Synthesis, radiofluorination and pharmacological evaluation of a fluoromethyl spirocyclic PET tracer for central σ1 receptors and comparison with fluoroalkyl homologs

The spirocyclic σ1 receptor ligand 1 (1′-benzyl-3-(fluoromethyl)-3H-spiro[[2]benzofuran-1,4′-piperidine]) was prepared in four steps starting from methoxy derivative 5. Due to its high σ1 affinity (Ki = 0.74 nM) and selectivity against several other relevant targets, 1 was investigated as 18F-labeled PET tracer and its biological properties were compared with those of homologous fluoroalkyl derivatives 2-4. The fluoromethyl derivative 1 was faster metabolized in vitro than homologs 2-4. In contrast to the radiosynthesis of [18F]2-4, the nucleophilic substitution of the tosylate 15 using the K[18F]F-K222-carbonate complex required heating to 150 °C in DMSO to achieve high labeling efficiencies. Whereas radiometabolites of [18F]2-4 were not detected in vivo in the brain of mice, two radiometabolites of [18F]1 were found. Analysis of ex vivo autoradiography images provided rather low target-to-nontarget ratio for [18F]1 compared with [18F]2-4. [18F]1 showed a fast uptake in the brain, which decreased continuously over time. The brain-to-plasma ratio of the radiotracer [18F]1 was only exceeded by the fluoroethyl tracer [18F]2.