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 Cu2+/+ 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.