Synthesis and evaluation of 18F-labelled 2-phenylbenzothiazoles as tracer agents for the in vivo diagnosis of Alzheimer's disease

Abstract

Table of contents Professional career Kim SERDONS i Table of contents vii List of abbreviations xiii CHAPTER I: Introduction 1. ALZHEIMER’S DISEASE 2 1.1. Introduction 2 1.1.1. Early-onset familial Alzheimer’s disease 2 1.1.2. Late-onset sporadic Alzheimer’s disease 3 1.1.3. Other types of dementia 3 1.2. Neuropathological features 4 1.2.1. Amyloid plaques 4 1.2.2. Neurofibrillary tangles 5 1.2.3. Cerebral atrophy 6 1.3. Neurochemical features 7 1.4. Pathogenesis 7 1.4.1. Amyloid cascade hypothesis 7 1.4.2. Tau hypothesis 9 1.4.3. Relation between amyloid and tau 10 1.5. Treatment 10 1.5.1. Current status: symptomatic strategies 11 1.5.2. Future: curative strategies 11 1.6. Animal models 12 2. DIAGNOSIS OF ALZHEIMER’S DISEASE 13 2.1. Clinical diagnosis 13 2.1.1. NINCDS-ADRDA criteria 14 2.1.2. MMSE test 14 2.2. Neuropathological and neurochemical diagnosis 15 2.2.1. Brain staining 15 2.2.2. SPECT and PET 15 2.2.2.1. General 15 2.2.2.2. Amyloid 17 2.2.2.3. Tau 19 2.2.2.4. Brain perfusion 19 2.2.2.5. Glucose metabolism 19 2.2.2.6. Inflammation 20 2.2.2.7. Neurochemical changes 20 2.2.3. CT and MRI 21 2.2.4. CSF and blood analysis 21 3. AIM OF THE STUDY 22 CHAPTER II: Synthesis of 18F-labelled 2-(4’-fluorophenyl)-1,3-benzothiazole and evaluation as amyloid imaging agent in comparison with [11C]PIB 1. Abstract 26 2. Key words 26 3. References and Notes 32 CHAPTER III: Synthesis and evaluation of 18F-labelled 2-phenylbenzothiazoles as positron emission tomography imaging agents for amyloid plaques in Alzheimer’s disease 1. Abstract 38 2. Introduction 38 3. Results and Discussion 40 3.1. Chemistry 40 3.2. Radiochemistry 42 3.3. Affinity 44 3.4. Distribution coefficient 45 3.5. Biodistribution in normal mice 45 3.6. µPET study in a normal rat 49 3.7. Biostability of [18F]7 in normal mice 49 3.8. Biostability of [18F]7 in brain of a normal rat 51 4. Conclusion 51 5. Experimental Section 52 5.1. Chemicals and reagents 52 5.2. Apparatus, instruments and general conditions 52 5.3. Synthesis 54 5.4. Production of [18F]fluoride and radiosynthesis of 6-methoxy-2-(4’-[18F]fluorophenyl)-1,3-benzothiazole [18F]5a, 6-hydroxy-2-(4’-[18F]fluorophenyl)-1,3-benzothiazole [18F]5b and 6-methyl-2-(4’-[18F]fluorophenyl)-1,3-benzothiazole [18F]7 61 5.5. Binding studies 62 5.6. Distribution coefficient determination 63 5.7. Biodistribution in normal mice 63 5.8. µPET study in a normal rat 64 5.9. Plasma radiometabolite analysis after injection of [18F]7 in normal mice 64 5.10. Brain radiometabolite analysis after injection of [18F]7 in normal mice 65 5.11. Brain radiometabolite analysis after injection of [18F]7 in normal rat 65 6. Supporting information 66 7. References 66 CHAPTER IV: Toxicity studies, biodistribution, radiation dosimetry and clinical evaluation of the amyloid imaging agent [18F]KS28 1. Abstract 70 2. Key words 70 3. Introduction 70 4. Results 72 4.1. Radiochemistry 72 4.2. Toxicity study in rats 73 4.3. Whole-body biodistribution and radiation dosimetry 73 4.4. Comparison between [11C]PIB and [18F]KS28 in AD patients 77 5. Discussion 82 6. Conclusions 84 7. Materials and methods 85 7.1. Radiochemistry 85 7.2. Toxicity study in rats 86 7.2.1. Animals 86 7.2.2. Dose formulation and calculation and procedure of injection 86 7.2.3. Observation protocol 86 7.2.4. Clinical pathology 87 7.2.5. Histopathologic examination 87 7.2.6. Genotoxicity 87 7.3. Whole-body biodistribution and radiation dosimetry 87 7.3.1. Healthy subjects 88 7.3.2. Whole-body PET data acquisition and study protocol 88 7.3.3. Data analysis 89 7.3.4. Metabolite analysis 89 7.4. Evaluation in AD patients 89 7.4.1. AD patients 89 7.4.2. Data acquisition and study protocol 90 7.4.3. Data analysis 91 7.4.4. Metabolite analysis 91 8. Acknowledgements 92 9. References 92 CHAPTER V: Synthesis and evaluation of three 18F-labelled aminophenylbenzothiazoles as amyloid imaging agents 1. Abstract 98 2. Introduction 98 3. Results and Discussion 100 3.1. Chemistry 100 3.2. Radiochemistry 102 3.3. Affinity 103 3.4. Distribution coefficient 104 3.5. Biodistribution in normal mice 104 3.6. µPET study in a normal rat 108 3.7. µPET study in a normal rhesus monkey 109 3.8. Biostability of [18F]12, [18F]13 and [18F]16 in normal mice 112 3.9. Plasma radiometabolite analysis after injection of [18F]12, [18F]13 and [18F]16 in a normal rhesus monkey 114 4. Conclusion 115 5. Experimental Section 116 5.1. Chemicals and reagents 116 5.2. Apparatus, instruments and general conditions 117 5.3. Synthesis 118 5.4. Production of [18F]fluoride and radiosynthesis of 6-amino-2-(4’-[18F]fluorophenyl)-1,3-benzothiazole [18F]12, 6-methylamino-2-(4’-[18F]fluorophenyl)-1,3-benzothiazole [18F]13 and 6-dimethylamino-2-(4’-[18F]fluorophenyl)-1,3-benzothiazole [18F]16 123 5.5. Binding studies 124 5.6. Distribution coefficient determination 125 5.7. Biodistribution in normal mice 125 5.8. µPET study in a normal rat 126 5.9. µPET study in a normal rhesus monkey 126 5.10. Plasma radiometabolite analysis after injection of [18F]12, [18F]13 and [18F]16 in normal mice 127 5.11. Brain radiometabolite analysis after injection of [18F]12, [18F]13 and [18F]16 in normal mice 127 5.12. Plasma radiometabolite analysis after injection of [18F]12, [18F]13 and [18F]16 in a normal rhesus monkey 128 6. References………………………………………….…………………………………...128 Chapter VI: General discussion 1. The amyloid cascade theory: valid hypothesis or just one of the possibilities? 132 2. Usefulness of amyloid imaging in the preclinical phase of Alzheimer’s disease 134 3. Amyloid imaging in drug development 136 4. Amyloid imaging in other forms of dementia 137 5. PET using a fluorine-18 labelled tracer as an ideal non-invasive imaging technique 138 6. Promising characteristics of 18F-labelled KS-compounds 139 7. Preclinical evaluation of PET amyloid tracers in animals 144 8. Clinical evaluation of PET amyloid tracers 144 Summary 147 Samenvatting 151 References 155nrpages: 162status: publishe