In vitro and in vivo Human Metabolism of (S)-[18F]Fluspidine – A Radioligand for Imaging σ1 Receptors With Positron Emission Tomography (PET)
(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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-06-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2019.00534/full |
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| author | Friedrich-Alexander Ludwig Steffen Fischer Richard Houska Alexander Hoepping Winnie Deuther-Conrad Dirk Schepmann Marianne Patt Philipp M. Meyer Swen Hesse Swen Hesse Georg-Alexander Becker Franziska Ruth Zientek Franziska Ruth Zientek Jörg Steinbach Bernhard Wünsch Osama Sabri Peter Brust |
| author_facet | Friedrich-Alexander Ludwig Steffen Fischer Richard Houska Alexander Hoepping Winnie Deuther-Conrad Dirk Schepmann Marianne Patt Philipp M. Meyer Swen Hesse Swen Hesse Georg-Alexander Becker Franziska Ruth Zientek Franziska Ruth Zientek Jörg Steinbach Bernhard Wünsch Osama Sabri Peter Brust |
| author_sort | Friedrich-Alexander Ludwig |
| collection | DOAJ |
| description | (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. |
| first_indexed | 2024-04-13T03:21:09Z |
| format | Article |
| id | doaj.art-7fa023e5037f427080aa634c67f8af79 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-13T03:21:09Z |
| publishDate | 2019-06-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-7fa023e5037f427080aa634c67f8af792022-12-22T03:04:46ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122019-06-011010.3389/fphar.2019.00534457211In vitro and in vivo Human Metabolism of (S)-[18F]Fluspidine – A Radioligand for Imaging σ1 Receptors With Positron Emission Tomography (PET)Friedrich-Alexander Ludwig0Steffen Fischer1Richard Houska2Alexander Hoepping3Winnie Deuther-Conrad4Dirk Schepmann5Marianne Patt6Philipp M. Meyer7Swen Hesse8Swen Hesse9Georg-Alexander Becker10Franziska Ruth Zientek11Franziska Ruth Zientek12Jörg Steinbach13Bernhard Wünsch14Osama Sabri15Peter Brust16Department of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, GermanyDepartment of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, GermanyDepartment of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, GermanyABX Advanced Biochemical Compounds GmbH, Radeberg, GermanyDepartment of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, GermanyDepartment of Pharmaceutical and Medicinal Chemistry, University of Münster, Münster, GermanyDepartment of Nuclear Medicine, Leipzig University, Leipzig, GermanyDepartment of Nuclear Medicine, Leipzig University, Leipzig, GermanyDepartment of Nuclear Medicine, Leipzig University, Leipzig, GermanyIntegrated Research and Treatment Center (IFB) Adiposity Diseases, Leipzig University, Leipzig, GermanyDepartment of Nuclear Medicine, Leipzig University, Leipzig, GermanyDepartment of Nuclear Medicine, Leipzig University, Leipzig, GermanyIntegrated Research and Treatment Center (IFB) Adiposity Diseases, Leipzig University, Leipzig, GermanyDepartment of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, GermanyDepartment of Pharmaceutical and Medicinal Chemistry, University of Münster, Münster, GermanyDepartment of Nuclear Medicine, Leipzig University, Leipzig, GermanyDepartment of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, Germany(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.https://www.frontiersin.org/article/10.3389/fphar.2019.00534/fullsigma-1 receptorsfluspidinepositron emission tomographyradiometabolitesliquid chromatography-mass spectrometryliver microsomes |
| spellingShingle | Friedrich-Alexander Ludwig Steffen Fischer Richard Houska Alexander Hoepping Winnie Deuther-Conrad Dirk Schepmann Marianne Patt Philipp M. Meyer Swen Hesse Swen Hesse Georg-Alexander Becker Franziska Ruth Zientek Franziska Ruth Zientek Jörg Steinbach Bernhard Wünsch Osama Sabri Peter Brust In vitro and in vivo Human Metabolism of (S)-[18F]Fluspidine – A Radioligand for Imaging σ1 Receptors With Positron Emission Tomography (PET) Frontiers in Pharmacology sigma-1 receptors fluspidine positron emission tomography radiometabolites liquid chromatography-mass spectrometry liver microsomes |
| title | In vitro and in vivo Human Metabolism of (S)-[18F]Fluspidine – A Radioligand for Imaging σ1 Receptors With Positron Emission Tomography (PET) |
| title_full | In vitro and in vivo Human Metabolism of (S)-[18F]Fluspidine – A Radioligand for Imaging σ1 Receptors With Positron Emission Tomography (PET) |
| title_fullStr | In vitro and in vivo Human Metabolism of (S)-[18F]Fluspidine – A Radioligand for Imaging σ1 Receptors With Positron Emission Tomography (PET) |
| title_full_unstemmed | In vitro and in vivo Human Metabolism of (S)-[18F]Fluspidine – A Radioligand for Imaging σ1 Receptors With Positron Emission Tomography (PET) |
| title_short | In vitro and in vivo Human Metabolism of (S)-[18F]Fluspidine – A Radioligand for Imaging σ1 Receptors With Positron Emission Tomography (PET) |
| title_sort | in vitro and in vivo human metabolism of s 18f fluspidine a radioligand for imaging σ1 receptors with positron emission tomography pet |
| topic | sigma-1 receptors fluspidine positron emission tomography radiometabolites liquid chromatography-mass spectrometry liver microsomes |
| url | https://www.frontiersin.org/article/10.3389/fphar.2019.00534/full |
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