Enantioselective σ1 receptor binding and biotransformation of the spirocyclic PET tracer 1’-Benzyl-3-(3-fluoropropyl)-3H-spiro[[2]benzofuran-1,4’-piperidine]


Enantioselective σ1 receptor binding and biotransformation of the spirocyclic PET tracer 1’-Benzyl-3-(3-fluoropropyl)-3H-spiro[[2]benzofuran-1,4’-piperidine]

Wiese, C.; Große Maestrup, E.; Schepmann, D.; Grimme, S.; Humpf, H.-U.; Brust, P.; Wünsch, B.

It was shown that racemic (±)-2 [1’-benzyl-3-(3-fluoropropyl)-3H-spiro[[2]benzofuran-1,4’-piperidine], WMS-1813] represents a promising positron emission tomography (PET) tracer for the investigation of centrally located σ1 receptors. To study the pharmacological activity of the enantiomers of 2, a preparative HPLC separation of (R)-2 and (S)-2 was performed. The absolute configuration of the enantiomers was determined by CD-spectroscopy together with theoretical calculations of the CD-spectrum of a model compound. In receptor binding studies with the radioligand [3H]-(+)-pentazocine, (S)-2 was thrice more potent than its (R)-configured enantiomer (R)-2. The metabolic degradation of the more potent (S)-enantiomer was considerably slower than the metabolism of (R)-2. The structures of the main metabolites of both enantiomers were elucidated by determination of the exact mass using an Orbitrap-LC-MS system. These experiments showed a stereoselective biotransformation of the enantiomers of 2.

Keywords: σ1 receptor ligands; PET tracer; resolution; CD spectroscopy; enantioselective receptor binding; enantioselective metabolism

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Publ.-Id: 14698