Synthesis, pharmacological activity and structure affinity relationships of spirocyclic σ1 receptor ligands with a (2-fluoroethyl) residue in 3-position

In order to develop a fluorinated radiotracer for imaging of σ1 receptors in the central nervous system a series of (2-fluoroethyl) substituted spirocyclic piperidines 3 has been prepared. In the key step of the synthesis 2-bromocinnamaldehyde acetal 5 was added to piperidones 6 with various substituents at the N-atom. Unexpectedly, this reaction led to 2-benzoxepines 8, which were contracted with acid to afford the spirocyclic 2-benzofuranacetaldehydes 9. The best yields were obtained, when the transformations up to the alcohols 10 were performed without isolation of intermediates. Generally the (2-fluoroethyl) derivatives 3 have higher σ1 affinity and σ1/σ2 selectivity than the corresponding (3-fluoropropyl) derivatives 2. The most promising candidate for the development as radiotracer is the (2-fluoroethyl) derivative 3a (WMS-1828, fluspidine, 1′-benzyl-3-(2-fluoroethyl)-3H-spiro[[2]benzofuran-1,4′-piperidine]), which shows subnanomolar σ1 affinity (Ki = 0.59 nM) and excellent selectivity over the σ2 subtype (1331-fold) as well as some other receptor systems. The novel synthetic strategy also allows the systematic pharmacological evaluation of intermediate alcohols 10. Despite their high σ1 affinity (Ki = 6-32 nM) and selectivity the alcohols 10 are 10-30-fold less potent than the bioisosteric fluoro derivatives 3.