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

Mingzhang Gao, Min Wang, Qi-Huang Zheng

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalBioorganic and Medicinal Chemistry Letters
DOIs
StateAccepted/In press - May 10 2016

Fingerprint

Orexin Receptors
Boronic Acids
Solid Phase Extraction
Carboxylic Acids
Methylation
Imaging techniques

Keywords

  • Orexin-2 receptor (OX2R)
  • Positron emission tomography (PET)
  • Sleep disorders
  • [C]MK-1064

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Synthesis of [11C]MK-1064 as a new PET radioligand for imaging of orexin-2 receptor. / Gao, Mingzhang; Wang, Min; Zheng, Qi-Huang.

In: Bioorganic and Medicinal Chemistry Letters, 10.05.2016.

Research output: Contribution to journalArticle

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abstract = "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.",
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