A 18 F‐Labeled Fluorobutyl‐Substituted Spirocyclic Piperidine Derivative as a Selective Radioligand for PET Imaging of Sigma 1 Receptors

In this study, we synthesized and evaluated a new spirocyclic piperidine derivative 3 , containing a 4‐fluorobutyl side chain, as a PET radioligand for neuroimaging of σ 1 receptors. In vitro, compound 3 displayed high affinity for σ 1 receptors ( K i =1.2 n M ) as well as high selectivity. [ 18 F] 3 radiosynthesis was performed from the corresponding tosylate precursor, with high radiochemical yield (45–51 %), purity (>98 %), and specific activity (>201 GBq μmol −1 ). Metabolic stability of [ 18 F] 3 in the brain of CD‐1 mice was verified, and no penetration of peripheral radiometabolites into the cerebral tissue was observed. Results of ex vivo autoradiography revealed that the distribution of [ 18 F] 3 in the brain corresponded to regions with high σ 1 receptor density. The highest region‐specific total‐to‐nonspecific ratio was determined in the facial nucleus (4.00). Biodistribution studies indicated rapid and high levels in brain uptake of [ 18 F] 3 (2.2 % ID per gram at 5 min p.i.). Pre‐administration of haloperidol significantly inhibited [ 18 F] 3 uptake into the brain and σ 1 receptor‐expressing organs, further confirming in vivo target specificity.