Structure-Affinity Relationships of Fluorinated Spirocyclic σ₂ Receptor Ligands with an Exocyclic Benzylamino Moiety

To identify a potent and selective σ₂ receptor ligand appropriate for development as a positron emission tomography (PET) tracer, several fluorinated analogues of the spirocyclic lead compounds trans- and cis-6 (N-(2,4-dimethylbenzyl)-3-methoxy-3,4-dihydrospiro[[2]benzopyran-1,1'-cyclohexan]-4'-amine) were designed. In multistep syntheses, a fluorine atom was introduced directly or as a 2-fluoroethoxy moiety on the 2-benzopyran scaffold, on the dimethylbenzylamino moiety, or on the central amino moiety. The σ₁ and σ₂ receptor affinity was determined in receptor binding studies with radioligands. With respect to σ₂ affinity and σ₂ /σ₁ selectivity, cis-N-(2,4-dimethylbenzyl)-5-fluoro-3-methoxy-3,4-dihydrospiro[[2]benzopyran-1,1'-cyclohexan]-4'-amine (cis-15 c, K_i (σ₂ )=51 nm) and cis-N-[4-(fluoromethyl)-2-methylbenzyl]-3-methoxy-3,4-dihydrospiro[[2]benzopyran-1,1'-cyclohexan]-4'-amine (cis-28 e, K_i (σ₂ )=57 nm) are the most promising ligands. The combination of both structural elements in one molecule, cis-N-[4-(fluoromethyl)-2-methylbenzyl]-5-fluoro-3-methoxy-3,4-dihydrospiro[[2]benzopyran-1,1'-cyclohexan]-4'-amine (cis-28 c: K_i (σ₂ )=874 nm), resulted in decreased σ₂ and σ₁ affinity. Methylation of secondary amines led to three tertiary methylamines with moderate affinity for both σ receptor subtypes.