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 σ1 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 σ1 affinity. However, introduction of an additional aryl moiety (12, 17) resulted in very potent σ1 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 σ1 receptor protein. The promising σ1 affinity and selectivity of the spirocyclic piperidine 3 led to the fluorinated PET-tracers [18F]18 and [18F]19 with excellent σ1 receptor affinity, receptor selectivity, pharmacokinetic and neuroimaging properties.