Activatable ¹⁹F NMR probes from drug scaffolds for assessing myeloperoxidase-associated inflammation

Myeloperoxidase (MPO)-derived hypochlorous acid (HClO) is a key oxidant in inflammatory diseases such as sepsis and neuroinflammation. Selective detection of MPO-derived HClO in complex biological matrices remains challenging. ¹⁹F NMR spectroscopy offers zero-background, environment-sensitive chemical shifts and easy quantification. Herein, we report a series of drug-derived, nitrone-based ¹⁹F NMR probes (¹⁹FP-1 to ¹⁹FP-14) that respond specifically to HClO via nitrone oxidation, producing a distinct ¹⁹F chemical shift change. Systematic screening identified ¹⁹FP-10 as the optimal probe, exhibiting a chemical shift change of >2 ppm, high selectivity over other reactive oxygen species, and a linear concentration-dependent response to HClO. Importantly, ¹⁹FP-10 enables effective detection of HClO in mouse plasma from a sepsis model and discriminates between inflamed and healthy brain tissue in a neuroinflammation model. Additionally, ¹⁹FP-10 protects cells from oxidative stress and exhibits good in vivo biosafety, underscoring its translational potential. This work successfully establishes a class of activatable ¹⁹F NMR probes based on drug scaffolds, featuring both low toxicity and high selectivity, providing a clinically translatable molecular tool for assessing MPO-associated inflammation.