Carbon-11 HOMADAM: a novel PET radiotracer for imaging serotonin transporters.
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, [(125)I]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.


CONCLUSIONS
HOMADAM is an excellent candidate for PET primate imaging of brain SERTs.
Jarkas
Nachwa
N
Center for Positron Emission Tomography, Emory University, Atlanta, GA 30322, USA.
Votaw
John R
JR
Voll
Ronald J
RJ
Williams
Larry
L
Camp
Vernon M
VM
Owens
Michael J
MJ
Purselle
David C
DC
Bremner
J Douglas
JD
Kilts
Clinton D
CD
Nemeroff
Charles B
CB
Goodman
Mark M
MM
D000818:Animals; D001596:Benzylamines / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D007668:Kidney / Q000000981:diagnostic imaging* / Q000378:metabolism*; D008253:Macaca mulatta; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D050486:Serotonin Plasma Membrane Transport Proteins; D014018:Tissue Distribution
D001596:Benzylamines; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C504057:N,N-dimethyl-2-(2'-amino-4'-hydroxymethylphenylthio)benzylamine; D009419:Nerve Tissue Proteins; D019275:Radiopharmaceuticals; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins