Presynaptic selectivity of a ligand for serotonin 1A receptors revealed by in vivo PET assays of rat brain.
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),...
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2012
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oai:doaj.org-article:69d91aaed4ba43c4bbce2afdcffb70e62021-11-18T07:09:26ZPresynaptic selectivity of a ligand for serotonin 1A receptors revealed by in vivo PET assays of rat brain.1932-620310.1371/journal.pone.0042589https://doaj.org/article/69d91aaed4ba43c4bbce2afdcffb70e62012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22880045/?tool=EBIhttps://doaj.org/toc/1932-6203A 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.Takeaki SaijoJun MaedaTakashi OkauchiJun-ichi MaedaYasunori MorioYasuhiro KuwaharaMasayuki SuzukiNobuharu GotoToshimitsu FukumuraTetsuya SuharaMakoto HiguchiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 8, p e42589 (2012) |
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Medicine R Science Q Takeaki Saijo Jun Maeda Takashi Okauchi Jun-ichi Maeda Yasunori Morio Yasuhiro Kuwahara Masayuki Suzuki Nobuharu Goto Toshimitsu Fukumura Tetsuya Suhara Makoto Higuchi Presynaptic selectivity of a ligand for serotonin 1A receptors revealed by in vivo PET assays of rat brain. |
| description |
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. |
| format |
article |
| author |
Takeaki Saijo Jun Maeda Takashi Okauchi Jun-ichi Maeda Yasunori Morio Yasuhiro Kuwahara Masayuki Suzuki Nobuharu Goto Toshimitsu Fukumura Tetsuya Suhara Makoto Higuchi |
| author_facet |
Takeaki Saijo Jun Maeda Takashi Okauchi Jun-ichi Maeda Yasunori Morio Yasuhiro Kuwahara Masayuki Suzuki Nobuharu Goto Toshimitsu Fukumura Tetsuya Suhara Makoto Higuchi |
| author_sort |
Takeaki Saijo |
| title |
Presynaptic selectivity of a ligand for serotonin 1A receptors revealed by in vivo PET assays of rat brain. |
| title_short |
Presynaptic selectivity of a ligand for serotonin 1A receptors revealed by in vivo PET assays of rat brain. |
| title_full |
Presynaptic selectivity of a ligand for serotonin 1A receptors revealed by in vivo PET assays of rat brain. |
| title_fullStr |
Presynaptic selectivity of a ligand for serotonin 1A receptors revealed by in vivo PET assays of rat brain. |
| title_full_unstemmed |
Presynaptic selectivity of a ligand for serotonin 1A receptors revealed by in vivo PET assays of rat brain. |
| title_sort |
presynaptic selectivity of a ligand for serotonin 1a receptors revealed by in vivo pet assays of rat brain. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/69d91aaed4ba43c4bbce2afdcffb70e6 |
| work_keys_str_mv |
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| _version_ |
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