Development of a potent series of MMP-2 and MMP-9 selective inhibitors.

Table of Contents ACKNOWLEDGEMENTS 3 SUMMARY......... 8 SAMENVATTING 10 LIST OF ABBREVIATIONS 13 GENERAL INTRODUCTION 14 0.1 ATHEROSCLEROSIS 14 0.1.1 The atherosclerotic plaque 14 0.1.2 Plaque stability 16 0.2 MATRIX METALLOPROTEINASES IN UNSTABLE PLAQUE 19 0.2.1 Matrix metalloproteinases 19 0.2.2 MMP structure and function 20 0.2.3 MMP-2 and MMP-9 20 0.2.4 Regulation of secreted MMPs 22 0.3 MATRIXMETALLOPROTEINASE INHIBITORS 24 0.4 HISTORICAL BACKGROUND OF HYDROXAMIC ACID CHEMISTRY 28 0.4.1 Hydroxamic acid 28 0.5 NEW AGE OF HYDROXAMIC ACIDS 29 0.5.1 Chemistry of hydroxamic acids 30 0.5.2 Hydroxamic acids and matrix metalloproteinases (MMPs) 31 0.5.3 Acylation of hydroxylamines 32 0.5.4 Acylation of protected hydroxylamine 34 0.6 DEVELOPMENT OF A SYNTHETIC STRATEGY TOWARD THE SYNTHESIS OF SELECTIVE AND POTENT MMP-2 AND MMP-9 INHIBITORS 35 0.6.1 MMP Inhibitors with potential for imaging of plaques 35 0.7 SELECTIVITY TOWARDS THE MMP ENZYME FAMILY 35 0.7.1 Selective MMP-2 / MMP-9 Inhibitors 35 0.8 IMAGING ATHEROSCLEROSIS 37 0.8.1 Imaging modalities and vulnerable plaques 37 0.9 RADIOCHEMISTRY 39 0.9.1 Background 39 0.9.2 Important definitions used in radiochemistry 39 0.10 RADIOIODINATION 40 0.10.1 General properties and physical properties of iodine-123 40 0.11 ASPECTS OF IODINE-123 PRODUCTION 41 0.11.1 Production of iodine-123 41 0.11.2 Radiochemical en radionuclidic purity of iodine-123 43 0.12 PROPERTIES AND REQUIREMENTS FOR SYNTHESIS OF RADIO- PHARMACEUTCALS 45 0.12.1 Requirements for the use of radiopharmaceuticals 45 0.13 METHODS FOR RADIOIODINATION 45 0.13.1 General information 45 0.13.2 Radioiodination: Nucleophilic and electrophilic aromatic substitution reaction 46 0.14 FLUORINE-18 CHEMISTRY 50 0.14.1 Physical properties of Fluorine-18 radionuclide 50 0.14.2 Principle of positron emission tomography (PET) 51 0.14.3 General properties of fluorine-18 52 0.14.4 The cyclotron production of Fluorine-18 53 0.14.5 Fluorine-18 labelling strategies 53 0.14.6 Production of Fluorine-18 for the nucleophilic fluorination method 55 0.14.7 Radiochemical purity of Fluorine-18 labelled radiopharmaceuticals 57 OBJECTIVES 58 CHAPTER 1 1.1 SYNTHETIC STRATEGIES AND BACKGROUND OF CLASS I MMPINHIBITORS (MMPI) 60 1.2 FIRST SYNTHETIC APPROACH TOWARD HALOGENATED HYDROXAMIC ACID DERIVATIVES 61 1.3 SYNTHESIS OF MODIFIED FLUORINE AND NITROGEN CONTAINING SULFONARYL HYDROXAMIC ACID COMPOUNDS1, 126 65 1.3.1 Introduction to the synthesis of fluorine containing selective MMP-2 and MMP-9 inhibitors 65 1.3.2 Synthesis of the fluorine containing inhibitors 65 CHAPTER 2 2.1 CHEMISTRY 67 2.2 IN VITRO MMP INHIBITORY ACTIVITY 68 2.3 RADIOCHEMISTRY 70 2.4 BIODISTRIBUTION EXPERIMENTS 72 2.5 RESULTS 72 2.6 CONCLUSION 76 CHAPTER 3 3.1 CHEMISTRY 77 3.2 IN VITRO MMP INHIBITORY ACTIVITY 83 3.3 CONCLUSION 84 CHAPTER 4 4.1 SYNTHESIS OF FIRST GROUP PRECURSOR E FOR THE SYNTHESIS OF 18F TARGET COMPOUND..........................................................................................................................85 4.2 DUAL ROLE OF PRECURSOR COMPOUND E 86 4.3 SYNTHESIS OF SECOND PRECURSOR COMPOUND H 88 4.4 SYNTHESIS OF THIRD PRECURSOR COMPOUND G 88 4.5 DECARBONYLATION OF COMPOUND G AS A MODEL REACTION 89 4.6 Preliminary radiofluorination of 18F target compound 91 4.6.1 Preliminary synthesis of [18F]-A & [18F]-15b 91 4.7 CONCLUSION 92 OVERALL CONCLUSION AND PERSPECTIVES 93 EXPERIMENTAL SECTION 96 REFERENCES.................................................................................................................150nrpages: 152status: publishe