AUTHOR=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 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.00534

DOI=10.3389/fphar.2019.00534

ISSN=1663-9812

ABSTRACT=<p>(<italic>S</italic>)-[<sup>18</sup>F]fluspidine ((<italic>S</italic>)-[<sup>18</sup>F]<bold>1</bold>) 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 (<italic>S</italic>)-[<sup>18</sup>F]<bold>1</bold> and elucidate their structures with LC-MS/MS. For the latter purpose additional <italic>in vitro</italic> studies were conducted by incubation of (<italic>S</italic>)-[<sup>18</sup>F]<bold>1</bold> and (<italic>S</italic>)-<bold>1</bold> with human liver microsomes (HLM). <italic>In vitro</italic> 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 <italic>in vitro</italic> and <italic>in vivo</italic> (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., <italic>n</italic> = 5-6), obtained from human subjects receiving 250–300 MBq (<italic>S</italic>)-[<sup>18</sup>F]<bold>1</bold> 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 <italic>in vitro</italic>. 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 (<italic>S</italic>)-[<sup>18</sup>F]<bold>1</bold> as PET radioligand for sigma-1 receptor imaging.</p>