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, containing a 4-fluorobutyl side chain, as a PET radioligand for neuroimaging of sigma(1) receptors. In vitro, compound 3 displayed high affinity for sigma(1) receptors (K-i = 1.2 nM) as well as high selectivity. [F-18]3 radiosynthesis was performed from the corresponding tosylate precursor, with high radiochemical yield (45-51 %), purity (> 98%), and specific activity (> 201 GBq mu mol(-1)). Metabolic stability of [F-18]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 [F-18]3 in the brain corresponded to regions with high sigma(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 [F-18]3 (2.2% ID per gram at 5 min p.i.). Pre-administration of haloperidol significantly inhibited [F-18]3 uptake into the brain and s1 receptor-expressing organs, further confirming in vivo target specificity.