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

Academic Article


  • 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 [(123)I]ZIENT and [(123)I]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 [(123)I]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 [(3)H]citalopram, [(3)H]WIN 35,428, and [(3)H]nisoxetine, respectively, demonstrated the following order of SERT affinity (K(i) 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 [(123)I]ZIENT was selective and specific for SERT-rich regions (hypothalamus, striatum, pons, and prefrontal cortex). SPECT brain imaging studies in monkeys demonstrated high [(123)I]ZIENT uptake in the diencephalon, which resulted in diencephalon-to-cerebellum ratios of 2.12 at 190 min. [(123)I]ZIENT uptake in the diencephalon achieved transient equilibrium at 157 min. In a displacement experiment of [(123)I]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 [(123)I]ZIENT for SERT support its candidacy as a radioligand for mapping brain SERT sites.
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  • Animals, Binding, Competitive, Brain, Carrier Proteins, Female, HeLa Cells, Humans, Iodine Radioisotopes, Isotope Labeling, Ligands, Macaca fascicularis, Male, Membrane Glycoproteins, Membrane Transport Proteins, Nerve Tissue Proteins, Nortropanes, Radioligand Assay, Radiopharmaceuticals, Rats, Rats, Sprague-Dawley, Serotonin, Serotonin Plasma Membrane Transport Proteins, Stereoisomerism, Structure-Activity Relationship, Tissue Distribution, Tomography, Emission-Computed, Single-Photon
  • Digital Object Identifier (doi)

    Author List

  • Goodman MM; Chen P; Plisson C; Martarello L; Galt J; Votaw JR; Kilts CD; Malveaux G; Camp VM; Shi B
  • Start Page

  • 925
  • End Page

  • 935
  • Volume

  • 46
  • Issue

  • 6