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Evaluation of a Novel Non-Competitive Antagonist As a Radioligand for the N-Methyl-D-Aspartate Receptor-Channel Complex in Vivo

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Evaluation of a Novel Non-Competitive Antagonist As a Radioligand for the N-Methyl-D-Aspartate Receptor-Channel Complex in Vivo Evaluation of a novel non-competitive antagonist as a radioligand for the N-methyl-D-aspartate receptor-channel complex in vivo AILSA L. McGREGOR A thesis submitted for the Degree of Doctor of Philisophy to the Faculty of Medicine, University of Glasgow Wellcome Surgical Institute and Hugh Fraser Neuroscience Laboratories, University of Glasgow, Garscube Estate, Bearsden Road, Glasgow, G61 1QH © A.L. McGregor, November 1997 ProQuest Number: 13818690 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 13818690 Published by ProQuest LLC(2018). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 ( gl T UNi f.TBBAkl GLASGOW UNIVERSITY LIBRARY v CONTENTS PAGE Contents i List of tables vii List of figures viii Acknowledgements xi Summary xiii Preface and declaration xviii CHAPTER I - INTRODUCTION 1.1 Excitatory amino acids as neurotransmitters in the CNS 1 1.2 Metabolism and release of glutamate 2 1.3 Glutamate receptor subtype classification 6 1.3.1 The NMD A receptor 6 1.3.2 The AMPA receptor 23 1.3.3 The Kainate receptor 25 1.3.4 The AP-4 receptor 26 1.3.5 The Metabotropic receptor 26 1.4 Excitotoxicity 29 1.4.1 NMDA-mediated neurotoxicity 29 1.4.2 Non-NMDA-mediated toxicity 31 1.4.3 The ischaemic penumbra 32 1.5 Therapeutic intervention in cerebral iscliaemia 33 1.5.1 Strategies for improving perfusion 33 1.5.2 NMDA antagonists 34 1.6 NMDA antagonists as clinically useful drugs 36 1.6.1 Safety and tolerability 36 1.6.2 Animal studies 36 1.6.3 Human studies 37 PAGE 1.7 Development of a novel NMDA antagonist 38 1.7.1 Basic concepts 38 1.7.2 Preclinical studies 38 1.7.3 Clinical studies 39 1.8 Receptor imaging in the central nervous system 41 1.8.1 Autoradiography 41 1.8.2 SPECTandPET 45 1.9 Synthesis of yV-(l-naphthyl)-W-(3-[*25I]iodo- 50 phenyI)-N'methylguanidine CHAPTER II - METHODS 2.1 Affinity and selectivity of CNS 1261 52 2.1.1 Whole crude synaptosomal membrane (WCSM) preparation 52 2.1.2 Assay procedure 53 2.1.3 Commercial screening of CNS 1261 53 2.2 Effect of CNS 1261 on local cerebral glucose utilisation 54 2.2.1 Surgical preparation of animals 55 2.2.2 The [14C]2-deoxyglucose technique 55 2.2.3 Preparation of autoradiograms 55 2.2.4 Quantification of autoradiograms 56 2.2.5 Experimental protocol 57 2.2.6 Data analysis 57 2.2.7 /ranking 57 2.3 In vivo [125I]MK801 autoradiography 58 2.3.1 Surgical preparation of animals 58 2.3.2 The [125I]MK801 technique 59 2.3.3 Preparation of autoradiograms 59 2.3.4 Quantification of autoradiograms 59 PAGE 2.4 In vivo [125I]CNS 1261 autoradiography 60 2.4.1 Surgical preparation of animals 60 2.4.2 The [125I]CNS 1261 technique 60 2.4.3 Preparation of autoradiograms 60 2.4.4 Quantification of autoradiograms 61 2.5 Uptake and retention of [125I]CNS 1261 and [125I]MK801 in normal rat brain 61 2.5.1 Experimental design 61 2.5.2 Data analysis 62 2 .6 Relative lipophilicity of [125I]CNS 1261 and [125I]M K801 62 2.6.1 Calculation of LogD values for CNS 1261 and MK801 62 2.6.2 Calculation of brain/aqueous partition ratios 62 2.6.3 Data analysis 63 2 .7 Metabolism of [125I]CNS 1261 and [125I]MK801 in the rat 63 2.7.1 Determination .of metabolites in rat plasma 63 2.7.2 Determination of metabolites in rat brain 64 2.7.3 Experimental analysis 64 2 .8 Effect of MK801 on the uptake and retention of [125I]CNS 1261 in normal rat brain 64 2.8.1 Experimental design 64 2.8.2 Data analysis 65 2 .9 Uptake and retention of [125I]MK801 and [125I]CNS 1261 following changes in arterial CO2 tension 65 2.9.1 [125I]MK801 uptake following changes in arterial CO 2 tension 65 2.9.2 Data analysis 66 2.9.3 [125I]CNS 1261 uptake following changes in CO 2 tension 66 2.9.4 Data analysis 66 iii PAGE 2.10 Uptake and retention of [125I]CNS1261 following intracortical injection of NMDA 67 2.10.1 Experimental design 67 2.10.2 Histological examination of the lesion 67 2.10.3 Data analysis 68 CHAPTER III - RESULTS 3.1 CNS 1261 binds to the NMDA receptor complex with high affinity and selectivity 69 3.1.1 Affinity of CNS 1261 69 3.1.2 Selectivity of CNS 1261 69 3 .2 Effect of CNS 1261 on local cerebral glucose use 72 3.2.1 General observations 72 3.2.2 Local cerebral glucose utilisation 74 3.3 Uptake and.retention of [125I]MK801 and[125I]CNS 1261 in normal rat brain 82 3.3.1 General observations 82 3.3.2 In vivo uptake and retention of [125I]CNS 1261 82 3.3.3 Comparison of [125I]CNS 1261 with [125l]MK801 88 3 .4 Relative lipophilicity of [125I]CNS 1261 and [125I]M K801 90 3.4.1 Lipophilicity of CNS 1261 90 3.4.2 Partition coefficients of [125I]CNS 1261 and [125I]MK801 in rat brain 90 3.4.3 Partition coefficients of [125I]CNS 1261 and [125I]MK801 in human brain 90 3.5 Metabolism of [125I]CNS 1261 in the rat 93 3.5.1 Stability of [125I]CNS 1261 in vitro 93 3.5.2 Metabolism of [125I]CNS 1261 in the rat 93 3.5.3 Metabolism of [l25I]MK801 in the rat 95 PAGE 3 .6 Effect of MK801 on the uptake and retention of [125I]CNS 1261 in the normal rat brain 97 3.6.1 General observations 97 3.6.2 Authenticity of MK801 97 3.6.3 Uptake and retention of [125I]CNS 1261 99 3.7 [125I]MK801 and [125I]CNS 1261 uptake following changes in arterial CO2 tension 101 3.7.1 [125I]MK801 - general observations 101 3.7.2 Analysis of [125I]MK801 autoradiograms 101 3.7.3 [125I]CNS 1261 - general observations 105 3.7.4 Analysis of [125I]CNS 1261 autoradiograms 106 3.8 [125I]CNS 1261 uptake following intracortical injection of NMDA 109 3.8.1 Verification of dose 109 3.8.2 General observations 109 3.8.3 Histology 112 3.8.4 Uptake and retention of [125I]CNS 1261 112 CHAPTER IV - DISCUSSION 4.1 CNS 1261 acts as a non-competitive NMDA receptor antagonist 116 4.2 [125I]CNS 1261 uptake within the normal brain 120 4.3 [125I]CNS 1261 produces superior images to [l25I]MK801 in normal brain 126 4.3.1 Kinetic modelling 128 4.4 Displacement of [125I]CNS 1261 from normal rat brain 131 4.5 Application of [125I]CNS 1261 133 4.6 SPECT imaging in man with [123I]CNS 1261 139 v PAGE References 143 Appendix 1 168 Appendix 2 170 Published abstracts 173 List of Tables PAGE 1. Excitatory amino acid receptors 7 2. Inhibition of radioligand binding by CNS 1261 70 3. CNS 1261 displayed no activity in a range of radioligand binding assays 71 4. Effect of CNS 1261 administration on physiological variables 73 5. Effect of CNS 1261 administration on glucose use in sensory and motor systems 75 6. Effect of CNS 1261 administration on glucose use in limbic system 76 7. Effect of CNS 1261 administration on glucose use in myelinated tracts 77 8. Hierarchy of regional responsiveness to CNS 1261 79 9. Hierarchy of regional responsiveness to MK801 80 10. Uptake and retention of [125I]MK801 and [125I]CNS 1261 - physiological variables 83 11. Comaprison of [125I]MK801 and [125I]CNS 1261 uptake 30 minutes post-administration 84 12. Comparison of [125I]MK801 and [125I]CNS 1261 uptake 60 minutes post-administration 85 13. Comparison of [12^I]MK801 and [l^IjCNS 1261 uptake 120 minutes post-administration 86 14. LogD values for CNS 1261 and other non-competitive NMDA antagonists 91 15. Brain/aqueous partition ratios in rat and human brain 92 16.. Species present in isotope solutions 6 hours after reconstitution 94 17. Physiological variables before and 60 minutes after initiation of MK801 infusion 98 18. Effect of MK801 on [l^IjCNS 1261 uptake 100 19. Physiological variables following changes in arterial CO 2 tension 102 20. [l^IjMKSOl uptake following changes in arterial CO 2 tension 104 21. Physiological variables following changes in arterial CO 2 tension 106 22. [125I]CNS 1261 uptake following changes in arterial CO 2 tension 107 23. Changes in glucose use following intracortical injection of NMDA 110 24. Physiological variables before and after intracortical injection of CSF or NMDA 111 25. Tracer uptake appears to reflect cereberal blood flow 5 minutes after administration 123 vii List of Figures AFTER PAGE 1. Pathways for glutamate utilisation and metabolism 2 2. Schematic illustration of the NMDA receptors 7 3. The modulatory actions of polyamines on the NMDA receptor 14 4.
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