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

Carbon-11-labeled N,N-dimethyl-2-(2'-amino-4'-hydroxymethylphenylthio)benzylamitie (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 [H-3]citalopram, [I-125]RTI-55 and [H-3]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 (K-i=0.6 nM). N-methyl-2-(2-amino-4-hydroxymethylphenylthio)benzyiamine 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. [C-11]HOMADAM was prepared from [C-11]iodomethane in approximately 25% radiochemical yield (decay-corrected to end of bombardment). MicroPET brain imaging studies in monkeys demonstrated that [C-11]HOMADAM uptake was selectively localized in the raidbrain, thalamus, pons, caudate, putamen and medulla. The inidbrain-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 rheses 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. (c) 2005 Elsevier Inc. All rights reserved.