ATYPICAL IN-VITRO AND IN-VIVO BINDING OF [H-3]S-14506 TO BRAIN 5-HT1ARECEPTORS

The tritiated derivative of the potent 5-HT1A receptor agonist S-14506 enzoylamino)ethyl]-4-(7-methoxynaphtyl)piperazine} was tested for its capacity to selectively label the serotonin 5-HT1A receptors both in vitro in the rat and the mouse brain, and in vivo in the mouse. In vit ro studies showed that the pharmacological profile and the distributio n of [H-3]S-14506 specific binding sites (Kd = 0.15 nM) in different b rain regions matched perfectly those of the prototypical 5-HT1A recept or ligand [H-3]8-OH-DPAT. However, in the three regions examined (hipp ocampus, septum, cerebral cortex), the density of [H-3]S-14506 specifi c binding sites was significantly higher (+ 66-90%) than that found wi th [H-3]8-OH-DPAT. Whereas the specific binding of [H-3]8-OH-DPAT was markedly reduced by GTP and Gpp(NH)p and increased by Mn2+, that of [H -3]S-14506 was essentially unaffected by these compounds. In addition, the alkylating agent N-ethylmaleimide was much less potent to inhibit the specific binding of [H-3]S-14506 than that of [H-3]8-OH-DPAT. Mea surement of in vivo accumulation of tritium one hour after i.v. inject ion of [H-3]S-14506 to mice revealed marked regional differences, with about 2.5 times more radioactivity in the hippocampus than in the cer ebellum. Pretreatment with 5-HT1A receptor ligands prevented tritium a ccumulation in the hippocampus but not in the cerebellum. Autoradiogra ms from brain sections of injected mice confirmed the specific in vivo labeling of 5-HT1A receptors by [H-3]S-14506, therefore suggesting fu rther developments with derivatives of this molecule for positron emis sion tomography in vivo in man.