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

We report the design and synthesis of several 4-phenylpiperidine-4-carbonitrile derivatives as sigma(1) receptor ligands. In vitro radioligand competition binding assays showed that all the ligands exhibited low nanomolar affinity for sigma(1) receptors (K-i(sigma(1))=1.22-2.14nM) and extremely high subtype selectivity (K-i(sigma(2))=830-1710nM; K-i(sigma(2))/K-i(sigma(1))=680-887). [F-18]9 was prepared in 42-46% isolated radiochemical yield, with a radiochemical purity of >99% by HPLC analysis after purification, via nucleophilic F-18(-) 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 5min prior to injection of [F-18]9 significantly reduced the accumulation of radiotracers in organs known to contain sigma(1) receptors. Two radioactive metabolites were observed in the brain at 30min after radiotracer injection. [F-18]9 may serve as a lead compound to develop suitable radiotracers for sigma(1) receptor imaging with positron emission tomography.