title: Synthesis and C-11 labeling of three potent norepinephrine transporter selective ligands ((R)-nisoxetine, lortalamine, and oxaprotiline) for comparative PET studies in baboons.
abstract: Three potent antidepressants, (R)-nisoxetine, lortalamine, and oxaprotiline, with high affinity and high selectivity for the norepinephrine transporter (NET) were synthesized and radiolabeled with C-11 via [11C]methylation. The reference compounds and their corresponding normethyl precursors were synthesized via multi-step synthetic approaches. The radiochemical syntheses were performed by simple alkylation of the corresponding normethyl precursors with no-carrier-added [11C]CH3I in DMF. After HPLC purification, (R)-[N-11CH3]nisoxetine, [11C]lortalamine, and [11C]oxaprotiline were obtained in 63-97% radiochemical yields, whereas (R)-[O-11CH3]nisoxetine was obtained in 23-29% radiochemical yields due to substantial formation of the undesired N-[11C]methylated byproduct (64-70%). These C-11 labeled tracers allowed us to carry out comparative studies of NET in baboons with positron emission tomography (PET) and evaluate their potential as PET tracers for imaging brain NET.
authors.affiliation: Chemistry Department, Brookhaven National Laboratory, Bldg 555, Upton, NY 11973, USA.
authors.forename: Kuo-Shyan
authors.initials: KS
authors.lastname: Lin
authors.forename: Yu-Shin
authors.initials: YS
authors.lastname: Ding
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000737:chemistry; D005473:Fluoxetine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008376:Maprotiline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010215:Papio; D049268:Positron-Emission Tomography; D013237:Stereoisomerism; D027981:Symporters / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D001578:Benzopyrans; D002250:Carbon Radioisotopes; D008024:Ligands; D050484:Norepinephrine Plasma Membrane Transport Proteins; D027981:Symporters; D005473:Fluoxetine; C011386:nisoxetine; D008376:Maprotiline; C027299:hydroxymaprotilin; C031101:lortalamine