title: Presynaptic selectivity of a ligand for serotonin 1A receptors revealed by in vivo PET assays of rat brain.
abstract: A novel investigational antidepressant with high affinity for the serotonin transporter and the serotonin 1A (5-HT(1A)) receptor, called Wf-516 (structural formula: (2S)-1-[4-(3,4-dichlorophenyl)piperidin-1-yl]-3-[2-(5-methyl-1,3,4-oxadiazol-2-yl)benzo[b]furan-4-yloxy]propan-2-ol monohydrochloride), has been found to exert a rapid therapeutic effect, although the mechanistic basis for this potential advantage remains undetermined. We comparatively investigated the pharmacokinetics and pharmacodynamics of Wf-516 and pindolol by positron emission tomographic (PET) and autoradiographic assays of rat brains in order to elucidate their molecular interactions with presynaptic and postsynaptic 5-HT(1A) receptors. In contrast to the full receptor occupancy by pindolol in PET measurements, the binding of Wf-516 to 5-HT(1A) receptors displayed limited capacity, with relatively high receptor occupancy being achieved in regions predominantly containing presynaptic receptors. This selectivity was further proven by PET scans of neurotoxicant-treated rats deficient in presynaptic 5-HT(1A) receptors. In addition, [(35)S]guanosine 5'-O-[γ-thio]triphosphate autoradiography indicated a partial agonistic ability of Wf-516 for 5-HT(1A) receptors. This finding has lent support to reports that diverse partial agonists for 5-HT(1A) receptors exert high sensitivity for presynaptic components. Thus, the present PET data suggest a relatively high capacity of presynaptic binding sites for partial agonists. Since our in vitro and ex vivo autoradiographies failed to illustrate these distinct features of Wf-516, in vivo PET imaging is considered to be, thus far, the sole method capable of pharmacokinetically demonstrating the unique actions of Wf-516 and similar new-generation antidepressants.
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Takeaki
authors.initials: T
authors.lastname: Saijo
authors.forename: Jun
authors.initials: J
authors.lastname: Maeda
authors.forename: Takashi
authors.initials: T
authors.lastname: Okauchi
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Maeda
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Morio
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kuwahara
authors.forename: Masayuki
authors.initials: M
authors.lastname: Suzuki
authors.forename: Nobuharu
authors.initials: N
authors.lastname: Goto
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Fukumura
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
authors.forename: Makoto
authors.initials: M
authors.lastname: Higuchi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008024:Ligands; D008297:Male; D010069:Oxadiazoles / Q000097:blood / Q000378:metabolism; D010869:Pindolol / Q000097:blood / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D010880:Piperidines / Q000097:blood / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods*; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D013997:Time Factors
chemical_list: D008024:Ligands; D010069:Oxadiazoles; D010879:Piperazines; D010880:Piperidines; D011725:Pyridines; C527744:Wf-516; D044282:Receptor, Serotonin, 5-HT1A; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D010869:Pindolol