DIARYLIODONIUM SALTS AS PRECURSORS TO 18 ELECTRON-RICH [ F]FLUOROARENES FOR USE IN THE MEDICAL IMAGING TECHNIQUE – POSITRON EMISSION TOMOGRAPHY SATWINDER SINGH BHATT Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy. Sir Bobby Robson Foundation PET Tracer Production Unit, School of Chemistry, Newcastle University January 2016 Contents Acknowledgements ....................................................................................... v List of Abbreviations ................................................................................... vii 1 Introduction ......................................................................................... 1 1.1 Positron Emission Tomography ................................................................. 1 1.2 Radioisotopes in PET Imaging ................................................................... 9 1.3 Fluorine in Pharmaceuticals .................................................................... 12 1.4 PET Imaging with Fluorine-18 ................................................................. 17 1.5 Cyclotron Production of Fluorine-18 ......................................................... 19 1.5.1 Radiochemical Terminology ................................................................. 21 1.5.2 Production of Electrophilic Fluorine-18 .................................................. 24 1.5.3 Production of Nucleophilic Fluorine-18 .................................................. 25 1.5.4 Radiopharmaceutical Production .......................................................... 27 1.6 Approaches to [18F]Fluorine Radiolabelling ............................................... 31 1.6.1 Electrophilic [18F]Fluorinations.............................................................. 32 1.6.2 Nucleophilic [18F]Fluorinations .............................................................. 37 1.6.2.1 Nucleophilic Aliphatic Substitutions with [18F]Fluoride ......................... 38 1.6.2.3 Nucleophilic Aromatic Substitutions with [18F]Fluoride ........................ 41 1.6.2.3 The Balz-Schiemann and Wallach Reactions ....................................... 47 1.6.2.4 Newer Strategies for Fluorine-18 Incorporation .................................. 49 1.7 Fluorine-18 Labelling with Prosthetic Groups ............................................ 59 1.7.1 Amine Reactive Prosthetic Groups ........................................................ 63 1.7.2 Thiol Reactive Prosthetic Groups .......................................................... 65 1.7.3 Click-Chemistry Approaches to Fluorine-18 Labelling ............................. 68 1.7.4 Transition-metal Catalysed Cross-coupling Prosthetic Groups ................. 70 1.7.5 Carbonyl Reactive Prosthetic groups ..................................................... 72 1.8 [18F]Fluorophenols as Prosthetic Groups .................................................. 73 2 Diaryliodonium Salts for Radiolabelling Electron-rich Aromatics ........ 79 2.1 Introduction to Hypervalent Iodine Chemistry .......................................... 79 2.2 Reactivity of Diaryliodonium Salts ............................................................ 83 2.2.1 Chemoselectivity of Diaryliodonium Salt Fluorination ............................. 85 2.2.2 Applications of Diaryliodonium Salts ..................................................... 92 2.3 Synthesis of Diaryliodonium Salts ............................................................ 93 2.4 A Strategy for 4-[18F]Fluorophenol Production .......................................... 97 i 2.5 Preparation of Aryliodobis(acetate)s ........................................................ 99 2.6 Preparation of Arylstannanes ................................................................. 105 2.7 Preparation of Diaryliodonium Salts for 4-[18F]Fluorophenol Production .... 111 2.8 [19F]Fluorination of Diaryliodonium Salts ................................................. 121 2.9 Improving Selectivity ............................................................................. 127 2.10 Chapter 2 Summary ........................................................................... 131 3 Microfluidic Radiofluorination of Diaryliodonium Salts...................... 132 3.1 Automated Radiochemistry .................................................................... 133 3.2 Radiosynthesis with the Advion NanoTek Microfluidic System ................... 138 3.3 Radiosynthesis of Protected-4-[18F]fluorophenol ...................................... 142 3.4 Chapter 3 Summary .............................................................................. 151 4 Diaryliodonium Routes to 6-[18F]Fluoro-m-tyramine ........................ 152 4.1 Diaryliodonium Salt Precursors to 6-[18F]Fluoro-m-tyramine .................... 154 4.2 [19F]Fluorination of 6-Fluoro-m-tyramine Precursors ................................ 159 4.3 [18F]Fluorination of 6-Fluoro-m-tyramine Precursors ................................ 163 4.4 Chapter 4 Summary .............................................................................. 167 5 Diaryliodonium Routes to [18F]FDOPA ............................................... 168 5.1 Introduction to [18F]FDOPA .................................................................... 168 5.2 Current Routes to [18F]FDOPA ............................................................... 172 5.3 [18F]FDOPA Diaryliodonium Salt Precursor Strategy ................................. 181 5.4 Initial Challenges in [18F]FDOPA Diaryliodonium Salt Development ........... 185 5.5 Diaryliodonium Salt Precursor to 6-[18F]Fluorodopamine .......................... 189 5.6 Redesign of the [18F]FDOPA Diaryliodonium Salt ..................................... 193 5.4 Chapter 5 Summary .............................................................................. 201 7 Conclusions and Further Work............................................................ 202 9 Experimental ....................................................................................... 204 9.1 Phenyliodobis(acetate) (132)261,412 ......................................................... 204 9.2 2-Thienyliodobis(acetate) (133)255,411 ..................................................... 205 9.3 4-Methoxyphenyliodobis(acetate) (134)255,412 .......................................... 205 9.4 2-Methoxyphenyliodobis(acetate) (135)255,412 .......................................... 206 9.5 4-Methylphenyliodobis(acetate) (136)261,412 ............................................ 206 9.6 2,4,6-Trimethylphenyliodobis(acetate) (137)261,412 ................................... 207 9.7 4-(Benzyloxy)phenyliodobis(acetate) (166)221 ......................................... 207 9.8 4-(Benzyloxy)-1-iodobenzene (140)413,414 ................................................ 208 9.9 4-(Benzyloxy)-1-bromobenzene (141)413,414 ............................................ 209 9.10 4-Iodophenyl acetate (142)415,416 ........................................................ 209 9.11 4-Bromophenyl acetate (143)415 .......................................................... 210 ii 9.12 4-(Benzyloxy)-1-fluorobenzene (157)416 ...............................................210 9.13 4-(Benzyloxy)-1-tributylstannylbenzene (146)318,319,320 ..........................211 9.14 4-(Acetoxy)-1-tributylstannylbenzene (147)318,319,320 .............................212 9.15 4-(Methoxy)-1-tributylstannylbenzene (148)318,319,320 ............................212 9.16 (3,4,5-trimethoxy)-1-tributylstannylbenzene (169)318,319,320 ...................213 9.17 (4-(Benzyloxy)phenyl)(4-methoxyphenyl)iodonium trifluoroacetate (149) ... .........................................................................................................213 9.18 (4-(Benzyloxy)phenyl)(2-thienyl)iodonium trifluoroacetate (150) ...........214 9.19 (4-(Benzyloxy)phenyl)(phenyl)iodonium trifluoroacetate (151) ..............215 9.20 (4-(Acetoxy)phenyl)(4-methoxyphenyl)iodonium trifluoroacetate (152) .215 9.21 (4-(Acetoxy)phenyl)(2-thienyl)iodonium trifluoroacetate (153) ..............216 9.22 Bis(4-(benzyoxyl)phenyl)iodonium trifluoroacetate (155) ......................217 9.23 (4-(Benzyloxy)phenyl)(3,4,5-trimethoxyphenyl)iodonium trifluoroacetate (170) .................................................................................................217 9.24 1-Methoxy-3-(2-nitrovinyl)benzene (177)417,418 .....................................218 9.25 2-(3-Methoxyphenyl)ethan-1-amine (178)417,418 ...................................218 9.26 2-(3-Methoxyphenethyl)isoindoline-1,3-dione (179) 418,419 .....................219 9.28 2-(2-(3-Methoxyphenethyl)isoindoline-1,3-dione)(4- methoxyphenyl)iodonium trifluoroacetate (181) ...................................220 9.29 2-(2-(3-Methoxyphenethyl)isoindoline-1,3-dione)(2- methoxyphenyl)iodonium trifluoroacetate (182) ...................................221 9.30 2-(3,4-dimethoxyphenethyl)isoindoline-1,3-dione (225)418 ....................221 9.31 2-(2-iodo-4,5-dimethoxyphenethyl)isoindoline-1,3-dione (227) .............222 9.32 2-(4,5-dimethoxy-2-(tributylstannyl)phenethyl)isoindoline-1,3-dione (228)176 .............................................................................................223 9.33 (4-(5-N-[2-(1,2-Dimethoxy-phenyl)ethyl]-phthalimide)(2-thienyl)iodonium trifluoroacetate (226) .........................................................................224 9.34 Methyl (S)-2-amino-3-(2-bromo-4,5- dihydroxyphenyl) propanoate (230)408 .........................................................................................................224