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

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.