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Magnetic resonance imaging (MRI) is a powerful and widely used in vivo imaging technique that enables whole body imaging without ionizing radiation. In clinical practice,¹H MRI is employed for imaging anatomical and physiological states via monitoring of protons in water and lipids. In order to monitor biochemical processes at the molecular level, several research groups are exploring responsive MRI agents that alter their signal upon interaction with an analyte or biological environment of interest. Fluorine (¹⁹F) MRI agents are promising due to the¹⁹F nucleus having similar magnetic resonance (MR) properties to proton and the absence of endogenous¹⁹F in living systems, resulting in no background signal. In order to make responsive¹⁹F MR agents for molecular imaging and analysis, fluorinated platforms must be developed in which their¹⁹F MR signal changes after interacting with a target analyte. A promising strategy is to use paramagnetic metals to modulate the¹⁹F MR signal by altering the relaxation rates and/or chemical shift of an appended¹⁹F imaging tag. In this concept, we provide an overview of the theoretical principles and molecular design strategies that have been exploited in the design of responsive¹⁹F MR agents, with a specific focus on agents based on small molecule paramagnetic metal ion chelates.

 

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 for¹⁹F MR sensing based on converting from low‐spin (S=0) to high‐spin (S=1) Ni²⁺are reported. Activation of diamagneticNiL₁andNiL₂by light or β‐galactosidase, respectively, converts them into paramagneticNiL₀, which displays a single¹⁹F 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 using¹⁹F 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 for¹⁹F MR based biosensing.

 

We report a first-in-class responsive, pentafluorosulfanyl (–SF 5 )-tagged 19 F MRI agent capable of reversibly detecting reducing environments via an Fe II/III redox couple. In the Fe III form, the agent displays no 19 F MR signal due to paramagnetic relaxation enhancement-induced signal broadening; however, upon rapid reduction to Fe II with one equivalent of cysteine, the agent displays a robust 19 F signal. Successive oxidation and reduction studies validate the reversibility of the agent. The –SF 5 tag in this agent enables ‘multicolor imaging’ in conjunction with sensors containing alternative fluorinated tags and this was demonstrated via simultaneous monitoring of the 19 F MR signal of this –SF 5 agent and a hypoxia-responsive agent containing a –CF 3 group. 

Targeting the low-oxygen (hypoxic) environments found in many tumours by using redox-active metal complexes is a strategy that can enhance efficacy and reduce the side effects of chemotherapies. We have developed a series of CuII complexes with tridentate pyridine aminophenolate-based ligands for preferential activation in the reduction window provided by hypoxic tissues. Furthermore, ligand functionalization with a pendant CF3 group provides a 19F spectroscopic handle for magnetic-resonance studies of redox processes at the metal centre and behaviour in cellular environments. The phenol group in the ligand backbone was substituted at the para position with H, Cl, and NO2 to modulate the reduction potential of the CuII centre, giving a range of values below the window expected for hypoxic tissues. The NO2-substituted complex, which has the highest reduction potential, showed enhanced cytotoxic selectivity towards HeLa cells grown under hypoxic conditions. Cell death occurs by apoptosis, as determined by analysis of the cell morphology. A combination of 19F NMR and ICP-OES indicates localization of the NO2 complex in HeLa cell nuclei and increased cellular accumulation under hypoxia. This correlates with DNA nuclease activity being the likely origin of cytotoxic activity, as demonstrated by cleavage of DNA plasmids in the presence of the CuII nitro complex and a reducing agent. Selective detection of the paramagnetic CuII complexes and their diamagnetic ligands by 19F MRI suggests hypoxia-targeting theranostic applications by redox activation. 

We report two highly fluorinated Cu-based imaging agents, CuL1 and CuL2 , for detecting cellular hypoxia as nanoemulsion formulations. Both complexes retained their initial quenched 19 F MR signals due to paramagnetic Cu 2+ ; however, both complexes displayed a large signal increase when the complex was reduced. DLS studies showed that the CuL1 nanoemulsion ( NE CuL1 ) had a hydrodiameter of approximately 100 nm and that it was stable for four weeks post-preparation. Hypoxic cells incubated with NE CuL1 showed that 40% of the Cu 2+ taken up was reduced in low oxygen environments.