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


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

Tian, J.; He, Y.; Deuther-Conrad, W.; Fu, H.; Xie, F.; Zhang, Y.; Wang, T.; Zhang, X.; Zhang, J.; Brust, P.; Huang, Y.; Jia, H.

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 σ1 receptor ligands. All seven ligands exhibited nanomolar affinity for σ1 receptors (Ki(σ1) = 0.61 – 12.0 nM) and moderate selectivity toward σ2 receptors (Ki(σ2)/ Ki(σ1) = 2 – 44). Compound 8 with the best selectivity among these ligands was selected for radiolabeling and further evaluation. Radioligand [18F]8 was prepared via nucleophilic 18F-substitution of the corresponding tosylate precursor, with an overall isolated radiochemical yield of 12-35%, a radiochemical purity of >99%, and molar activity of 94 – 121 GBq/μmol. Biodistribution studies of [18F]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 σ1 receptor-rich brain areas. These findings suggest that [18F]8 could be a lead compound for further structural modification to develop potential brain imaging agent for σ1 receptors.

Keywords: 1-oxa-8-azaspiro[4.5]decane derivatives; 1,5-dioxa-9-azaspiro[5.5]undecane derivatives; σ1 receptor; fluorine-18; positron emission tomography

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Publ.-Id: 30882