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 σ₁ receptor ligands. In vitro radioligand competition binding assays showed that all the ligands exhibited low nanomolar affinity for σ₁ receptors ( K_i(σ₁) = 1.22-2.14 nM) and extremely high subtype selectivity ( K_i(σ₂) = 830-1710 nM; K_i(σ₂)/ K_i(σ₁) = 680-887). [¹⁸F]9 was prepared in 42-46% isolated radiochemical yield, with a radiochemical purity of >99% by HPLC analysis after purification, via nucleophilic ¹⁸F^- 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 [¹⁸F]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. [¹⁸F]9 may serve as a lead compound to develop suitable radiotracers for σ₁ receptor imaging with positron emission tomography. [ABSTRACT FROM AUTHOR]