TY - JOUR T1 - Determination of the In Vivo Selectivity of a New κ-Opioid Receptor Antagonist PET Tracer <sup>11</sup>C-LY2795050 in the Rhesus Monkey JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 1668 LP - 1674 DO - 10.2967/jnumed.112.118877 VL - 54 IS - 9 AU - Su Jin Kim AU - Ming-Qiang Zheng AU - Nabeel Nabulsi AU - David Labaree AU - Jim Ropchan AU - Soheila Najafzadeh AU - Richard E. Carson AU - Yiyun Huang AU - Evan D. Morris Y1 - 2013/09/01 UR - http://jnm.snmjournals.org/content/54/9/1668.abstract N2 - 11C-LY2795050 is a novel κ-selective antagonist PET tracer. The in vitro binding affinities (Ki) of LY2795050 at the κ-opioid (KOR) and μ-opioid (MOR) receptors are 0.72 and 25.8 nM, respectively. Thus, the in vitro KOR/MOR binding selectivity is about 36:1. Our goal in this study was to determine the in vivo selectivity of this new KOR antagonist tracer in the monkey. Methods: To estimate the ED50 value (dose of a compound [or drug] that gives 50% occupancy of the target receptor) of LY2795050 at the MOR and KOR sites, 2 series of blocking experiments were performed in 3 rhesus monkeys using 11C-LY2795050 and 11C-carfentanil with coinjections of various doses of unlabeled LY2795050. Kinetic modeling was applied to calculate regional binding potential (BPND), and 1- and 2-site binding curves were fitted to these data to measure 11C-LY2795050 binding selectivity. Results: The LY2795050 ED50 at MOR was 119 μg/kg based on a 1-site model for 11C-carfentanil. The 1-site binding model was also deemed sufficient to describe the specific binding of 11C-LY2795050 at KOR. The ED50 at KOR estimated from the 1-site model was 15.6 μg/kg. Thus, the ED50 ratio for MOR:KOR was 7.6. Conclusion: The in vivo selectivity of 11C-LY2795050 for KOR over MOR is 7.6. 11C-LY2795050 has 4.7-fold-lower selectivity at KOR over MOR in vivo as compared with in vitro. Nevertheless, on the basis of our finding in vivo, 88% of the PET-observed specific binding of 11C-LY2795050 under baseline conditions will be due to binding of the tracer at the KOR site in a region with similar prevalence of KOR and MOR. 11C-LY2795050 is sufficiently selective for KOR over MOR in vivo to be considered an appropriate probe for studying the KOR with PET. ER -