Pharmacophore Models and Development of Spirocyclic Ligands for σ1 Receptors

The existing pharmacophore models for 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 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 1 affinity. However, introduction of an additional aryl moiety (12, 17) resulted in very potent 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 1 receptor protein. The promising 1 affinity and selectivity of the spirocyclic piperidine 3 led to the fluorinated PET-tracers [18F]18 and [18F]19 with excellent 1 receptor affinity, receptor selectivity, pharmacokinetic and neuroimaging properties.