γ-Hydroxybutyric acid (GHB) is a drug and an endogenous substance, which binds to both high- and low-affinity sites in the brain. For studying the molecular mechanisms and the biological role of the GHB high-affinity binding sites, ligands with high and specific affinity are essential. The GHB analogue, 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA), is one such compound. The objective of this study was to investigate the transport of HOCPCA across the blood-brain barrier and to investigate the hypothesis that HOCPCA, like GHB, is a substrate for the monocarboxylate transporters (MCTs). When MCT1, -2, and -4 were recombinantly expressed in Xenopus laevis oocytes, HOCPCA inhibited the uptake of the endogenous MCT substrate, l-[¹⁴C]lactate, and [³H]HOCPCA was shown to act as substrate for MCT1 and -2. MCT1-mediated brain entry of HOCPCA was confirmed in mice by coadministration of an MCT antagonist, which inhibited brain penetration of HOCPCA. Overall, this study provides evidence that MCT1 is an important brain entry site and recommends the use of HOCPCA as an investigative tool.

See article at J Pharmacol Exp Ther 2015, 354:166–174.

• Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics