In vitro and ex vivo autoradiography of the NK-1 antagonist [³H]-LY686017 in Guinea pig brain.

NK-1 receptor antagonists have shown potential for the clinical treatment of chemotherapy-induced nausea and vomiting, depression and alcoholism. In a recent study, we disclosed the potential for the NK-1 antagonist, LY686017, to treat alcoholism in a clinical population. To assess whether this compound could be utilized as a platform for a brain imaging ligand, we evaluated the binding of [³H]-LY686017 to sections of guinea pig in vitro. In these studies, [³H]-LY686017 bound with a distribution and pharmacology consistent with the NK-1 receptor. Using sections through the region of the caudate nucleus, we obtained a K(d) of 0.34 nM and a B(max) of 31.37 fmoles/mg tissue. Based on its high potency and low nonspecific binding in vitro, we initiated studies to evaluate the radioligand as a tool to measure in vivo receptor occupancy. In initial studies, 25 microCi of [³H]-LY686017 was administered via an indwelling jugular catheter and accumulation of radioactivity in the caudate (NK-1 containing tissue) and cerebellum (low NK-1 expression) were assessed. The ratios of caudate to cerebellum radioactivity were optimal 2 h after radioligand administration so this time point was used for subsequent studies. To assess the pharmacological specificity of the radioactivity accumulation, we administered various doses of Aprepitant, a potent NK-1 antagonists 1h prior to intravenous administration of [³H]-LY686017. Aprepitant produced a dose-dependent reduction in radioactivity in the caudate with an approximate 70% reduction at 10 mg/kg. To image NK-1 receptors, 100 microCi of [³H]-LY686017 was administered and the brains sectioned for autoradiography. In these studies, a characteristic distribution on NK-1 receptors was observed. Based on these results, LY686017 should serve as a suitable chemical platform for future imaging ligand development.