Non-invasive in vivo assessment of 11β-hydroxysteroid dehydrogenase type 1 activity by 19F-Magnetic Resonance Spectroscopy

  • Sci Rep. 2022 Sep 29;12(1):16268. doi: 10.1038/s41598-022-18740-5.
Gregorio Naredo-Gonzalez  1 ,  Rita Upreti  1 ,  Maurits A Jansen  1  2 ,  Scott Semple  1  2 ,  Oliver B Sutcliffe  3 ,  Ian Marshall  2  4 ,  Brian R Walker  #  1  5 ,  Ruth Andrew  #  6
Affiliations
  • 1. University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, EH16 4TJ, Scotland, UK.
  • 2. Edinburgh Imaging, Queen's Medical Research Institute, 47 Little France Crescent, University of Edinburgh, Edinburgh, EH16 4TJ, Scotland, UK.
  • 3. Department of Natural Sciences, Faculty of Science and Engineering, Manchester Metropolitan University, Chester Street, Manchester, M1 5GD, UK.
  • 4. Centre for Clinical Brain Sciences, Chancellor's Building, 49 Little France Crescent, University of Edinburgh, Edinburgh, EH16 4SB, Scotland, UK.
  • 5. Institute of Translational and Clinical Research, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
  • 6. University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, EH16 4TJ, Scotland, UK. [email protected].
  • # Contributed equally.
PMID: 36175417 DOI: 10.1038/s41598-022-18740-5
Abstract

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 19Fluorine magnetic resonance spectroscopy (19F-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 19F-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.

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