Kappa opioid receptor (KOR) modulation has been pursued in many conceptual frameworks for the treatment of human pain, depression, and anxiety. As such, several imaging tools have been developed to characterize the density of KORs in the human brain and its occupancy by exogenous drug-like compounds. While exploring the pharmacology of KOR tool compounds using positron emission tomography (PET), we observed discrepancies in the apparent competition binding as measured by changes in binding potential (BPND, binding potential with respect to non-displaceable uptake). This prompted us to systematically look at the relationships between baseline BPND maps for three common KOR PET radioligands, the antagonists [11C]LY2795050 and [11C]LY2459989, and the agonist [11C]GR103545. We then measured changes in BPND using kappa antagonists (naloxone, naltrexone, LY2795050, JDTic, nor-BNI), and found BPND was affected similarly between [11C]GR103545 and [11C]LY2459989. Longitudinal PET studies with nor-BNI and JDTic were also examined, and we observed a persistent decrease in [11C]GR103545 BPND up to 25 days after drug administration for both nor-BNI and JDTic. Kappa agonists were also administered, and butorphan and GR89696 (racemic GR103545) impacted binding to comparable levels between the two radiotracers. Of greatest significance, kappa agonists salvinorin A and U-50488 caused dramatic reductions in [11C]GR103545 BPND but did not change [11C]LY2459989 binding. This discrepancy was further examined in dose-response studies with each radiotracer as well as in vitro binding experiments.

中文翻译：

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通过PET成像揭示了Kappa阿片激动剂结合中的差异。

在许多概念性框架中，人们一直在追求κ阿片受体（KOR）调节来治疗人类疼痛，抑郁和焦虑。这样，已经开发了几种成像工具来表征人脑中KOR的密度及其在外源性类药物化合物中的占有率。在使用正电子发射断层扫描（PET）探索KOR工具化合物的药理学时，我们观察到了表观竞争结合方面的差异，该差异通过结合势（BPND，相对于不可置换吸收的结合势）的变化来衡量。这促使我们系统地研究三种常见的KOR PET放射性配体，拮抗剂[11C] LY2795050和[11C] LY2459989以及激动剂[11C] GR103545的基线BPND图之间的关系。然后，我们使用kappa拮抗剂（纳洛酮，纳曲酮，LY2795050，JDTic，也没有BNI），发现BPND在[11C] GR103545和[11C] LY2459989之间也受到类似的影响。还研究了使用nor-BNI和JDTic进行的纵向PET研究，我们观察到在给药后25天，对于nor-BNI和JDTic而言，[11C] GR103545 BPND持续下降。还施用了κ激动剂，但是butorphan和GR89696（外消旋体GR103545）影响到两种放射性示踪剂之间的可比水平的结合。最重要的是，κ激动剂salvinorin A和U-50488引起[11C] GR103545 BPND的显着降低，但并未改变[11C] LY2459989的结合。在每种放射性示踪剂的剂量反应研究以及体外结合实验中，都进一步检查了这种差异。还研究了使用nor-BNI和JDTic进行的纵向PET研究，我们观察到在给药后25天，对于nor-BNI和JDTic而言，[11C] GR103545 BPND持续下降。还施用了κ激动剂，但是butorphan和GR89696（外消旋体GR103545）影响到两种放射性示踪剂之间的可比水平的结合。最重要的是，κ激动剂salvinorin A和U-50488引起[11C] GR103545 BPND的显着降低，但并未改变[11C] LY2459989的结合。在每种放射性示踪剂的剂量反应研究以及体外结合实验中，都进一步检查了这种差异。还研究了使用nor-BNI和JDTic进行的纵向PET研究，我们观察到在给药后25天，对于nor-BNI和JDTic而言，[11C] GR103545 BPND持续下降。还施用了κ激动剂，但是butorphan和GR89696（外消旋体GR103545）影响到两种放射性示踪剂之间的可比水平的结合。最重要的是，κ激动剂salvinorin A和U-50488引起[11C] GR103545 BPND的显着降低，但并未改变[11C] LY2459989的结合。在每种放射性示踪剂的剂量反应研究以及体外结合实验中，都进一步检查了这种差异。Butorphan和GR89696（外消旋GR103545）影响到两种放射性示踪剂之间可比水平的结合。最重要的是，κ激动剂salvinorin A和U-50488引起[11C] GR103545 BPND的显着降低，但并未改变[11C] LY2459989的结合。在每种放射性示踪剂的剂量反应研究以及体外结合实验中，都进一步检查了这种差异。Butorphan和GR89696（外消旋GR103545）影响到两种放射性示踪剂之间可比水平的结合。最重要的是，κ激动剂salvinorin A和U-50488引起[11C] GR103545 BPND的显着降低，但并未改变[11C] LY2459989的结合。在每种放射性示踪剂的剂量反应研究以及体外结合实验中，都进一步检查了这种差异。