Synthesis, biodistribution, and primate imaging of fluorine-18 labeled 2 beta-carbo-1 '-fluoro-2-propoxy-3 beta-(4-chlorophenyl) tropanes. Ligands for the imaging of dopamine transporters by positron emission tomography

2 beta-(R)-Carbo-1-fluoro-2-propoxy-3 beta-(4-chlorophenyl)tropane ((R)-FIP CT, R-6) and 2 beta-(S)-carbo-1-fluoro-2-propoxy-3 beta-(4-chlorophenyl)tro pane ((S)-FIPCT, S-6) were prepared and evaluated in vitro and in vivo for dopamine transporter (DAT) selectivity and specificity. High specific activ ity [F-18](R)-FIPCT and [F-18](S)-FIPCT were synthesized in 5% radiochemica l yield (decay-corrected to end of bombardment (EOB)) by preparation of the precursors 2 beta-carbo-R-1-mesyloxy-2-propoxy-3 beta-(4-chlorophenyl)tr ( R-12) and 2 beta-carbo-S-1-mesyloxy-2-propoxy-3 beta-(4-chlorophenyl)tropan e (S-12) followed by treatment with no carrier-added potassium[F-18]-fluori de and kyrptofix K222 in acetonitrile. Competition binding in cells stably expressing the transfected human DAT and serotonin transporter (SERT) label ed by [H-3]WIN 35428 and [H-3]-citalopram, respectively, demonstrated the f ollowing order of DAT affinity (K-i in nM): GBR 12909 (0.36) > CIT(0.48) > (S)-FIPCT(0.67) much greater than (R)-FIPCT (3.2). The affinity of(S)-FIPCT and (R)-FIPCT for SERT was 127- and 20-fold lower, respectively, than for DAT. In vivo biodistribution studies were performed in male rats and demons trated that the brain uptake of [F-18](R)-FIPCT and [F-18](S)-FIPCT were se lective and specific for DAT rich regions (caudate and putamen). PET brain imaging studies in monkeys demonstrated high [F-18](R)-FIPCT and [F-18](S)- FIPCT uptake in the caudate and putamen which resulted in caudate-to-cerebe llum and putamen-to-cerebellum ratios of 2.5-3.5 at 115 min. [F-18](R)-FIPC T uptake in the caudate/putamen achieved transient equilibrium at 75 min. I n an imaging experiment with [F-18](S)-FIPCT in a rhesus monkey with its le ft hemisphere lesioned with MPTP, radioactivity was reduced to background i n the caudate and putamen of the lesioned hemisphere. The high specific act ivity one-step radiolabeling preparation and high specificity and selectivi ty of [F-18](R)-FIPCT and [F-18](S)-FIPCT for DAT indicate [F-18](R)-FIPCT and [F-18](S)-FIPCT are potential radioligands for mapping brain DAT in hum ans using PET.