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

2β-(R)-Carbo-1-fluoro-2-propoxy-3β-(4-chlorophenyl)tropane ((R)-FIPCT, R-6) and 2β-(S)-carbo-1-fluoro-2-propoxy-3β-(4-chlorophenyl)tropane ((S)- FIPCT, S-6) were prepared and evaluated in vitro and in vivo for dopamine transporter (DAT) selectivity and specificity. High specific activity [¹⁸F](R)-FIPCT and [¹⁸F](S)-FIPCT were synthesized in 5% radiochemical yield (decay-corrected to end of bombardment (EOB)) by preparation of the precursors 2β-carbo-R-1-mesyloxy-2-propoxy-3β-(4-chlorophenyl)tropane (R- 12) and 2β-carbo-S-1-mesyloxy-2-propoxy-3β-(4-chlorophenyl)tropane (S-12) followed by treatment with no carrier-added potassium[¹⁸F]-fluoride and kyrptofix K222 in acetonitrile. Competition binding in cells stably expressing the transfected human DAT and serotonin transporter (SERT) labeled by [³]WIN 35428 and [³H]-citalopram, respectively, demonstrated the following order of DAT affinity (K(i) in nM): GBR 12909 (0.36) > CIT (0.48) > (S)-FIPCT (0.67) >> (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 demonstrated that the brain uptake of [¹⁸F](R)-FIPCT and [¹⁸F](S)-FIPCT were selective and specific for DAT rich regions (caudate and putamen). PET brain imaging studies in monkeys demonstrated high [¹⁸F](R)-FIPCT and [¹⁸F](S)-FIPCT uptake in the caudate and putamen which resulted in caudate-to-cerebellum and putamen-to-cerebellum ratios of 2.5-3.5 at 115 min. [¹⁸F](R)-FIPCT uptake in the caudate/putamen achieved transient equilibrium at 75 min. In an imaging experiment with [¹⁸F](S)-FIPCT in a rhesus monkey with its left hemisphere lesioned with MPTP, radioactivity was reduced to background in the caudate and putamen of the lesioned hemisphere. The high specific activity one-step radiolabeling preparation and high specificity and selectivity of [¹⁸F](R)-FIPCT and [¹⁸F](S)-FIPCT for DAT indicate [¹⁸F](R)-FIPCT and [¹⁸F](S)-FIPCT are potential radioligands for mapping brain DAT in humans using PET.