Carbon-11 HOMADAM: A novel PET radiotracer for imaging serotonin transporters

Nachwa Jarkas, John R. Votaw, Ronald J. Voll, Larry Williams, Vernon M. Camp, Michael J. Owens, David C. Purselle, J. Douglas Bremner, Clinton D. Kilts, Charles B. Nemeroff, Mark M. Goodman

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Carbon-11-labeled N,N-dimethyl-2-(2′-amino-4′- hydroxymethylphenylthio)benzylamine (HOMADAM) was synthesized as a new serotonin transporter (SERT) imaging agent. Methods: Carbon-11 was introduced into HOMADAM by preparation of N-methyl-2-(2′-amino-4′- hydroxymethylphenylthio)benzylamine followed by alkylation with carbon-11 iodomethane. Binding affinities of HOMADAM and the radiolabeling substrate, N-methyl-2-(2′-amino-4′-hydroxymethylphenylthio)benzylamine, were determined in cDNA transfected cells expressing human SERT, dopamine transporters (DAT) and norepinephrine transporters NET using [ 3H]citalopram, [125I]RTI-55 and [3H]nisoxetine, respectively. MicroPET brain imaging was performed in monkeys. Arterial plasma metabolites of HOMADAM were analyzed in a rhesus monkey by high-performance liquid chromatography (HPLC). Results: HOMADAM displayed high affinity for the SERT (Ki=0.6 nM). N-methyl-2-(2′-amino-4′- hydroxymethylphenylthio)benzylamine displayed moderate affinity for the SERT (Ki=15.11 nM). The affinities of HOMADAM for the DAT and NET were 2000- and 253-fold lower, respectively, than for the SERT. [11C] HOMADAM was prepared from [11C]iodomethane in approximately 25% radiochemical yield (decay-corrected to end of bombardment). MicroPET brain imaging studies in monkeys demonstrated that [11C]HOMADAM uptake was selectively localized in the midbrain, thalamus, pons, caudate, putamen and medulla. The midbrain-to-cerebellum, pons-to-cerebellum, thalamus-to-cerebellum and putamen-to-cerebellum ratios at 85 min were 4.2, 2.8, 2.3 and 2.0, respectively. HOMADAM binding achieved quasi-equilibrium at 45 min. Radioactivity in the SERT-rich regions of monkey brain was displaceable with R,S-citalopram. Radioactivity in the DAT-rich regions of monkey brain was not displaceable with the DAT ligand RTI-113. Radioactivity in the SERT-rich regions of monkey brain was displaceable with the R,S-reboxetine, a NET ligand with a high nanomolar affinity for SERT. Arterial plasma metabolites of HOMADAM were analyzed in a rhesus monkey by HPLC and displayed a single peak that corresponded to unmetabolized HOMADAM. Conclusion: HOMADAM is an excellent candidate for PET primate imaging of brain SERTs.

Original languageEnglish (US)
Pages (from-to)211-224
Number of pages14
JournalNuclear Medicine and Biology
Volume32
Issue number3
DOIs
StatePublished - Apr 2005
Externally publishedYes

Keywords

  • Carbon-11
  • HOMADAM
  • MicroPET
  • N, N-dimethylbenzylamine
  • Serotonin transporter

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging

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  • Cite this

    Jarkas, N., Votaw, J. R., Voll, R. J., Williams, L., Camp, V. M., Owens, M. J., Purselle, D. C., Bremner, J. D., Kilts, C. D., Nemeroff, C. B., & Goodman, M. M. (2005). Carbon-11 HOMADAM: A novel PET radiotracer for imaging serotonin transporters. Nuclear Medicine and Biology, 32(3), 211-224. https://doi.org/10.1016/j.nucmedbio.2004.11.007