Discovery and development of brain-penetrant 18F-labeled radioligands for neuroimaging of the sigma-2 receptors


Discovery and development of brain-penetrant 18F-labeled radioligands for neuroimaging of the sigma-2 receptors

Zhang, Y.; Wang, T.; Zhang, X.; Deuther-Conrad, W.; Fu, H.; Cui, M.; Zhang, J.; Brust, P.; Huang, Y.; Jia, H.

Six indole-based derivatives with a methoxy group at the indole ring were synthesized and evaluated as σ2 receptor ligands with nanomolar affinity (Ki (σ2) = 4.40-9.46 nM) and moderate subtype selectivity (Ki(σ2)/Ki(σ1) = 7-102). Radioligands 1-(4-(5,6-dimethoxyisoindolin-2-yl)butyl)-4-(2-[18F]fluoroethoxy)-1H-indole ([18F]3) and 1-(4-(5,6-dimethoxyisoindolin-2-yl)butyl)-5-(2-[18F]fluoroethoxy)-1H-indole ([18F]4) with high σ2 receptor affinity and subtype selectivity were synthesized through a direct SN2 displacement reaction, with radiochemical yields of 36-50% and 20-29%, radiochemical purity of >99%, and molar activities of 29-151 GBq/μmol and 55-72 GBq/μmol, respectively. Radioligand [18F]3 displayed high brain uptake, high brain-to-blood ratio and slow washout from the brain in male ICR mice. Administration of compound CM398 5 min prior to the radiotracer injection led to a significantly dose-dependent reduction of the brain accumulation (29-54%) and the brain-to-blood ratio (60-88%) at 30 min, indicating high specific binding of [18F]3 to the σ2 receptors in the brain. Ex vivo autoradiography in male ICR mice showed widely and heterogeneous distribution of [18F]3 in the brain. Small animal positron emission tomography imaging in rats confirmed different distribution and high specific binding of [18F]3 to σ2 receptors in rat brain. These findings warrant [18F]3 as a potential probe used for neuroimaging of the σ2 receptors in the brain.

Keywords: indole-based derivatives; σ2 receptor; fluorine-18; positron emission tomography; neuroimaging

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Publ.-Id: 32573