Synthesis and characterization of iodine-123 labeled 2β-carbomethoxy-3β-(4′-((Z)-2-iodoethenyl)phenyl)nortropane.: A ligand for in vivo Imaging of serotonin transporters by single-photon-emission tomography

2beta-Carbomethoxy-3beta-(4'-((Z)-2-iodoethenyl)phenyl)nortropane (ZIENT) (6) and 2beta-carbomethoxy-3beta-(4'-((E)-2-iodoethenyl)phenyl)nortropane (EIENT) (10) were prepared and evaluated in vitro and in vivo for serotonin transporter (SERT) selectivity and specificity. High specific activity [I-123] ZIENT and [I-123]EIENT were synthesized in 45% (n = 5) and 42% (n = 4) radiochemical yield (decay-corrected to end of bombardment (EOB)), respectively, by preparation of the precursor carbomethoxy-3beta-(4'-((Z)-2-trimethylstannylethenyl)phenyl)nortropane (7) and 2beta-carbomethoxy-3beta-(4'-((E)-2-tributylstannylethenyl)phenyl)nortropane (9), respectively, followed by treatment with no carrier-added sodium [I-123] iodide and hydrogen peroxide in ethanolic HCl. Competition binding in cells stably expressing the transfected human SERT, dopamine transporter (DAT), and norepinephrine transporter (NET) using [H-3]citalopram, [H-3]WIN 35,428, and [H-3]nisoxetine, respectively, demonstrated the following order of SERT affinity (K-i in nM): ZIENT (0.05) > nor-CIT (0.12) much greater thanEIENT(1.15) > fluvoxamine (1.46). The affinity of ZIENT and EIENT for DAT was 69 and 1.6-fold lower; respectively, than for SERT. In vivo biodistribution and blocking studies were performed in male rats and demonstrated that the brain uptake of [I-123]ZIENT was selective and specific for SERT-rich regions (hypothalamus, striatum, pons, and prefrontal cortex). SPECT brain imaging studies in monkeys demonstrated high [I-123]ZIENT uptake in the diencephalon, which resulted in diencephalon-to-cerebellum ratios of 2.12 at 190 min. [I-123] ZIENT uptake in the diencephalon achieved transient equilibrium at 157 min. In a displacement experiment of [I-123] ZIENT in a cynomolgus monkey, radioactivity was reduced by 39% in the diencephalon at 101 min following injection of citalopram. The high specific activity one-step radiolabeling preparation and high selectivity of [I-123] ZIENT for SERT support its candidacy as a radioligand for mapping brain SERT sites.