title: Atypical in vitro and in vivo binding of [3H]S-14506 to brain 5-HT1A receptors.
abstract: The tritiated derivative of the potent 5-HT1A receptor agonist S-14506 ¿1[2-(4-fluorobenzoylamino)ethyl]-4-(7-methoxynaphtyl)pipera zine¿ 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 vitro studies showed that the pharmacological profile and the distribution of [3H]S-14506 specific binding sites (Kd = 0.15 nM) in different brain regions matched perfectly those of the prototypical 5-HT1A receptor ligand [3H]8-OH-DPAT. However, in the three regions examined (hippocampus, septum, cerebral cortex), the density of [3H]S-14506 specific binding sites was significantly higher (+66-90%) than that found with [3H]8-OH-DPAT. Whereas the specific binding of [3H]8-OH-DPAT was markedly reduced by GTP and Gpp(NH)p and increased by Mn2+, that of [3H]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 [3H]S-14506 than that of [3H]8-OH-DPAT. Measurement of in vivo accumulation of tritium one hour after i.v. injection of [3H]S-14506 to mice revealed marked regional differences, with about 2.5 times more radioactivity in the hippocampus than in the cerebellum. Pretreatment with 5-HT1A receptor ligands prevented tritium accumulation in the hippocampus but not in the cerebellum. Autoradiograms from brain sections of injected mice confirmed the specific in vivo labeling of 5-HT1A receptors by [3H]S-14506, therefore suggesting further developments with derivatives of this molecule for positron emission tomography in vivo in man.
authors.affiliation: INSERM U. 288, Neuropsychopharmacologie moléculaire, cellulaire et fonctionnelle, Faculté de Médecine Pitié-Salpêtrière, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Lima
authors.forename: A M
authors.initials: AM
authors.lastname: Laporte
authors.forename: C
authors.initials: C
authors.lastname: Gaymard
authors.forename: M
authors.initials: M
authors.lastname: Spedding
authors.forename: E
authors.initials: E
authors.lastname: Mocaër
authors.forename: M
authors.initials: M
authors.lastname: Hamon
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000493:pharmacokinetics; D000818:Animals; D001345:Autoradiography; D001549:Benzamides / Q000493:pharmacokinetics*; D001921:Brain / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005033:Ethylmaleimide / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D008566:Membranes / Q000378:metabolism; D051379:Mice; D010879:Piperazines / Q000493:pharmacokinetics*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000493:pharmacokinetics*
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D008024:Ligands; D010879:Piperazines; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; C092824:1-((4-fluorobenzoylamino)ethyl)-4-(7-methoxy-1-naphthyl)piperazine hydrochloride; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D005033:Ethylmaleimide