Evaluation of spirocyclic 3-(3-fluoropropyl)-2-benzofurans as sigma1 receptor ligands for neuroimaging with positron emission tomography.

Abstract

A series of various N-substituted 3-(3-fluoropropyl)-3H-spiro[[2]benzofuran-1,4'-piperidines] (7) has been synthesized. In receptor binding studies, the N-benzyl derivative 7a (WMS-1813) revealed extraordinarily high sigma(1) receptor affinity (K(i) = 1.4 nM) and excellent sigma(1)/sigma(2) selectivity (>600 fold). In vitro biotransformation of 7a with rat liver microsomes led to three main metabolites. N-Debenzylation was inhibited by introduction of an N-phenylethyl residue (7 g). The PET tracer [(18)F]7a was synthesized by nucleophilic substitution of the tosylate 13 with K[(18)F]F-K222-carbonate complex. The decay corrected radiochemical yield of [(18)F]7a was 35-48% with a radiochemical purity of >99.5% and a specific activity of 150-238 GBq/micromol. The radiotracer properties were evaluated in female CD-1 mice by organ distribution and ex vivo brain autoradiography. The radiotracer uptake in the brain was fast and sufficient, with values of approximately 4% injected dose per gram. Target specificity of [(18)F]7a was validated in blocking studies by preapplication of haloperidol, and significant reduction in the uptake of radioactivity was observed in the brain and peripheral organs expressing sigma(1) receptors.

DOI: 10.1021/jm900909e

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@article{Maestrup2009EvaluationOS, title={Evaluation of spirocyclic 3-(3-fluoropropyl)-2-benzofurans as sigma1 receptor ligands for neuroimaging with positron emission tomography.}, author={Eva Grosse Maestrup and Steffen Fischer and C . Anway - Wiese and Dirk Schepmann and Achim Hiller and Winnie Deuther-Conrad and J{\"{o}rg Steinbach and Bernhard W{\"{u}nsch and Peter Brust}, journal={Journal of medicinal chemistry}, year={2009}, volume={52 19}, pages={6062-72} }