Structure–Affinity Relationships of Fluorinated Spirocyclic σ 2 Receptor Ligands with an Exocyclic Benzylamino Moiety

To identify a potent and selective σ 2 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 σ 1 and σ 2 receptor affinity was determined in receptor binding studies with radioligands. With respect to σ 2 affinity and σ 2 /σ 1 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 (σ 2 )=51 n m ) and cis ‐ N ‐[4‐(fluoromethyl)‐2‐methylbenzyl]‐3‐methoxy‐3,4‐dihydrospiro[[2]benzopyran‐1,1′‐cyclohexan]‐4′‐amine ( cis ‐ 28 e , K i (σ 2 )=57 n m ) 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 (σ 2 )=874 n m ), resulted in decreased σ 2 and σ 1 affinity. Methylation of secondary amines led to three tertiary methylamines with moderate affinity for both σ receptor subtypes.