A Reactive and Specific Sensor for Activity-Based ¹⁹F-MRI Sensing of Zn²

The rapid fluctuations of metal ion levels in biological systems are faster than the time needed to map fluorinated sensors designed for the ¹⁹F-MRI of cations. An attractive modular solution might come from the activity-based sensing approach. Here, we propose a highly reactive but still ultimately specific synthetic fluorinated sensor for ¹⁹F-MRI mapping of labile Zn²⁺. The sensor comprises a dipicolylamine scaffold for Zn²⁺ recognition conjugated to a fluorophenyl acetate entity. Upon binding to Zn²⁺, the synthetic sensor is readily hydrolyzed, and the frequency of its ¹⁹F-functional group in ¹⁹F-NMR is shifted by 12 ppm, allowing the display of the Zn²⁺ distribution as an artificial MRI-colored map highlighting its specificity compared to other metal ions. The irreversible Zn²⁺-induced hydrolysis results in a "turn-on" ¹⁹F-MRI, potentially detecting the cation even upon a transient elevation of its levels. We envision that additional metal-ion sensors can be developed based on the principles demonstrated in this work, expanding the molecular toolbox currently used for ¹⁹F-MRI.