Receptor Occupancy of the κ-Opioid Antagonist LY2456302 Measured with Positron Emission Tomography and the Novel Radiotracer 11C-LY2795050

The kappa opioid receptor (KOR) is thought to play an important therapeutic role in a wide range of neuropsychiatric and substance abuse disorders, including alcohol dependence. LY2456302 is a recently-developed KOR antagonist with high affinity and selectivity, and showed efficacy in suppression of ethanol consumption in rats. This study investigated brain penetration and KOR target engagement after single oral doses (from 0.5 mg up to 25 mg) of LY2456302 in 13 healthy human subjects. Three positron emission tomography (PET) scans with the KOR antagonist radiotracer 11C-LY2795050 were conducted at baseline, 2.5 h post-dose, and 24 h post-dose. LY2456302 was well tolerated in all subjects without serious adverse events. Distribution volume was estimated using the multilinear analysis 1 (MA1) method for each scan. Receptor occupancy (RO) was derived from a graphical occupancy plot and related to LY2456302 plasma concentration to determine maximum occupancy ( r max) and IC 50. LY2456302 dose-dependently blocked the binding of 11C-LY2795050, and nearly saturated the receptors at 10 mg, 2.5 h postdose. Thus, a dose of 10 mg LY2456302 appears very well suited for further clinical testing. Based on the PK/RO model, the r max and IC 50 of LY2456302 were estimated as 93% and 0.58 to 0.65 ng/mL, respectively. Assuming that r max is 100%, IC 50 was estimated as 0.83 ng/mL.