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

Mark M. Goodman, Ping Chen, Christophe Plisson, Laurent Martarello, James Galt, John R. Votaw, Clinton D. Kilts, Gene Malveaux, Vernon M. Camp, Bing Shi, Timothy D. Ely, Leonard Howell, Jon McConathy, Charles Nemeroff

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)925-935
Number of pages11
JournalJournal of Medicinal Chemistry
Volume46
Issue number6
DOIs
StatePublished - Mar 13 2003
Externally publishedYes

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Nortropanes
Serotonin Plasma Membrane Transport Proteins
Photons
Iodine
Tomography
Ligands
Imaging techniques
Diencephalon
Citalopram
Dopamine Plasma Membrane Transport Proteins
nisoxetine
2-carbomethoxy-3-(4'-(2-iodoethenyl)phenyl)nortropane
Norepinephrine Plasma Membrane Transport Proteins
Sodium Iodide
Brain Mapping
Fluvoxamine
Macaca fascicularis
Pons
Brain
Brain mapping

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

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. / Goodman, Mark M.; Chen, Ping; Plisson, Christophe; Martarello, Laurent; Galt, James; Votaw, John R.; Kilts, Clinton D.; Malveaux, Gene; Camp, Vernon M.; Shi, Bing; Ely, Timothy D.; Howell, Leonard; McConathy, Jon; Nemeroff, Charles.

In: Journal of Medicinal Chemistry, Vol. 46, No. 6, 13.03.2003, p. 925-935.

Research output: Contribution to journalArticle

Goodman, Mark M. ; Chen, Ping ; Plisson, Christophe ; Martarello, Laurent ; Galt, James ; Votaw, John R. ; Kilts, Clinton D. ; Malveaux, Gene ; Camp, Vernon M. ; Shi, Bing ; Ely, Timothy D. ; Howell, Leonard ; McConathy, Jon ; Nemeroff, Charles. / 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. In: Journal of Medicinal Chemistry. 2003 ; Vol. 46, No. 6. pp. 925-935.
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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.",
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T1 - 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

AU - Goodman, Mark M.

AU - Chen, Ping

AU - Plisson, Christophe

AU - Martarello, Laurent

AU - Galt, James

AU - Votaw, John R.

AU - Kilts, Clinton D.

AU - Malveaux, Gene

AU - Camp, Vernon M.

AU - Shi, Bing

AU - Ely, Timothy D.

AU - Howell, Leonard

AU - McConathy, Jon

AU - Nemeroff, Charles

PY - 2003/3/13

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N2 - 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.

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