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[摘要]：The existing pharmacophore models for sigma(1) receptor ligands are summarized. A common feature of these models is a basic amino group surrounded by different hydrophobic structural elements. The development of novel spirocyclic sigma(1) receptor ligands (e. g. 3, 4) is based on these models. Enlargement of the distance between the basic amino group and the "Primary Hydrophobic Region" by attachment of the amino group at the cyclohexane ring (9, 10) did not lead to increased sigma(1) affinity. However, introduction of an additional aryl moiety (12, 17) resulted in very potent sigma(1) receptor ligands. The high affinity of these compounds is explained by interaction of the additional aryl moiety with a previously unrecognized hydrophobic pocket of the sigma(1) receptor protein. The promising sigma(1) affinity and selectivity of the spirocyclic piperidine 3 led to the fluorinated PET-tracers [(18)F]18 and [(18)F]19 with excellent sigma(1) receptor affinity, receptor selectivity, pharmacokinetic and neuroimaging properties. |
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