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Exploring the Metabolism of (+)-[(18)F]Flubatine In Vitro and In Vivo: LC-MS/MS Aided Identification of Radiometabolites in a Clinical PET Study †
Both (+)-[(18)F]flubatine and its enantiomer (−)-[(18)F]flubatine are radioligands for the neuroimaging of α4β2 nicotinic acetylcholine receptors (nAChRs) by positron emission tomography (PET). In a clinical study in patients with early Alzheimer’s disease, (+)-[(18)F]flubatine ((+)-[(18)F]1) was ex...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017759/ https://www.ncbi.nlm.nih.gov/pubmed/29461507 http://dx.doi.org/10.3390/molecules23020464 |
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author | Ludwig, Friedrich-Alexander Fischer, Steffen Smits, René Deuther-Conrad, Winnie Hoepping, Alexander Tiepolt, Solveig Patt, Marianne Sabri, Osama Brust, Peter |
author_facet | Ludwig, Friedrich-Alexander Fischer, Steffen Smits, René Deuther-Conrad, Winnie Hoepping, Alexander Tiepolt, Solveig Patt, Marianne Sabri, Osama Brust, Peter |
author_sort | Ludwig, Friedrich-Alexander |
collection | PubMed |
description | Both (+)-[(18)F]flubatine and its enantiomer (−)-[(18)F]flubatine are radioligands for the neuroimaging of α4β2 nicotinic acetylcholine receptors (nAChRs) by positron emission tomography (PET). In a clinical study in patients with early Alzheimer’s disease, (+)-[(18)F]flubatine ((+)-[(18)F]1) was examined regarding its metabolic fate, in particular by identification of degradation products detected in plasma and urine. The investigations included an in vivo study of (+)-flubatine ((+)-1) in pigs and structural elucidation of formed metabolites by LC-MS/MS. Incubations of (+)-1 and (+)-[(18)F]1 with human liver microsomes were performed to generate in vitro metabolites, as well as radiometabolites, which enabled an assignment of their structures by comparison of LC-MS/MS and radio-HPLC data. Plasma and urine samples taken after administration of (+)-[(18)F]1 in humans were examined by radio-HPLC and, on the basis of results obtained in vitro and in vivo, formed radiometabolites were identified. In pigs, (+)-1 was monohydroxylated at different sites of the azabicyclic ring system of the molecule. Additionally, one intermediate metabolite underwent glucuronidation, as also demonstrated in vitro. In humans, a fraction of 95.9 ± 1.9% (n = 10) of unchanged tracer remained in plasma, 30 min after injection. However, despite the low metabolic degradation, both radiometabolites formed in humans could be characterized as (i) a product of C-hydroxylation at the azabicyclic ring system, and (ii) a glucuronide conjugate of the precedingly-formed N8-hydroxylated (+)-[(18)F]1. |
format | Online Article Text |
id | pubmed-6017759 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-60177592018-11-13 Exploring the Metabolism of (+)-[(18)F]Flubatine In Vitro and In Vivo: LC-MS/MS Aided Identification of Radiometabolites in a Clinical PET Study † Ludwig, Friedrich-Alexander Fischer, Steffen Smits, René Deuther-Conrad, Winnie Hoepping, Alexander Tiepolt, Solveig Patt, Marianne Sabri, Osama Brust, Peter Molecules Article Both (+)-[(18)F]flubatine and its enantiomer (−)-[(18)F]flubatine are radioligands for the neuroimaging of α4β2 nicotinic acetylcholine receptors (nAChRs) by positron emission tomography (PET). In a clinical study in patients with early Alzheimer’s disease, (+)-[(18)F]flubatine ((+)-[(18)F]1) was examined regarding its metabolic fate, in particular by identification of degradation products detected in plasma and urine. The investigations included an in vivo study of (+)-flubatine ((+)-1) in pigs and structural elucidation of formed metabolites by LC-MS/MS. Incubations of (+)-1 and (+)-[(18)F]1 with human liver microsomes were performed to generate in vitro metabolites, as well as radiometabolites, which enabled an assignment of their structures by comparison of LC-MS/MS and radio-HPLC data. Plasma and urine samples taken after administration of (+)-[(18)F]1 in humans were examined by radio-HPLC and, on the basis of results obtained in vitro and in vivo, formed radiometabolites were identified. In pigs, (+)-1 was monohydroxylated at different sites of the azabicyclic ring system of the molecule. Additionally, one intermediate metabolite underwent glucuronidation, as also demonstrated in vitro. In humans, a fraction of 95.9 ± 1.9% (n = 10) of unchanged tracer remained in plasma, 30 min after injection. However, despite the low metabolic degradation, both radiometabolites formed in humans could be characterized as (i) a product of C-hydroxylation at the azabicyclic ring system, and (ii) a glucuronide conjugate of the precedingly-formed N8-hydroxylated (+)-[(18)F]1. MDPI 2018-02-20 /pmc/articles/PMC6017759/ /pubmed/29461507 http://dx.doi.org/10.3390/molecules23020464 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Ludwig, Friedrich-Alexander Fischer, Steffen Smits, René Deuther-Conrad, Winnie Hoepping, Alexander Tiepolt, Solveig Patt, Marianne Sabri, Osama Brust, Peter Exploring the Metabolism of (+)-[(18)F]Flubatine In Vitro and In Vivo: LC-MS/MS Aided Identification of Radiometabolites in a Clinical PET Study † |
title | Exploring the Metabolism of (+)-[(18)F]Flubatine In Vitro and In Vivo: LC-MS/MS Aided Identification of Radiometabolites in a Clinical PET Study † |
title_full | Exploring the Metabolism of (+)-[(18)F]Flubatine In Vitro and In Vivo: LC-MS/MS Aided Identification of Radiometabolites in a Clinical PET Study † |
title_fullStr | Exploring the Metabolism of (+)-[(18)F]Flubatine In Vitro and In Vivo: LC-MS/MS Aided Identification of Radiometabolites in a Clinical PET Study † |
title_full_unstemmed | Exploring the Metabolism of (+)-[(18)F]Flubatine In Vitro and In Vivo: LC-MS/MS Aided Identification of Radiometabolites in a Clinical PET Study † |
title_short | Exploring the Metabolism of (+)-[(18)F]Flubatine In Vitro and In Vivo: LC-MS/MS Aided Identification of Radiometabolites in a Clinical PET Study † |
title_sort | exploring the metabolism of (+)-[(18)f]flubatine in vitro and in vivo: lc-ms/ms aided identification of radiometabolites in a clinical pet study † |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017759/ https://www.ncbi.nlm.nih.gov/pubmed/29461507 http://dx.doi.org/10.3390/molecules23020464 |
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