Abstract

The κ-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 the suppression of ethanol consumption in rats. This study investigated brain penetration and KOR target engagement after single oral doses (0.5–25 mg) of LY2456302 in 13 healthy human subjects. Three positron emission tomography scans with the KOR antagonist radiotracer ¹¹C-LY2795050 were conducted at baseline, 2.5 hours postdose, and 24 hours postdose. LY2456302 was well tolerated in all subjects without serious adverse events. Distribution volume was estimated using the multilinear analysis 1 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 IC₅₀. LY2456302 dose dependently blocked the binding of ¹¹C-LY2795050 and nearly saturated the receptors at 10 mg, 2.5 hours postdose. Thus, a dose of 10 mg of LY2456302 appears well suited for further clinical testing. Based on the pharmacokinetic (PK)-RO model, the r_max and IC₅₀ of LY2456302 were estimated as 93% and 0.58 ng/ml to 0.65 ng/ml, respectively. Assuming that r_max is 100%, IC₅₀ was estimated as 0.83 ng/ml.