 10 |
Wound Healing and Organ Transplantation | p. 11 |
Joint Hypoxia | p. 11 |
Other Cutaneous and Mucosal Pathologies | p. 12 |
Aspects of Cellular Metabolism in Hypoxia | p. 13 |
Radiotherapy and Hypoxia | p. 14 |
Radiobiological Hypoxia | p. 14 |
Radiosensitizers | p. 15 |
Hypoxic Binding of 2-Nitroimidazoles | p. 15 |
Further Reading | p. 16 |
The Biology of Technetium Based Hypoxic Tissue Localising Compounds | |
Introduction | p. 19 |
Oxygen concentrations in tissues | p. 20 |
Oxygen levels required for trapping of nitroimidazoles | p. 21 |
Individual cells | p. 22 |
Isolated perfused hearts | p. 23 |
Myocardium in vivo | p. 26 |
Conclusions | p. 27 |
Flow levels required for trapping | p. 28 |
Myocardium | p. 28 |
Brain | p. 30 |
Conclusions | p. 30 |
Trapping mechanisms | p. 31 |
Imaging/Kinetics | p. 34 |
Brain | p. 34 |
Heart | p. 34 |
Tumours | p. 35 |
Comparison to other metabolic imaging agents | p. 36 |
Toxicity | p. 38 |
Toxicity of therapeutic nitroimidazoles | p. 38 |
Pharmacokinetics of therapeutic nitroimidazoles | p. 40 |
Assessment of toxicity of diagnostic doses | p. 41 |
Basic Chemistry of 2-Nitroimidazoles (Azomycin Derivates) | |
Introduction | p. 47 |
Imidazole | p. 48 |
2-Nitroimidazole (Azomycin) | p. 48 |
Preparation of 2-nitroimidazole | p. 49 |
Chemical properties of 2-nitroimidazole | p. 50 |
Reactivity of 2-nitroimidazole | p. 50 |
5-Substituted 2-nitroimidazoles | p. 54 |
2-Nitroimidazole nucleosides and analogs | p. 54 |
Azomycin riboside | p. 54 |
Azomycin nucleosides | p. 55 |
Azomycin nucleoside analogs | p. 55 |
Molecular Design Approaches of Hypoxia Tracers | |
Introduction | p. 61 |
Modelling of Ligand Protein Interaction Complexes | p. 62 |
The QSAR Approach | p. 65 |
Threedimensional QSAR and Pseudoreceptors | p. 66 |
Material and Methods | p. 67 |
Results | p. 70 |
Molecular electrostatic potentials | p. 70 |
Formation of Radicals | p. 71 |
Outlook | p. 73 |
Syntheses of PET-Tracers for the Determination of Hypoxia | |
Syntheses of [[superscript 18]F]FMISO | p. 75 |
Synthesis of alternative [[superscript 18]F]-labelled agents for hypoxia imaging | p. 80 |
Summary and future directions | p. 81 |
Quantifying Hypoxia with Radiolabeled Fluoromisonidazole: Pre-Clinical and Clinical Studies | |
Introduction | p. 85 |
Rational approach | p. 85 |
Properties of fluromisonidazole that make it a useful tracer | p. 87 |
Development of FMISO as a PET tracer: From cells in vitro to patient imaging | p. 87 |
Cell Monolayers and Spheroids in Culture | p. 88 |
Cell monolayer studies | p. 88 |
Spheroid Studies | p. 89 |
Isolated myocyte studies | p. 90 |
Studies in Animals | p. 90 |
Mice | p. 90 |
Rats | p. 95 |
Tumor studies in dogs | p. 98 |
Heart studies in dogs | p. 100 |
Patient Studies | p. 103 |
Tumor studies | p. 103 |
Heart studies | p. 111 |
Summary and Conclusions | p. 113 |
Detection of Liver Hypoxia by [[superscript 18]F]Fluoromisonidazole and Application in Liver Transplant Disorders | |
Introduction | p. 119 |
Liver tissue hypoxia in transplant dysfunctions | p. 119 |
Hypoxia and rejection | p. 119 |
Hypoxia and immunosuppressive therapy | p. 120 |
Differential diagnoses in transplant dysfunctions | p. 121 |
Material and methods | p. 121 |
Results | p. 122 |
Discussion | p. 125 |
Conclusion | p. 126 |
The Evaluation of Hypoxia in Diabetes | |
Introduction | p. 129 |
Microangiopathy in Diabetic Patients | p. 130 |
Biochemical Processes and Pathways | p. 130 |
Structural and Functional Changes | p. 131 |
The Diabetic Foot | p. 132 |
Assessment of Hypoxia in the Diabetic Foot | p. 133 |
Imaging and Nuclear Medicine Methods in the Evaluation of Tissue Hypoxia in Diabetes | p. 138 |
Non-Radionuclide Imaging | p. 138 |
Radiopharmaceuticals and Diabetic Hypoxia | p. 139 |
Conclusions | p. 145 |
Radiohalogenated Nitroimidazoles for Single-photon Scintigraphic Imaging of Hypoxic Tissues | |
Rational Design of Hypoxia-specific Radiotracers | p. 155 |
The 'oxygen effect' and chemical radiosensitizers | p. 155 |
Nitroimidazole radiosensitizer design | p. 155 |
Metabolism of 2-nitroimidazoles | p. 157 |
Radiohalogenated Imidazole-based Radiopharmaceuticals for SPECT and Planar Imaging | p. 158 |
Hypoxia tracers labelled with [superscript 82]Br | p. 158 |
Radioiodinated 4(5)-nitroimidazole analogues | p. 159 |
Radioiodinated 2-Nitroimidazoles | p. 160 |
Azomycin Nucleosides | p. 163 |
Discussion | p. 169 |
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