title: Synthesis and characterization of EADAM: a selective radioligand for mapping the brain serotonin transporters by positron emission tomography.
abstract: [11C]N,N-Dimethyl-2-(2'-amino-4'-ethylphenylthio)benzylamine ([11C]EADAM) was synthesized in the development of a serotonin transporter (SERT) imaging ligand for positron emission tomography (PET). The methods of ligand synthesis, results of in vitro characterization, 11C labeling and in vivo micro-PET imaging studies of [11C]EADAM in cynomolgus monkey brain are described. 11C was introduced into N,N-dimethyl-2-(2'-amino-4'-ethylphenylthio)benzylamine (5) by alkylation of N-methyl-2-(2'-amino-4'-ethylphenylthio)benzylamine (10) in 32% radiochemical yield (end of bombardment [EOB], decay-corrected from [11C]methyl iodide). Competition binding assays in cells stably expressing the transfected human dopamine transporter (DAT), SERT and norepinephrine transporter (NET) labeled with [3H]WIN 35428 or [(125)I]RTI-55, [3H]citalopram and [3H]nisoxetine, respectively, indicated the following order of SERT affinity: ADAM>EADAM>>fluvoxamine. The affinity of EADAM for DAT and NET was 500- and >1000-fold lower, respectively, than for SERT. Micro-PET brain imaging studies in a cynomolgus monkey demonstrated high [11C]EADAM uptake in the striatum, thalamus and brainstem. [11C]EADAM uptake in these brain regions peaked in less than 60 min following administration of [11C]EADAM. The tissue-to-cerebellum ratios of the striatum, thalamus and brainstem were 1.67, 1.71 and 1.63, respectively, at 120 min postinjection of [11C]EADAM. Analysis of monkey arterial plasma samples using high-pressure liquid chromatography determined there was no detectable formation of lipophilic radiolabeled metabolites capable of entering the brain. In a displacement experiment with citalopram in a cynomolgus monkey, radioactivity in the striatum, thalamus and brainstem was displaced 20-60 min after administration of citalopram. In a blocking experiment with citalopram in a cynomolgus monkey, radioactivity in the striatum, thalamus and brainstem was significantly reduced. These results support the candidacy of [11C]EADAM as a radioligand for visualizing brain SERT using PET.
authors.affiliation: Department of Radiology, Division of Radiological Sciences, Emory University, Atlanta, GA 30322, USA.
authors.forename: Nachwa
authors.initials: N
authors.lastname: Jarkas
authors.forename: Jonathan
authors.initials: J
authors.lastname: McConathy
authors.forename: John R
authors.initials: JR
authors.lastname: Votaw
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Voll
authors.forename: Eugene
authors.initials: E
authors.lastname: Malveaux
authors.forename: Vernon M
authors.initials: VM
authors.lastname: Camp
authors.forename: Larry
authors.initials: L
authors.lastname: Williams
authors.forename: Robin R
authors.initials: RR
authors.lastname: Goodman
authors.forename: Clinton D
authors.initials: CD
authors.lastname: Kilts
authors.forename: Mark M
authors.initials: MM
authors.lastname: Goodman
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000493:pharmacokinetics*; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D008252:Macaca fascicularis; 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
chemical_list: D001596:Benzylamines; D002250:Carbon Radioisotopes; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C470437:N,N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine; D009419:Nerve Tissue Proteins; D019275:Radiopharmaceuticals; D050486:Serotonin Plasma Membrane Transport Proteins