CONSPECTUS: Fluorine magnetic resonance imaging ( 19 F MRI) is a promising bioimaging technique due to the favorable magnetic resonance properties of the 19 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, fluorinerich 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 19 F nuclei. Paramagnetic centers will enhance relaxation rates of nearby 19 F nuclei through paramagnetic relaxation enhancement (PRE). Further, metals with anisotropic unpaired electrons can induce changes in 19 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 19 F nucleus relative to the metal center. One intriguing prospect in 19 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 19 F response that results from changes in the metal complex structure and subsequently PRE/PCS. Broadly speaking, when designing paramagnetic 19 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 19 F signal. We discuss probes that use conversion from Cu 2+ to Cu + in response to reducing environments to dequench the 19 F MR signal. Probes in which oxidants convert Co 2+ to Co 3+ , resulting in chemical shift responses, are also described. Finally, we explore our foray into using Ni 2+ coordination switching to furnish probes with different 19 F signals when they are converted between 4-coordinate square planar and higher coordination numbers. A major barrier for 19 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.
A Tm(iii) complex displays an “off–on” 19F NMR/MRI response to Zn(ii) upon tuning the chemical exchange rate.
A Cu2+ complex for bimodal imaging of cellular hypoxia using 19F magnetic resonance and fluorescence.
19F magnetic resonance (MR) based detection coupled with well‐designed inorganic systems shows promise in biological investigations. Two proof‐of‐concept inorganic probes that exploit a novel mechanism for 19F MR sensing based on converting from low‐spin (S=0) to high‐spin (S=1) Ni2+ are reported. Activation of diamagnetic NiL1 and NiL2 by light or β‐galactosidase, respectively, converts them into paramagnetic NiL0, which displays a single 19F NMR peak shifted by >35 ppm with accelerated relaxation rates. This spin‐state switch is effective for sensing light or enzyme expression in live cells using 19F MR spectroscopy and imaging that differentiate signals based on chemical shift and relaxation times. This general inorganic scaffold has potential for developing agents that can sense analytes ranging from ions to enzymes, opening up diverse possibilities for 19F MR based biosensing.
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