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Non-invasive in vivo assessment of 11β-hydroxysteroid dehydrogenase type 1 activity by (19)F-Magnetic Resonance Spectroscopy
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies tissue glucocorticoid levels and is a pharmaceutical target in diabetes and cognitive decline. Clinical translation of inhibitors is hampered by lack of in vivo pharmacodynamic biomarkers. Our goal was to monitor substrates and products of...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9523021/ https://www.ncbi.nlm.nih.gov/pubmed/36175417 http://dx.doi.org/10.1038/s41598-022-18740-5 |
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author | Naredo-Gonzalez, Gregorio Upreti, Rita Jansen, Maurits A. Semple, Scott Sutcliffe, Oliver B. Marshall, Ian Walker, Brian R. Andrew, Ruth |
author_facet | Naredo-Gonzalez, Gregorio Upreti, Rita Jansen, Maurits A. Semple, Scott Sutcliffe, Oliver B. Marshall, Ian Walker, Brian R. Andrew, Ruth |
author_sort | Naredo-Gonzalez, Gregorio |
collection | PubMed |
description | 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies tissue glucocorticoid levels and is a pharmaceutical target in diabetes and cognitive decline. Clinical translation of inhibitors is hampered by lack of in vivo pharmacodynamic biomarkers. Our goal was to monitor substrates and products of 11β-HSD1 non-invasively in liver via (19)Fluorine magnetic resonance spectroscopy ((19)F-MRS). Interconversion of mono/poly-fluorinated substrate/product pairs was studied in Wistar rats (male, n = 6) and healthy men (n = 3) using 7T and 3T MRI scanners, respectively. Here we show that the in vitro limit of detection, as absolute fluorine content, was 0.625 μmole in blood. Mono-fluorinated steroids, dexamethasone and 11-dehydrodexamethasone, were detected in phantoms but not in vivo in human liver following oral dosing. A non-steroidal polyfluorinated tracer, 2-(phenylsulfonyl)-1-(4-(trifluoromethyl)phenyl)ethanone and its metabolic product were detected in vivo in rat liver after oral administration of the keto-substrate, reading out reductase activity. Administration of a selective 11β-HSD1 inhibitor in vivo in rats altered total liver (19)F-MRS signal. We conclude that there is insufficient sensitivity to measure mono-fluorinated tracers in vivo in man with current dosage regimens and clinical scanners. However, since reductase activity was observed in rats using poly-fluorinated tracers, this concept could be pursued for translation to man with further development. |
format | Online Article Text |
id | pubmed-9523021 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-95230212022-10-01 Non-invasive in vivo assessment of 11β-hydroxysteroid dehydrogenase type 1 activity by (19)F-Magnetic Resonance Spectroscopy Naredo-Gonzalez, Gregorio Upreti, Rita Jansen, Maurits A. Semple, Scott Sutcliffe, Oliver B. Marshall, Ian Walker, Brian R. Andrew, Ruth Sci Rep Article 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies tissue glucocorticoid levels and is a pharmaceutical target in diabetes and cognitive decline. Clinical translation of inhibitors is hampered by lack of in vivo pharmacodynamic biomarkers. Our goal was to monitor substrates and products of 11β-HSD1 non-invasively in liver via (19)Fluorine magnetic resonance spectroscopy ((19)F-MRS). Interconversion of mono/poly-fluorinated substrate/product pairs was studied in Wistar rats (male, n = 6) and healthy men (n = 3) using 7T and 3T MRI scanners, respectively. Here we show that the in vitro limit of detection, as absolute fluorine content, was 0.625 μmole in blood. Mono-fluorinated steroids, dexamethasone and 11-dehydrodexamethasone, were detected in phantoms but not in vivo in human liver following oral dosing. A non-steroidal polyfluorinated tracer, 2-(phenylsulfonyl)-1-(4-(trifluoromethyl)phenyl)ethanone and its metabolic product were detected in vivo in rat liver after oral administration of the keto-substrate, reading out reductase activity. Administration of a selective 11β-HSD1 inhibitor in vivo in rats altered total liver (19)F-MRS signal. We conclude that there is insufficient sensitivity to measure mono-fluorinated tracers in vivo in man with current dosage regimens and clinical scanners. However, since reductase activity was observed in rats using poly-fluorinated tracers, this concept could be pursued for translation to man with further development. Nature Publishing Group UK 2022-09-29 /pmc/articles/PMC9523021/ /pubmed/36175417 http://dx.doi.org/10.1038/s41598-022-18740-5 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Naredo-Gonzalez, Gregorio Upreti, Rita Jansen, Maurits A. Semple, Scott Sutcliffe, Oliver B. Marshall, Ian Walker, Brian R. Andrew, Ruth Non-invasive in vivo assessment of 11β-hydroxysteroid dehydrogenase type 1 activity by (19)F-Magnetic Resonance Spectroscopy |
title | Non-invasive in vivo assessment of 11β-hydroxysteroid dehydrogenase type 1 activity by (19)F-Magnetic Resonance Spectroscopy |
title_full | Non-invasive in vivo assessment of 11β-hydroxysteroid dehydrogenase type 1 activity by (19)F-Magnetic Resonance Spectroscopy |
title_fullStr | Non-invasive in vivo assessment of 11β-hydroxysteroid dehydrogenase type 1 activity by (19)F-Magnetic Resonance Spectroscopy |
title_full_unstemmed | Non-invasive in vivo assessment of 11β-hydroxysteroid dehydrogenase type 1 activity by (19)F-Magnetic Resonance Spectroscopy |
title_short | Non-invasive in vivo assessment of 11β-hydroxysteroid dehydrogenase type 1 activity by (19)F-Magnetic Resonance Spectroscopy |
title_sort | non-invasive in vivo assessment of 11β-hydroxysteroid dehydrogenase type 1 activity by (19)f-magnetic resonance spectroscopy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9523021/ https://www.ncbi.nlm.nih.gov/pubmed/36175417 http://dx.doi.org/10.1038/s41598-022-18740-5 |
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