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

• Published in: Bioorganic & medicinal chemistry letters Vol. 26; no. 15; pp. 3694 - 3699
• Main Authors: Gao, Mingzhang, Wang, Min, Zheng, Qi-Huang
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.08.2016; Elsevier
• Subjects: [11C]MK-1064; Carbon Radioisotopes; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Humans; Life Sciences & Biomedicine; Ligands; Molecular Structure; Orexin Receptors - analysis; Orexin-2 receptor (OX2R); Pharmacology & Pharmacy; Physical Sciences; Positron emission tomography (PET); Positron-Emission Tomography; Radioligand Assay; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - isolation & purification; Science & Technology; Sleep disorders; Sleep disorders; Positron emission tomography (PET); [11C]MK-1064; Orexin-2 receptor (OX2R); TRACERS; RADIOTRACERS; [C-11]MK-1064; RADIOSYNTHESIS; COEFFICIENTS; AGENTS; ANTAGONISTS; DERIVATIVES; HPLC; HIGH-YIELD SYNTHESIS; LIPOPHILICITY; [C]MK-1064
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.05.083

[Display omitted] The reference standard MK-1064 {5″-chloro-N-((5,6-dimethoxypyridin-2-yl)methyl)-[2,2′:5′,3″-terpyridine]-3′-carboxamide} was synthesized from methyl 2-chloro-5-iodonicotinate and 5-(chloropyridin-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 [11C]MK-1064 {5″-chloro-N-((5-[11C]methoxy-6-methoxypyridin-2-yl)methyl)-[2,2′:5′,3″-terpyridine]-3′-carboxamide} was prepared by O-[11C]methylation of its corresponding precursor desmethyl-MK-1064 with [11C]CH3OTf under basic condition and isolated by a simplified solid-phase extraction (SPE) method in 50–60% decay corrected radiochemical yields based on [11C]CO2 at end of bombardment (EOB). The overall synthesis time from EOB was 23min, the radiochemical purity was >99%, and the specific activity at end of synthesis (EOS) was 185–555GBq/μmol.