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

AI Article Synopsis

  • Wf-516 is a novel antidepressant that targets serotonin transporters and serotonin 1A receptors, showing rapid therapeutic effects, although its exact mechanism is still unclear.
  • Research compared Wf-516 to pindolol, revealing that Wf-516 binds selectively to presynaptic serotonin 1A receptors, whereas pindolol fully occupies the receptor sites.
  • In vivo PET imaging emerged as a crucial method for demonstrating Wf-516's unique pharmacokinetic properties, which were not evident in traditional in vitro and ex vivo studies.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3413639PMC
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0042589PLOS

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