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

• Published in: Nuclear medicine and biology 2005-04, Vol.32 (3), p.211-224
• Main Authors: Jarkas, Nachwa, Votaw, John R., Voll, Ronald J., Williams, Larry, Camp, Vernon M., Owens, Michael J., Purselle, David C., Bremner, J. Douglas, Kilts, Clinton D., Nemeroff, Charles B., Goodman, Mark M.
• Format: Article
• Language: English
• Subjects: Animals; Benzylamines - chemistry; Benzylamines - pharmacology; Brain - diagnostic imaging; Brain - metabolism; Carbon-11; Cell Line; HOMADAM; Humans; Kidney - diagnostic imaging; Kidney - metabolism; Macaca mulatta; Male; Membrane Glycoproteins - metabolism; Membrane Transport Proteins - metabolism; Metabolic Clearance Rate; MicroPET; N, N-dimethylbenzylamine; Nerve Tissue Proteins - metabolism; Positron-Emission Tomography - methods; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - pharmacokinetics; Serotonin Plasma Membrane Transport Proteins; Serotonin transporter; Tissue Distribution
• ISSN: 0969-8051; 1872-9614
• DOI: 10.1016/j.nucmedbio.2004.11.007

Carbon-11-labeled N, N-dimethyl-2-(2′-amino-4′-hydroxymethylphenylthio)benzylamine (HOMADAM) was synthesized as a new serotonin transporter (SERT) imaging agent. 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). HOMADAM displayed high affinity for the SERT ( K i=0.6 nM). N-methyl-2-(2′-amino-4′-hydroxymethylphenylthio)benzylamine displayed moderate affinity for the SERT ( K i=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. HOMADAM is an excellent candidate for PET primate imaging of brain SERTs.