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

• Published in: Journal of labelled compounds & radiopharmaceuticals 2016-07, Vol.59 (9), p.332-339
• Main Authors: Ye, Jiajun, Wang, Xia, Deuther-Conrad, Winnie, Zhang, Jinming, Li, Jianzhou, Zhang, Xiaojun, Wang, Liang, Steinbach, Jörg, Brust, Peter, Jia, Hongmei
• Format: Article
• Language: English
• Subjects: Animals; Chemistry Techniques, Synthetic; Drug Stability; Fluorine Radioisotopes; Isotope Labeling; Ligands; Male; Mice; Mice, Inbred ICR; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - metabolism; Piperidines - pharmacokinetics; Positron-Emission Tomography; Receptors, sigma - metabolism; Tissue Distribution
• ISSN: 1099-1344
• DOI: 10.1002/jlcr.3408

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.