Abstract
(S)-[18F]fluspidine ((S)-[18F]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)-[18F]1 and elucidate their structures with LC-MS/MS. For the latter purpose additional in vitro studies were conducted by incubation of (S)-[18F]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)-[18F]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)-[18F]1 as PET radioligand for sigma-1 receptor imaging.
Highlights
The two enantiomers (S)- and (R)-[18F]fluspidine ((S)- and (R)-[18F]1 -benzyl-3-(2-fluoroethyl)-3H-spiro[2-benzofuran-1,4 -piperidine], (S)-1 and (R)-1, Figure 1) are radioligands which have been developed for positron emission tomography (PET) imaging of sigma-1 receptors (S1R) in human (Weber et al, 2017).S1R are expressed in the central nervous system (CNS) as well as in peripheral tissues (Rousseaux and Greene, 2015)
Time- and Concentration-Dependent Microsomal Transformation In order to obtain basic information about the metabolic stability in vitro, the time course of the degradation of (S)-[18F]1 was investigated in presence of different concentrations of (S)-1 [nocarrier-added (n.c.a.,
Incubations were performed in phosphate-buffered saline (PBS) with human liver microsomes (HLM) and NADPH at 37◦C
Summary
S1R are expressed in the central nervous system (CNS) as well as in peripheral tissues (Rousseaux and Greene, 2015). They are located in both the plasma membrane and the mitochondriaassociated membrane of the endoplasmatic reticulum, where they are involved in different physiological and pathophysiological processes, e.g., regulations of ion channels and neurotransmitter receptors. (S)-1 and (R)-1 are derived from a structural optimization process for the purpose of PET of spirocyclic piperidines which possess high affinity toward S1R and selectivity over a variety of other receptors (Maier and Wünsch, 2002a,b; Große Maestrup et al, 2009a, 2011; Maisonial et al, 2011; Holl et al, 2014; Nakane et al, 2018).
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