Enantioselective σ1 receptor binding and biotransformation of the spirocyclic PET tracer 1'-benzyl-3-(3-fluoropropyl)-3H-spiro[[2]benzofuran-1,4'-piperidine].
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 σ(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 [(3)H]-(+)-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.
Wiese
Christian
C
Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Hittorfstraße 58-62, Münster, Germany.
Grosse Maestrup
Eva
E
Schepmann
Dirk
D
Grimme
Stefan
S
Humpf
Hans-Ulrich
HU
Brust
Peter
P
Wünsch
Bernhard
B
D000818:Animals; D001572:Benzofurans / Q000378:metabolism* / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D005462:Fluorine Radioisotopes; D006168:Guinea Pigs; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D010423:Pentazocine / Q000378:metabolism; D010880:Piperidines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D049268:Positron-Emission Tomography / Q000379:methods; D011849:Radioactive Tracers; D051381:Rats; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013141:Spiro Compounds / Q000378:metabolism / Q000493:pharmacokinetics*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000097605:Sigma-1 Receptor
D001572:Benzofurans; D005462:Fluorine Radioisotopes; D010423:Pentazocine; D010880:Piperidines; D011849:Radioactive Tracers; D017480:Receptors, sigma; D013141:Spiro Compounds; D000097605:Sigma-1 Receptor; C557461:1'-benzyl-3-(3-fluoropropyl)-3H-spiro((2)benzofuran-1,4'-piperidine)