Synthesis and C-11 labeling of three potent norepinephrine transporter selective ligands ((R)-nisoxetine, lortalamine, and oxaprotiline) for comparative PET studies in baboons.
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.
Lin
Kuo-Shyan
KS
Chemistry Department, Brookhaven National Laboratory, Bldg 555, Upton, NY 11973, USA.
Ding
Yu-Shin
YS
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*
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