Occupancy of Nociceptin/Orphanin FQ Peptide Receptors by the Antagonist LY2940094 in Rats and Healthy Human Subjects.

Therapeutic benefits from nociceptin opioid peptide receptor (NOP) antagonism were proposed for obesity, eating disorders, and depression. LY2940094 ([2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol) is a novel, orally bioavailable, potent, and selective NOP antagonist. We studied NOP receptor occupancy (RO) after single oral LY2940094 doses in rat hypothalamus and human brain by use of liquid chromatography with tandem mass spectrometry (LC-MS/MS) (LSN2810397) and positron emission tomography (PET) ([(11)C]NOP-1A) tracers, respectively. A bolus plus constant infusion tracer protocol with PET was employed in humans at 2.5 and 26.5 hours after administration of the LY2940094 dose. The RO was calculated from the change in regional distributional volume (VT) corrected for nondisplaceable volume using Lasson plots. The RO followed a simple Emax relationship to plasma LY2940094 concentration, reaching near complete occupancy in both species. For rat hypothalamus, the plasma concentration at half-maximum RO (EC50) was 5.8 ng/ml. In humans, LY2940094 was well tolerated and safe over the 4-40 mg dose range, and it peaked in plasma at 2 to 6 hours after a 1- to 2-hour lag, with approximate dose-proportional exposure. After 4-40 mg doses, NOP RO was similar across the prefrontal cortex, occipital cortex, putamen, and thalamus, with EC50 of 2.94 to 3.46 ng/ml, less than 2-fold lower than in rats. Over 4-40 mg doses, LY2940094 mean plasma levels at peak and 24 hours were 7.93-102 and 1.17-14.1 ng/ml, corresponding to the cross-region average NOP RO of 73%-97% and 28%-82%, respectively. The rat EC50 translates well to humans. LY2940094 readily penetrates the human brain, and a once-daily oral dose of 40 mg achieves sustainably high (>80%) NOP RO levels suitable for testing clinical efficacy.