Hypoxia-Responsive ¹⁹F MRI Probes with Improved Redox Properties and Biocompatibility

¹⁹F magnetic resonance imaging (MRI), an emerging modality in biomedical imaging, has shown promise for in vitro and in vivo preclinical studies. Here we present a series of fluorinated Cu(II)ATSM derivatives for potential use as ¹⁹F magnetic resonance agents for sensing cellular hypoxia. The synthesized complexes feature a hypoxia-targeting Cu²⁺ coordination core, nine equivalent fluorine atoms connected via a variable-length poly(ethylene glycol) linker. Introduction of the fluorine moiety maintains the planar coordination geometry of the Cu²⁺ center, while the linker length modulates the Cu^2+/+ reduction potential, ¹⁹F NMR relaxation properties, and lipophilicity. In particular, the ¹⁹F NMR relaxation properties were quantitatively evaluated by the Solomon-Bloembergen model, revealing a regular pattern of relaxation enhancement tuned by the distance between Cu²⁺ and F atoms. Finally, the potential utility of these complexes for sensing reductive environments was demonstrated using both ¹⁹F MR phantom imaging and ¹⁹F NMR, including experiments in intact live cells.