GHB (gamma-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(3)H- and(11)C-labeled HOCPCA as radioligands for selectively probing GHB high-affinity binding sites and their application in drug discovery. As such, [H-3]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 vitroas well asex vivoautoradiography. Moreover, the successful synthesis of [C-11]HOCPCA is a starting point for further ligand development for futurein vivoinvestigations of GHB high-affinity binding sites.