Yale PET Center, Yale University, New Haven, Connecticut 06510, USA.
J Nucl Med. 2013 Sep;54(9):1668-74. doi: 10.2967/jnumed.112.118877. Epub 2013 Aug 5.
(11)C-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.
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 (11)C-LY2795050 and (11)C-carfentanil with coinjections of various doses of unlabeled LY2795050. Kinetic modeling was applied to calculate regional binding potential (BP(ND)), and 1- and 2-site binding curves were fitted to these data to measure (11)C-LY2795050 binding selectivity.
The LY2795050 ED50 at MOR was 119 μg/kg based on a 1-site model for (11)C-carfentanil. The 1-site binding model was also deemed sufficient to describe the specific binding of (11)C-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.
The in vivo selectivity of (11)C-LY2795050 for KOR over MOR is 7.6. (11)C-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 (11)C-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. (11)C-LY2795050 is sufficiently selective for KOR over MOR in vivo to be considered an appropriate probe for studying the KOR with PET.
本研究旨在确定新型 κ 阿片受体（KOR）拮抗剂示踪剂（11）C-LY2795050 在猴体内的选择性。
为了估算 LY2795050 在 MOR 和 KOR 上的 ED50 值（使目标受体占据 50%的化合物[或药物]剂量），在 3 只恒河猴中进行了 2 系列阻断实验，使用（11）C-LY2795050 和（11）C-卡芬太尼，同时注入不同剂量的未标记 LY2795050。应用动力学模型计算区域结合潜能（BP（ND）），并对这些数据进行 1 位和 2 位结合曲线拟合，以测量（11）C-LY2795050 的结合选择性。
基于（11）C-卡芬太尼的 1 位模型，LY2795050 在 MOR 的 ED50 为 119μg/kg。1 位结合模型也足以描述（11）C-LY2795050 在 KOR 上的特异性结合。从 1 位模型估算的 KOR 的 ED50 为 15.6μg/kg。因此，MOR：KOR 的 ED50 比值为 7.6。
（11）C-LY2795050 在体内对 KOR 的选择性优于 MOR，比值为 7.6。与体外相比，（11）C-LY2795050 在体内对 KOR 的选择性高 4.7 倍。然而，根据我们在体内的发现，在基线条件下，（11）C-LY2795050 的 PET 观察到的特异性结合的 88%将归因于该示踪剂在 KOR 部位的结合，该部位 KOR 和 MOR 的存在率相似。（11）C-LY2795050 在体内对 MOR 具有足够的 KOR 选择性，可被视为研究 KOR 的 PET 合适探针。
