A ¹⁸F-labeled Fluorobutyl-substituted spirocyclic piperidine derivative as a selective radioligand for PET imaging of sigma₁ receptors

In this study we synthesized and evaluated a new spirocyclic piperidine derivative (3), bearing a 4-fluorobutyl side chain, as PET radioligand for neuroimaging of σ1 receptors. In vitro, 3 displayed a high affinity for σ1 receptors (Ki = 1.2 nM) and high selectivity. [18F]3 radiosynthesis was performed from corresponding tosylate precursor, with high radiochemical yield (45-51%), purity (> 98%) and specific activity (> 201 GBq/μmol). The metabolic stability of [18F]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 [18F]3 in brain corresponded to regions with high σ1 receptor density. The highest target-to-nontarget tissue ratio (2.83) was determined in the facial nucleus. Biodistribution study indicated a rapid and high brain uptake of [18F]3 (2.2% ID/g at 5 min p.i.). Pre-administration of haloperidol significantly inhibited [18F]3 uptake into the brain and in σ1 receptor expressing organs, supporting the in vivo target specificity.