PT  - JOURNAL ARTICLE
AU  - Mika Naganawa
AU  - Gemma L. Dickinson
AU  - Ming-Qiang Zheng
AU  - Shannan Henry
AU  - Francois Vandenhende
AU  - Jennifer Witcher
AU  - Robert Bell
AU  - Nabeel Nabulsi
AU  - Shu-Fei Lin
AU  - Jim Ropchan
AU  - Alexander Neumeister
AU  - Mohini Ranganathan
AU  - Johannes Tauscher
AU  - Yiyun Huang
AU  - Richard E. Carson
TI  - Receptor Occupancy of the κ-Opioid Antagonist LY2456302 Measured with Positron Emission Tomography and the Novel Radiotracer <sup>11</sup>C-LY2795050
AID  - 10.1124/jpet.115.229278
DP  - 2016 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 260--266
VI  - 356
IP  - 2
4099  - http://jpet.aspetjournals.org/content/356/2/260.short
4100  - http://jpet.aspetjournals.org/content/356/2/260.full
SO  - J Pharmacol Exp Ther2016 Feb 01; 356
AB  - 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 (rmax) 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 rmax and IC50 of LY2456302 were estimated as 93% and 0.58 ng/ml to 0.65 ng/ml, respectively. Assuming that rmax is 100%, IC50 was estimated as 0.83 ng/ml.