Synthesis and Evaluation of Novel 18F-Labeled Spirocyclic Piperidine Derivatives as σ1 Receptor Ligands for Positron Emission Tomography Imaging


Synthesis and Evaluation of Novel 18F-Labeled Spirocyclic Piperidine Derivatives as σ1 Receptor Ligands for Positron Emission Tomography Imaging

Li, Y.; Wang, X.; Zhang, J.; Deuther-Conrad, W.; Xie, F.; Zhang, X.; Liu, J.; Qiao, J.; Cui, M.; Steinbach, J.; Brust, P.; Liu, B.; Jia, H.

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 (Ki= 0.79 nM) and excellent σ12 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 isolated radiochemical yield of 35–60%, radiochemical purity of >99%, and specific activity of 30–55 GBq/Qmol. Biodistribution studies in ICR mice indicated that [18F]19 displayed excellent initial brain uptake and slow washout. Ex vivo autoradiography in Sprague-Dawley rat demonstrated high accumulation of the radiotracer in brain areas known to express high levels of σ1 receptors. MicroPET imaging and blocking studies confirmed the specific binding of [18F]19 to σ1 receptors in vivo.

Keywords: σ1 receptor; brain; spirocyclic piperidine derivatives; 18F; PET imaging

Permalink: https://www.hzdr.de/publications/Publ-18655
Publ.-Id: 18655