Department of Psychiatry, Columbia University, New York, NY, USA.
Biochem Pharmacol. 2012 Jan 15;83(2):193-8. doi: 10.1016/j.bcp.2011.09.008. Epub 2011 Sep 16.
Positron Emission Tomography (PET) has been used for more than three decades to image and quantify dopamine D2 receptors (D2R) in vivo with antagonist radioligands but in the recent years agonist radioligands have also been employed. In vitro competition studies have demonstrated that agonists bind to both a high and a low-affinity state of the D2Rs, of which the high affinity state reflects receptors that are coupled to G-proteins and the low-affinity state reflects receptors uncoupled from G-proteins. In contrast, antagonists bind with uniform affinity to the total pool of receptors. Results of these studies led to the proposal that D2Rs exist in high and low-affinity states for agonists in vivo and sparked the development and use of agonist radioligands for PET imaging with the primary purpose of measuring the proportion of receptors in the high-affinity (activating) state. Although several lines of research support the presence of high and low-affinity states of D2Rs and their detection by in vivo imaging paradigms, a growing body of controversial data has now called this into question. These include both in vivo and ex vivo studies of anesthesia effects, rodent models with increased proportions of high-affinity state D2Rs as well as the molecular evidence for stable receptor-G-protein complexes. In this commentary we review these data and discuss the evidence for the in vivo existence of D2Rs configured in high and low-affinity states and whether or not the high-affinity state of the D2R can, in fact, be imaged in vivo with agonist radioligands.
正电子发射断层扫描（PET）已经使用了三十多年，通过使用拮抗剂放射性配体来对体内的多巴胺 D2 受体（D2R）进行成像和定量，但近年来也使用了激动剂放射性配体。体外竞争研究表明，激动剂与 D2R 的高亲和力和低亲和力两种状态结合，其中高亲和力状态反映与 G 蛋白偶联的受体，而低亲和力状态反映与 G 蛋白解偶联的受体。相比之下，拮抗剂以均匀的亲和力与总受体池结合。这些研究的结果导致了 D2R 在体内对激动剂存在高亲和力和低亲和力状态的假设，并激发了激动剂放射性配体的开发和使用，主要目的是测量高亲和力（激活）状态下的受体比例。尽管有几条研究线支持 D2R 的高亲和力和低亲和力状态的存在及其通过体内成像范式的检测，但现在越来越多的有争议的数据对此提出了质疑。这些包括麻醉效应的体内和体外研究、高亲和力状态 D2R 比例增加的啮齿动物模型以及稳定的受体-G 蛋白复合物的分子证据。在这篇评论中，我们回顾了这些数据，并讨论了 D2R 以高亲和力和低亲和力状态存在于体内的证据，以及激动剂放射性配体实际上是否可以在体内对 D2R 的高亲和力状态进行成像。
