title: In vitro and ex vivo autoradiography of the NK-1 antagonist [³H]-LY686017 in Guinea pig brain.
abstract: 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.
authors.affiliation: Neuroscience and Endocrine Discovery Research, Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Gackenheimer
authors.forename: Donald R
authors.initials: DR
authors.lastname: Gehlert
mesh_terms: D000818:Animals; D001345:Autoradiography / Q000379:methods*; D001665:Binding Sites; D001921:Brain / Q000033:anatomy & histology / Q000000981:diagnostic imaging* / Q000378:metabolism; D006168:Guinea Pigs; D015394:Molecular Structure; D064729:Neurokinin-1 Receptor Antagonists; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D011877:Radionuclide Imaging; D014230:Triazoles / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*
chemical_list: C527551:LY686017; D064729:Neurokinin-1 Receptor Antagonists; D011725:Pyridines; D014230:Triazoles