GHB (γ‐hydroxybutyrate) is not only an endogenously present small molecule but also a clinically prescribed drug for the symptomatic treatment of narcolepsy. However, GHB's mechanism of action remains to be uncovered. Within the CNS, GHB targets both GABA_B receptors and a pharmacologically distinct population of high‐affinity binding sites with unknown molecular identity. HOCPCA (3‐hydroxycyclopent‐1‐enecarboxylic acid) is a structural analog of GHB selectively targeting GHB high‐affinity binding sites. Here, we discuss the usefulness of ³H‐ and ¹¹C‐labeled HOCPCA as radioligands for selectively probing GHB high‐affinity binding sites and their application in drug discovery. As such, [³H]HOCPCA's exceptional affinity and selectivity makes it an indispensable tool in drug discovery, and its utility has been demonstrated in, for example, homogenate binding studies, in vitro as well as ex vivo autoradiography. Moreover, the successful synthesis of [¹¹C]HOCPCA is a starting point for further ligand development for future in vivo investigations of GHB high‐affinity binding sites.

中文翻译：

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放射性标记的HOCPCA作为药物发现和药理学中非常有用的工具

GHB（γ-羟基丁酸酯）不仅是内源性存在的小分子，还是临床上用于发作性睡病症状治疗的处方药。但是，GHB的作用机制仍有待发现。在中枢神经系统内，GHB既靶向GABA _B受体，又靶向具有未知分子同一性的药理学上不同的高亲和力结合位点。HOCPCA（3-羟基环戊-1-烯羧酸）是GHB的结构类似物，选择性靶向GHB高亲和力结合位点。在这里，我们讨论³ H和¹¹ C标记的HOCPCA作为放射性配体对选择性探测GHB高亲和力结合位点的有用性及其在药物发现中的应用。因此，[ ³H] HOCPCA出色的亲和力和选择性使其成为药物发现中必不可少的工具，并且其效用已在例如匀浆结合研究，体外以及离体放射自显影中得到证明。此外，[ ¹¹ C] HOCPCA的成功合成是进一步配体开发的起点，可用于将来对GHB高亲和力结合位点进行体内研究。