Synthesis and evaluation of a (18) F-labeled 4-phenylpiperidine-4-carbonitrile radioligand for σ1 receptor imaging.

ABSTRACT

We report the design and synthesis of several 4-phenylpiperidine-4-carbonitrile derivatives as σ1 receptor ligands. In vitro radioligand competition binding assays showed that all the ligands exhibited low nanomolar affinity for σ1 receptors (Ki (σ1 ) = 1.22-2.14 nM) and extremely high subtype selectivity (Ki (σ2 ) = 830-1710 nM; Ki (σ2 )/Ki (σ1 ) = 680-887). [(18) F]9 was prepared in 42-46% isolated radiochemical yield, with a radiochemical purity of >99% by HPLC analysis after purification, via nucleophilic (18) F(-) substitution of the corresponding tosylate precursor. Biodistribution studies in mice demonstrated high initial brain uptakes and high brain-to-blood ratios. Administration of SA4503 or haloperidol 5 min prior to injection of [(18) F]9 significantly reduced the accumulation of radiotracers in organs known to contain σ1 receptors. Two radioactive metabolites were observed in the brain at 30 min after radiotracer injection. [(18) F]9 may serve as a lead compound to develop suitable radiotracers for σ1 receptor imaging with positron emission tomography.