In vitro and in vivo Human Metabolism of (S)-[18F]Fluspidine – A Radioligand for Imaging σ1 Receptors With Positron Emission Tomography (PET)

• Published in: Frontiers in pharmacology 2019-06, Vol.10, p.534-534
• Main Authors: Ludwig, Friedrich-Alexander, Fischer, Steffen, Houska, Richard, Hoepping, Alexander, Deuther-Conrad, Winnie, Schepmann, Dirk, Patt, Marianne, Meyer, Philipp M., Hesse, Swen, Becker, Georg-Alexander, Zientek, Franziska Ruth, Steinbach, Jörg, Wünsch, Bernhard, Sabri, Osama, Brust, Peter
• Format: Article
• Language: English
• Subjects: fluspidine; liquid chromatography-mass spectrometry; liver microsomes; Pharmacology; positron emission tomography; radiometabolites; sigma-1 receptors
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2019.00534

( S )-[ 18 F]fluspidine (( S )-[ 18 F] 1 ) has recently been explored for positron emission tomography (PET) imaging of sigma-1 receptors in humans. In the current report, we have used plasma samples of healthy volunteers to investigate the radiometabolites of ( S )-[ 18 F] 1 and elucidate their structures with LC-MS/MS. For the latter purpose additional in vitro studies were conducted by incubation of ( S )-[ 18 F] 1 and ( S )- 1 with human liver microsomes (HLM). In vitro metabolites were characterized by interpretation of MS/MS fragmentation patterns from collision-induced dissociation or by use of reference compounds. Thereby, structures of corresponding radio-HPLC-detected radiometabolites, both in vitro and in vivo (human), could be identified. By incubation with HLM, mainly debenzylation and hydroxylation occurred, beside further mono- and di-oxygenations. The product hydroxylated at the fluoroethyl side chain was glucuronidated. Plasma samples (10, 20, 30 min p.i., n = 5-6), obtained from human subjects receiving 250–300 MBq ( S )-[ 18 F] 1 showed 97.2, 95.4, and 91.0% of unchanged radioligand, respectively. In urine samples (90 min p.i.) the fraction of unchanged radioligand was only 2.6% and three major radiometabolites were detected. The one with the highest percentage, also found in plasma, matched the glucuronide formed in vitro . Only a small amount of debenzylated metabolite was detected. In conclusion, our metabolic study, in particular the high fractions of unchanged radioligand in plasma, confirms the suitability of ( S )-[ 18 F] 1 as PET radioligand for sigma-1 receptor imaging.