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PET Radiochemistry for the Investigation of the Biology of Pain and Inflammation

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PET Radiochemistry for the Investigation of the Biology of Pain and Inflammation PET Radiochemistry for the Investigation of the biology of pain and inflammation A thesis submitted to the University of Manchester for the degree of PhD in the Faculty of Medical and Human Sciences 2015 Michael Fairclough School of Medicine Institute of Population Health, Imaging Sciences Contents Abbreviations ............................................................................................................. 9 List of Figures ........................................................................................................... 14 List of Tables ............................................................................................................ 19 List of Equations ...................................................................................................... 21 Abstract ..................................................................................................................... 22 Declaration ................................................................................................................ 23 Copyright Statement ................................................................................................ 23 Dedication ................................................................................................................. 24 CHAPTER 1: Introduction (Part 1) – The endogenous opiate system ............... 25 Pain in Rheumatoid Arthritis ................................................................................. 25 The Pain Matrix...................................................................................................... 26 The Endogenous Opioid System ............................................................................ 27 Biology of the opioidergic system. ........................................................................ 31 Pharmacology of the opioid receptor sub-types ..................................................... 33 Introduction (Part 2) – An Introduction to Positron Emission Tomography (PET) and the use of PET for studying the opioidergic system. .......................... 41 Positron Emission Tomography ............................................................................. 41 Carbon-11 - [11C] ............................................................................................... 46 Fluorine-18 - [18F] .............................................................................................. 51 Copper-64 - [64Cu] ............................................................................................. 57 Zirconium-89 - [89Zr] ......................................................................................... 63 Synthetic Opiates used with PET ........................................................................... 68 Introduction (Part 3) – Inflammation and Rheumatoid Arthritis....................... 77 Inflammation as a therapeutic target ...................................................................... 77 Inflammation Imaging ............................................................................................ 78 The Interleukin receptor family and interleukin-1 receptor antagonist (IL-1RA) . 79 Page 2 of 223 Radiolabelling white blood cells for cell trafficking and diagnosis ....................... 82 Radiolabelling with SPECT isotopes 111In and 99mTc ........................................ 82 Radiolabelling cells with PET isotopes ............................................................. 86 References .............................................................................................................. 91 CHAPTER 2: The automated radiosynthesis and purification of the opioid receptor antagonist, [6-O-methyl-11C]Diprenorphine on the GE TRACERlab FXFE radiochemistry module. .................................................................................. 97 Abstract .................................................................................................................. 98 Introduction ............................................................................................................ 99 Materials and Equipment ..................................................................................... 102 Methods ................................................................................................................ 102 Production of [11C]carbon dioxide. .................................................................. 102 Production of [11C]methyl iodide. .................................................................... 102 Production of [11C]methyl trifluoromethanesulfonate. .................................... 103 Production of [6-O-methyl-11C]diprenorphine using [11C]methyl iodide. ....... 103 Production of [6-O-methyl-11C]diprenorphine using [11C] methyl triflate ...... 104 [6-O-methyl-11C]Diprenorphine quality control. ............................................. 104 Results .................................................................................................................. 105 [6-O-methyl-11C]Diprenorphine from [11C]methyl iodide .............................. 105 [6-O-methyl-11C]Diprenorphine from [11C]methyl triflate .............................. 107 [6-O-methyl-11C]Diprenorphine Quality Control ............................................ 109 Discussion ............................................................................................................ 111 [6-O-methyl-11C]Diprenorphine radiochemistry and automation .................... 111 [11C]Methyl trifluoromethanesulphonate ([11C]methyl triflate) as carbon-11 methylating synthon to [6-O-methyl-11C]diprenorphine. ................................ 114 Conclusion ........................................................................................................... 116 References ............................................................................................................ 117 Supplementary Data ............................................................................................. 119 Page 3 of 223 CHAPTER 3: A highly reproducible method for the Measurement of [6-O- methyl-11C]diprenorphine and its radiometabolites based on Solid Phase Extraction (SPE) and radio-HPLC ...................................................................... 121 Abstract ................................................................................................................ 122 Introduction .......................................................................................................... 123 Materials and Equipment ..................................................................................... 127 Methods ................................................................................................................ 128 [6-O-methyl-11C]Diprenorphine production .................................................... 128 [6-O-methyl-11C]Diprenorphine metabolite analysis for PET scans. .............. 128 Production of [6-O-methyl-11C]diprenorphine metabolites by means of digest, using pooled human liver microsomes ............................................................. 130 Results .................................................................................................................. 130 In Silico Analysis of [6-O-methyl-11C]diprenorphine metabolites .................. 130 SPE column loading and elution ...................................................................... 131 [6-O-methyl-11C]Diprenorphine metabolite analysis for PET ......................... 132 Recoveries of various SPE stationary phases................................................... 133 Discussion ............................................................................................................ 134 In SilicoAnalysis of [6-O-methyl-11C]diprenorphine metabolites ................... 134 SPE column loading and elution ...................................................................... 136 [6-O-methyl-11C]Diprenorphine metabolite analysis for PET ......................... 136 Recoveries of various SPE stationary phases................................................... 136 Conclusion ........................................................................................................... 138 References ............................................................................................................ 138 CHAPTER 4: Striatal opioid receptor availability predicts acute and chronic pain perception in arthritis: evidence for opioid adaption to chronic pain. ..... 140 Abstract ................................................................................................................ 141 Introduction .......................................................................................................... 142 Materials and Methods ......................................................................................... 144 Page 4 of 223 Participants ....................................................................................................... 144 MRI data acquisition and pre-processing ......................................................... 144 Questionnaire assessments ............................................................................... 145 Positron Emission Tomography (PET) scans .................................................. 145 Derivation of arterial input function ................................................................ 147 11 15 [ C]-DPN and H2 O PET image reconstruction ...........................................
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