| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
We synthesized methylvesamicol analogs and investigated the binding characteristics of 2-[4-phenylpiperidino]cyclohexanol (vesamicol) and methylvesamicol analogs, with a methyl group introduced into the 4-phenylpiperidine moiety, to sigma receptors (σ-1, σ-2) and to vesicular acetylcholine transporters (VAChT) in membranes of the rat brain and liver. In competitive inhibition studies, (-)-o-methylvesamicol [(-)-oMeV] (Ki = 6.7 nM), as well as (-)-vesamicol (Ki = 4.4 nM) had a high affinity for VAChT. (+)-p-methylvesamicol [(+)-pMeV] (Ki = 3.0 nM), as well as SA4503 (Ki = 4.4 nM), reported as a σ-1 mapping agent for positron emission tomography (PET), had a high affinity for the σ-1 receptor. The binding affinity of (+)-pMeV for the σ-1 receptor (Ki = 3.0 nM), was about 13 times higher than the sigma-2 (σ-2) receptor (Ki = 40.7 nM). (+)-pMeV (Ki = 199 nM) had a much lower affinity for VAChT than SA4503 (Ki = 50.2 nM) and haloperidol (Ki = 41.4 nM). These results showed that the binding characteristics of (-)-oMeV (13) to VAChT were similar to that of (-)-vesamicol and, that (+)-pMeV (16) bound to the σ-1 receptor with high affinity. In conclusion, (-)-oMeV and (+)-pMeV(16), which had a suitable structure, with a methyl group for labeling with 11C, may become not only a new VAChT ligand and a new type of σ receptor ligand, respectively, but may also become a new target compound of VAChT and the σ-1 receptor radiolig and for positron emission tomography (PET), respectively.
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