Synthesis and evaluation of new 1-oxa-8-azaspiro[4.5]decane derivatives as candidate radioligands for sigma-1 receptors.

We report the design, synthesis, and evaluation of a series of 1-oxa-8-azaspiro[4.5]decane and 1,5-dioxa-9-azaspiro[5.5]undecane derivatives as selective σ receptor ligands. All seven ligands exhibited nanomolar affinity for σ receptors (K(σ) = 0.47 - 12.1 nM) and moderate selectivity over σ receptors (K(σ)/ K(σ) = 2 - 44). Compound 8, with the best selectivity among these ligands, was selected for radiolabeling and further evaluation. Radioligand [F]8 was prepared via nucleophilic F-substitution of the corresponding tosylate precursor, with an overall isolated radiochemical yield of 12-35%, a radiochemical purity of greater than 99%, and molar activity of 94 - 121 GBq/μmol. Biodistribution studies of [F]8 in mice demonstrated high initial brain uptake at 2 min. Pretreatment with SA4503 resulted in significantly reduced brain-to-blood ratio (70% - 75% at 30 min). Ex vivo autoradiography in ICR mice demonstrated high accumulation of the radiotracer in σ receptor-rich brain areas. These findings suggest that [F]8 could be a lead compound for further structural modifications to develop potential brain imaging agents for σ receptors.