Synthesis and evaluation of novel 18F-labeled spirocyclic piperidine derivatives as σ1 receptor ligands for positron emission tomography imaging

Article abstract of DOI:10.1021/jm301734g

A series of spirocyclic piperidine derivatives were designed and synthesized as σ₁ receptor ligands. In vitro competition binding assays showed that 1′-(4-(2-fluoroethoxy)benzyl)-3H-spiro[2- benzofuran-1,4′-piperidine] (19) possessed high σ₁ receptor affinity (K_i = 0.79 nM) and excellent σ₁/ σ₂ subtype selectivity (350-fold) as well as high σ₁/VAChT selectivity (799-fold). The radiolabeled compound [¹⁸F]19 was synthesized by substitution of the tosylate precursor 24 with [¹⁸F]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 [ ¹⁸F]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 σ₁ receptors. Micro positron emission tomography imaging and blocking studies confirmed the specific binding of [¹⁸F]19 to σ₁ receptors in vivo.