19F Magnetic Resonance Activity-Based Sensing Using Paramagnetic Metals

Fluorine magnetic resonance imaging (¹⁹F MRI) is a promising bioimaging technique due to the favorable magnetic resonance properties of the ¹⁹F nucleus and the lack of detectable biological background signal. A range of imaging agents have been developed for this imaging modality including small molecule perfluorocarbons, fluorine-rich macromolecules and nanoparticles, and paramagnetic metal-containing agents. Incorporation of paramagnetic metals into fluorinated agents provides a unique opportunity to manipulate relaxation and chemical shift properties of ¹⁹F nuclei. Paramagnetic centers will enhance relaxation rates of nearby ¹⁹F nuclei through paramagnetic relaxation enhancement (PRE). Further, metals with anisotropic unpaired electrons can induce changes in ¹⁹F chemical shift through pseudocontact shift (PCS) effects. PRE and PCS are dependent on the nature of the metal center itself, the molecular scaffold surrounding it, and the position of the ¹⁹F nucleus relative to the metal center. One intriguing prospect in ¹⁹F magnetic resonance molecular imaging is to design responsive agents that can serve to provide a read out biological activity, including the activity of enzymes, redox activity, the activity of ions, etc. Paramagnetic agents are well suited for this activity-based sensing as metal complexes can be designed to respond to specific biological activities and give a corresponding ¹⁹F response that results from changes in the metal complex structure and subsequently PRE/PCS. Broadly speaking, when designing paramagnetic ¹⁹F MR biosensors, one can envision that in response to changes in analyte activity, the number of unpaired electrons of the metal changes or the ligand conformation/chemical composition changes. This Account highlights activity-based probes from the Que lab that harness paramagnetic metals to modulate ¹⁹F signal. We discuss probes that use conversion from Cu²⁺ to Cu⁺ in response to reducing environments to dequench the ¹⁹F MR signal. Probes in which oxidants convert Co²⁺ to Co³⁺, resulting in chemical shift responses, are also described. Finally, we explore our foray into using Ni²⁺ coordination switching to furnish probes with different ¹⁹F signals when they are converted between 4-coordinate square planar and higher coordination numbers. A major barrier for ¹⁹F MR molecular imaging is in vivo application, as signal sensitivity is relatively low, requiring long imaging times to detect imaging agents. Nanoparticle and macromolecular agents show promise due to their higher fluorine density and longer circulation times; however, their analyte scope is limited to analytes that induce cleavage events. A grand challenge for researchers in this area is adapting lessons learned from small molecule paramagnetic probes with promising in vitro activities for the development of probes with enhanced in vivo utility for basic biological and clinical applications.