Enantioselective sigma(1) Receptor Binding and Biotransformation of the Spirocyclic PET Tracer 1 '-Benzyl-3-(3-fluoropropyl)-3H-spiro[[2]benzofuran-1,4 '-piperidine]

Wiese C, Maestrup EG, Schepmann D, Grimme S, Humpf HU, Brust P, Wunsch B

Zusammenfassung

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 sigma(1) 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 [H-3]-(+)-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. Chirality 23:148-154, 2011. (C) 2010 Wiley-Liss, Inc.