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

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Abstract
2β-Carbomethoxy-3β-(4‘-((Z)-2-iodoethenyl)phenyl)nortropane (ZIENT) (6) and 2β-carbomethoxy-3β-(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 [123I]ZIENT and [123I]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-3β-(4‘-((Z)-2-trimethylstannylethenyl)phenyl)nortropane (7) and 2β-carbomethoxy-3β-(4‘-((E)-2-tributylstannylethenyl)phenyl)nortropane (9), respectively, followed by treatment with no carrier-added sodium [123I]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 [3H]citalopram, [3H]WIN 35,428, and [3H]nisoxetine, respectively, demonstrated the following order of SERT affinity (Ki in nM): ZIENT (0.05) > nor-CIT (0.12) ≫ EIENT (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 [123I]ZIENT was selective and specific for SERT-rich regions (hypothalamus, striatum, pons, and prefrontal cortex). SPECT brain imaging studies in monkeys demonstrated high [123I]ZIENT uptake in the diencephalon, which resulted in diencephalon-to-cerebellum ratios of 2.12 at 190 min. [123I]ZIENT uptake in the diencephalon achieved transient equilibrium at 157 min. In a displacement experiment of [123I]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 [123I]ZIENT for SERT support its candidacy as a radioligand for mapping brain SERT sites.