An Iron-Based MRI Probe with Tunable Spin State for Bioorthogonally Catalyzed Activation Imaging

Designing a targeted magnetic resonance imaging (MRI) probe is challenging due to the intrinsically micromolar-millimolar sensitivity of MRI and the high background signal associated with traditional gadolinium complexes. To address the challenges, we introduce a bioorthogonal catalysis-activated Fe^II-based MRI probe. The Fe^II probe exhibited near zero relaxivity (0.01 mM^-1 s^-1) in its low-spin state. Upon bioorthogonal catalysis mediated by a ruthenium complex, the probe undergoes a spin-state conversion from low-spin to high-spin followed by spontaneous oxidation to high-spin Fe^III, yielding a mixture of high-spin Fe^II and Fe^III species under photophysical conditions. This transition led to over a 100-fold enhancement in relaxivity with a high turnover number (>200), generating robust MRI contrast. The ruthenium complex was conjugated to bovine serum albumin and predelivered to the tumor site. In vivo bioorthogonal catalysis was subsequently demonstrated in a subcutaneous tumor model. At the tumor site, the catalyst specifically triggers a "turn-on" in relaxivity of the MRI probe, producing markedly enhanced MRI contrast via bioorthogonally catalyzed activation. By combining the specificity of bioorthogonal chemistry with the MRI probe with a tunable spin state, this work establishes the potential of the spin-modulated probe for targeted imaging with low background signals and high imaging contrast.