Co(salen)-mediated enantioselective radiofluorination of epoxides. Synthesis and biological evaluation of both enantiomers of [18F]FMISO

The purpose of this PhD project was to develop an enantioselective cobalt-mediated radiofluorination of epoxides and apply this methodology for radiosynthesis of the PET radiopharmaceutical [18F]FMISO. The developed procedure utilizes [18F]HF-gas (as an efficient source of nucleophilic 18F-fluoride) in a combination with chiral base ((-)tetramisole), chiral Lewis acid ((R,R)-Co(salen)) and hexafluoroisopropanol, providing the corresponding (S)-[18F]fluorohydrines enantioselectively (20-46% enantiomeric excess) with high yields (78-93 % radiochemical yield). The enantioselective Co(salen)-mediated no-carrier-added radiofluorination of epoxides has been achieved for the first time. A number of model meso-epoxides were successfully radiofluorinated producing 18F-fluorohidrines in high RCC and RCY, and modest enantioselectivity. The developed procedure is simple, rapid and lends itself to easy automation. This methodology was adopted for the first automated enantioselective single step radiosynthesis of PET hypoxia radiotracer [18F]FMISO in 81% RCY and 55% enantioselectivity. The use of enantiopure substrates for the synthesis of both enantiomers allowed us to obtain the (S) and (R)-[18F]FMISO enantiomers with > 99% enantiopurity. In vivo quantitative and pharmacokinetic data were obtained for the first time for the both enantiomers of [18F]FMISO. The R-form showed higher uptake in tumor as well as in muscle tissues, thus displaying nearly identical tumor-to muscle ratios and showing very similar imaging profiles of both the (S) and the (R)-[18F]FMISO enantiomers.