Synthesis and evaluation of novel ~(18)F-labeled spirocyclic piperidine derivatives as σ_1 receptor ligands for positron emission tomography imaging

摘要

A series of spirocyclic piperidine derivatives were designed and synthesized as σ_1 receptor ligands. In vitro competition binding assays showed that 1′-(4-(2-fluoroethoxy)benzyl)-3H-spiro[2- benzofuran-1,4′-piperidine] (19) possessed high σ_1 receptor affinity (K_i = 0.79 nM) and excellent σ_1/ σ_2 subtype selectivity (350-fold) as well as high σ_1/VAChT selectivity (799-fold). The radiolabeled compound [~(18)F]19 was synthesized by substitution of the tosylate precursor 24 with [~(18)F]fluoride, with an isolated radiochemical yield of 35-60%, a radiochemical purity of >99%, and a specific activity of 30-55 GBq/μmol. Biodistribution studies in imprinting control region mice indicated that [ ~(18)F]19 displayed excellent initial brain uptake and slow washout. Ex vivo autoradiography in Sprague-Dawley rats demonstrated high accumulation of the radiotracer in brain areas known to express high levels of σ_1 receptors. Micro positron emission tomography imaging and blocking studies confirmed the specific binding of [~(18)F]19 to σ_1 receptors in vivo.