¹⁹F Magnetic Resonance Activity-Based Sensing Using Paramagnetic Metals

Abstract

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.

Partially Fluorinated Copolymers as Oxygen Sensitive 19F MRI Agents

“…[14][15][16][17][18][19][20] Due to the instability of PFCe mulsions, [21,22] encapsulating PFCs into alginatec apsuleso rs ilica nanoparticles has recently been pursued. [23][24][25][26][27] Lastly,h ypoxia-responsive 19 F probesu tilizing paramagnetic relaxation enhancement (PRE) have been shown to accumulate selectively in hypoxic cells, [28][29][30][31] but the low loading of 19 Fn uclei limits their sensitivity.…”

Perfluorocarbons in Chemical Biology

“…Que and co-workers have shown that fluorinated redox-sensitive metal complexes can be employed to study changes in biological environments, like enzyme activity, redox events, and the presence of reactive species or ions ( Figure 9C). [148] A known copper positron emission tomography (PET) probe was modified to alter the ligand scaffold by fluorination to access 33. [149] In this system, paramagnetic d 9 Cu 2 + shortens the spin-spin relaxation time (T 2 ) of nearby 19 F nuclei, weakening the signal of the fluorine nuclei providing an "off" state for the probe.…”

“…The high sensitivity of fluorine nuclei to its environment has also been capitalized on by the Que group. Que and co‐workers have shown that fluorinated redox‐sensitive metal complexes can be employed to study changes in biological environments, like enzyme activity, redox events, and the presence of reactive species or ions (Figure 9C) [148] . A known copper positron emission tomography (PET) probe was modified to alter the ligand scaffold by fluorination to access 33 [149] .…”

Nanoparticle‐Based Activatable Probes for Bioimaging

“…Heteronuclear MRI, especially fluorine MRI, is one of the most promising MR techniques owing to the desirable MR properties of the 19 F nucleus, lack of endogenous 19 F, and good bioinertness of CF bonds. The 19 F nucleus has a nuclear spin of 1/2, and a gyromagnetic ratio that is 94% of 1 H, accounting for an 83% overall signal sensitivity compared to 1 H. [ 10 ] Chemical exchange saturation transfer (CEST) MRI is another imaging technique that can indirectly detect nonlabeled, native molecules by manipulating the water proton signal through selective saturation of exchangeable protons. [ 11 ] CEST MRI has now undergone clinical translation for the imaging of dilute biomarkers associated with the microenvironment as well as administered diamagnetic chemical exchange saturation transfer contrast agents.…”