Presynaptic selectivity of a ligand for serotonin 1A receptors revealed by in vivo PET assays of rat brain

• Published in: PloS one Vol. 7; no. 8; p. e42589
• Main Authors: Saijo, Takeaki, Maeda, Jun, Okauchi, Takashi, Maeda, Jun-ichi, Morio, Yasunori, Kuwahara, Yasuhiro, Suzuki, Masayuki, Goto, Nobuharu, Fukumura, Toshimitsu, Suhara, Tetsuya, Higuchi, Makoto
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07.08.2012; Public Library of Science (PLoS)
• Subjects: Administration, Oral; Animals; Antidepressants; Autoradiography; Binding sites; Biology; Brain; Brain - drug effects; Brain - metabolism; Dose-Response Relationship, Drug; Guanosine; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; Health aspects; In vivo methods and tests; Isopropyl alcohol; Ligands; Male; Medical imaging; Medicine; Molecular interactions; Neuroimaging; Oxadiazoles - blood; Oxadiazoles - metabolism; Pharmacodynamics; Pharmacokinetics; Pharmacology; Phenols (Class of compounds); Pindolol; Pindolol - blood; Pindolol - metabolism; Piperazines - administration & dosage; Piperazines - blood; Piperazines - pharmacology; Piperidines - blood; Piperidines - metabolism; Positron emission; Positron emission tomography; Positron-Emission Tomography - methods; Psychotropic drugs; Pyridines - administration & dosage; Pyridines - blood; Pyridines - pharmacology; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1A - metabolism; Receptors; Resveratrol; Rodents; Selectivity; Serotonin; Serotonin S1 receptors; Serotonin transporter; Synapses - metabolism; Time Factors; Tomography; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0042589

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.