Synthesis of 13 C6 -labeled, dual-target inhibitor of cannabinoid-1 receptor (CB1 R) and inducible nitric oxide synthase (iNOS)

Malliga R Iyer; Resat Cinar; Nathan J Coffey; George Kunos

doi:10.1002/jlcr.3639

Synthesis of ¹³ C₆ -labeled, dual-target inhibitor of cannabinoid-1 receptor (CB₁ R) and inducible nitric oxide synthase (iNOS)

J Labelled Comp Radiopharm. 2018 May 23. doi: 10.1002/jlcr.3639. Online ahead of print.

Authors

Malliga R Iyer¹, Resat Cinar¹, Nathan J Coffey¹, George Kunos¹

Affiliation

¹ Laboratory of Physiologic Studies and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland, USA.

PMID: 29790591
DOI: 10.1002/jlcr.3639

Abstract

Cannabinoid-1 receptor (CB₁ R) antagonists/inverse agonists have great potential in the treatment of metabolic disorders like dyslipidemia, type 2 diabetes, and nonalcoholic steatohepatitis. Cannabinoid-1 receptor inverse agonists have also been reported to be effective in mitigating fibrotic disorders in murine models. Inducible nitric oxide synthase is another promising target implicated in fibrotic and inflammatory disorders. We have disclosed MRI-1867 as a potent and selective, peripherally acting dual-target inhibitor of the CB₁ R and inducible nitric oxide synthase (iNOS). Herein, we report the synthesis of [¹³ C₆ ]-MRI-1867 as a racemate from commercially available chlorobenzene-¹³ C₆ as the starting, stable-isotope label reagent. The racemic [¹³ C₆ ]-MRI-1867 was further processed to the stable-isotope-labeled enantiopure compounds using chiral chromatography. Both racemic [¹³ C₆ ]-MRI-1867 and S-¹³ C₆ -MRI-1867 will be used to quantitate unlabeled S-MRI-1867 during clinical drug metabolism and pharmacokinetics studies and will be used as a liquid chromatography-tandem mass spectrometry bioanalytical standard.

Keywords: ADME; CB1R CB2R; DMPK; EC; NASH; PSA; iNOS.