Abstract
N-(2-(4-(2-Methoxyphenyl)-1-piperazinyl)ethyl)- N-(2-pyridyl)cyclohexanecarboxamide trihydrochloride (WAY-100635) is a new, potent and selective 5-HT 1A receptor antagonist. We have evaluated radiolabelled WAY-100635 as a prospective radioligand for positron emission tomography (PET) by studying biodistribution in rat ex vivo. After intravenous injection, [ O-methyl- 3H]WAY-100635 cleared rapidly from plasma but was retained in brain. Specific binding was quantified from kinetic studies, using a reference-tissue compartment model, fitting for binding potential ( k 3/ k 4). The regional variation in binding potential correlated with the known distribution of 5-HT 1A receptors. Saturation studies gave B max values in vivo that were consistent with those reported in vitro. At 60 min after injection, the ratio of radioactivity in 5-HT 1A receptor-rich regions (e.g. septum, entorhinal cortex and hippocampus) to that in cerebellum reached ∼16. Pre-dosing the rats with WAY-100635 (2 mg/kg) reduced this ratio to one, whereas similar pre-dosing with citalopram (5-HT uptake site inhibitor), prazosin ( α 1A- adrenoceptor antagonist) or idazoxan ( α 2-adrenoceptor antagonist) caused little or no reduction. Substantial (77%) blockade of [ 3H]WAY-100635 binding was achieved with the 5-HT 1A receptor agonist, 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT), and the partial agonists, ipsapirone and buspirone. Thus, the properties of WAY-100635 are such that, when labelled with carbon-11, it could provide a radioligand suitable for clinical and pharmacological investigations of central 5-HT 1A receptors in man using PET.
Published Version
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