Synthesis of [C-11]MK-1064 as a new PET radioligand for imaging of orexin-2 receptor

摘要

The reference standard MK-1064 {5 ''-chloro-N-((5,6-dimethoxypyridin-2-yl)methyl)-[2,2':5',3 ''-ter-pyridine]- 3'-carboxamide} was synthesized from methyl 2-chloro-5-iodonicotinate and 5-(chloro-pyridin-3-yl)boronic acid in 4 steps with 33% overall chemical yield. The precursor desmethyl-MK-1064 {5 ''-chloro-N-((5-hydroxy-6-methoxypyridin-2-yl) methyl)-[2,2':5',3 ''-terpyridine]-3'-carboxamide} for radiolabeling was synthesized from 2-bromopyridin-3-ol and 5 ''-chloro-[2,2': 5',3 ''-terpyridine]-3'-carboxylic acid in 6 steps with 17% overall chemical yield. The target tracer [C-11]MK-1064 {5 ''-chloro-N-((5-[C-11]methoxy-6-methoxypyridin-2-yl)methyl)-[2,2':5',3 ''-terpyridine]-3'-carboxamide} was prepared by O-[C-11]methylation of its corresponding precursor desmethyl-MK-1064 with [C-11]CH3OTf under basic condition and isolated by a simplified solid-phase extraction (SPE) method in 50-60% decay corrected radiochemical yields based on [C-11]CO2 at end of bombardment (EOB). The overall synthesis time from EOB was 23 min, the radiochemical purity was >99%, and the specific activity at end of synthesis (EOS) was 185-555 GBq/lmol. (C) 2016 Elsevier Ltd. All rights reserved.