EVALUATION OF [O-METHYL-H-3]WAY-100635 AS AN IN-VIVO RADIOLIGAND FOR 5-HT1A RECEPTORS IN RAT-BRAIN

razinyl)ethyl)-N-(2-pyridyl)cyclohexanecarboxamide trihydrochloride (W AY-100635) is a new, potent and selective 5-HT1A receptor antagonist. We have evaluated radiolabelled WAY-100635 as a prospective radioligan d for positron emission tomography (PET) by studying biodistribution i n rat ex vivo. After intravenous injection, [O-methyl-H-3]WAY-100635 c leared rapidly from plasma but was retained in brain. Specific binding was quantified from kinetic studies, using a reference-tissue compart ment model, fitting for binding potential (k(3)/k(4)). The regional va riation in binding potential correlated with the known distribution of 5-HT1A receptors. Saturation studies gave B-max values in vivo that w ere consistent with those reported in vitro. At 60 min after injection , the ratio of radioactivity in 5-HT1A receptor-rich regions (e.g. sep tum, entorhinal cortex and hippocampus) to that in cerebellum reached similar to 16. Pre-dosing the rats with WAY-100635 (2 mg/kg) reduced t his ratio to one, whereas similar pre-dosing with citalopram (5-HT upt ake site inhibitor), prazosin (alpha(1A)-adrenoceptor antagonist) or i dazoxan (alpha(2)-adrenoceptor antagonist) caused little or no reducti on. Substantial (77%) blockade of [3H]WAY-100635 binding was achieved with the 5-HT1A receptor agonist, 8-hydroxy 2-(di-n-propylamino)tetral in (8-OH-DPAT), and the partial agonists, ipsapirone and buspirone. Th us, the properties of WAY-100635 are such that, when labelled with car bon-11, it could provide a radioligand suitable for clinical and pharm acological investigations of central 5-HT1A receptors in man using PET .