Complexes of Fe³⁺ engage in rich aqueous solution speciation chemistry in which discrete molecules can react with solvent water to form multinuclear μ-oxo and μ-hydroxide bridged species. Here we demonstrate how pH- and concentration-dependent equilibration between monomeric and μ-oxo-bridged dimeric Fe³⁺ complexes can be controlled through judicious ligand design. We purposed this chemistry to develop a first-in-class Fe³⁺-based MR imaging probe, Fe-PyCy2AI, that undergoes relaxivity change via pH-mediated control of monomer vs dimer speciation. The monomeric complex exists in a S = 5/2 configuration capable of inducing efficient T₁-relaxation, whereas the antiferromagnetically coupled dimeric complex is a much weaker relaxation agent. The mechanisms underpinning the pH dependence on relaxivity were interrogated by using a combination of pH potentiometry, ¹H and ¹⁷O relaxometry, electronic absorption spectroscopy, bulk magnetic susceptibility, electron paramagnetic resonance spectroscopy, and X-ray crystallography measurements. Taken together, the data demonstrate that PyCy2AI forms a ternary complex with high-spin Fe³⁺ and a rapidly exchanging water coligand, [Fe(PyCy2AI)(H₂O)]⁺ (ML), which can deprotonate to form the high-spin complex [Fe(PyCy2AI)(OH)] (ML(OH)). Under titration conditions of 7 mM Fe complex, water coligand deprotonation occurs with an apparent pK_a 6.46. Complex ML(OH) dimerizes to form the antiferromagnetically coupled dimeric complex [(Fe(PyCy2AI))₂O] ((ML)₂O) with an association constant (K_a) of 5.3 ± 2.2 mM^-1. The relaxivity of the monomeric complexes are between 7- and 18-fold greater than the antiferromagnetically coupled dimer at applied field strengths ranging between 1.4 and 11.7 T. ML(OH) and (ML)₂O interconvert rapidly within the pH 6.0-7.4 range that is relevant to human pathophysiology, resulting in substantial observed relaxivity change. Controlling Fe³⁺ μ-oxo bridging interactions through rational ligand design and in response to local chemical environment offers a robust mechanism for biochemically responsive MR signal modulation.

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