Inorganic methods for ¹⁹F magnetic resonance-based biosensing

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. One intriguing opportunity in ¹⁹F magnetic resonance molecular imaging is to design responsive agents that can serve as a readout of biological activity, including but not limited to the activity of enzymes, redox activity, the activity of ions, etc. Paramagnetic centers have the ability to 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 the pseudo-contact shift (PCS) effect. Paramagnetic agents are therefore 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 effect of PRE/PCS. In this thesis, we demonstrated the application of copper (Chapter 2-4) and nickel (Chapter 5-6) complexes as redox- and coordination-based sensors, respectively, for ¹⁹F magnetic resonance biosensing. Fluorinated CuATSM derivatives were prepared for sensing biological hypoxia due to its one-electron Cu²⁺/Cu⁺ redox well matched with cellular reduction potential under hypoxia and its fluorine MR signal effectively attenuated and restored between Cu²⁺ and Cu⁺ state. Prepared probes CuATSM-F₃ (Chapter 2), Cu4 (Chapter 3), and CuL₁ (Chapter 4) possessed an appropriate potential for hypoxia selectivity, and reduction to diamagnetic Cu⁺ complex and ligand dissociation to regenerate the ¹⁹F signal was demonstrated by NMR in cells grown under low O₂ tension. The successful employment of these Cu probes facilitates the translation to in vivo hypoxia sensing via ¹⁹F MR-based techniques. The development of Ni-based probes enables expansion of biosensing strategies and applications beyond biological redox. Proof-of-concept Ni probes based on dioxocyclam (Chapter 5) and side-bridged cyclam (Chapter 6) ligand framework exhibited the magnetic switching properties of the Ni²⁺ center in aqueous media and the potential to couple with ¹⁹F NMR/MRI to achieve sensing of pH, light irradiation and enzymatic activities in living biosystems.