F Magnetic Resonance Activity-Based Sensing Using Paramagnetic Metals.

Fluorine magnetic resonance imaging (F MRI) is a promising bioimaging technique due to the favorable magnetic resonance properties of the F 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 F nuclei. Paramagnetic centers will enhance relaxation rates of nearby F nuclei through paramagnetic relaxation enhancement (PRE). Further, metals with anisotropic unpaired electrons can induce changes in F 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 F nucleus relative to the metal center. One intriguing prospect in F 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 F response that results from changes in the metal complex structure and subsequently PRE/PCS. Broadly speaking, when designing paramagnetic F 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 F signal. We discuss probes that use conversion from Cu to Cu in response to reducing environments to dequench the F MR signal. Probes in which oxidants convert Co to Co, resulting in chemical shift responses, are also described. Finally, we explore our foray into using Ni coordination switching to furnish probes with different F signals when they are converted between 4-coordinate square planar and higher coordination numbers. A major barrier for F 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.