[H-3]Alnespirone: A novel specific radioligand of 5-HT1A receptors in the rat brain

Determination of the optimal assay conditions for the specific binding of a tritiated derivative of the novel potential anxiolytic drug alnespirone (S-20499, (+)-3-[N-(5-methoxy-chroman-3-yl)-N-propylamino]butyl-8-azaspiro(4,5)-decane-7,9-dione) allowed the demonstration that this radioligand bound with a high affinity (K-d = 0.36 nM) to a homogeneous class of sites in rat hippocampal membranes. The pharmacological properties of [H-3]alnespirone specific binding sites matched exactly (r = 0.95) those of 5-HT1A receptors identified with [H-3]8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) as radioligand. Furthermore, membrane binding experiments and autoradiographic labeling of tissue sections showed that the regional distribution of [H-3]alnespirone specific binding sites in the rat brain and spinal cord superimposed over that of 5-HT1A receptors specifically labeled by [H-3]8-OH-DPAT. However, the differential sensitivity of [H-3]alnespirone and [H-3]8-OH-DPAT specific binding to various physicochemical effecters (temperature, pH, Mn2+, N-ethyl-maleimide) supports the idea that these two agonist radioligands did not recognize 5-HT1A receptors exactly in the same way. These differences probably account for the reported inability of alnespirone, in contrast to 8-OH-DPAT, to induce some 5-HT1A receptor-mediated behavioural effects in rats. (C) 1997 Elsevier Science B.V.