Abstract
Complexes of Fe(3+) 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 Fe(3+) complexes can be controlled through judicious ligand design. We purposed this chemistry to develop a first-in-class Fe(3+)-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 T(1)-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, (1)H and (17)O 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 Fe(3+) and a rapidly exchanging water coligand, [Fe(PyCy2AI)(H(2)O)](+) (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))(2)O] ((ML)(2)O) 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)(2)O interconvert rapidly within the pH 6.0-7.4 range that is relevant to human pathophysiology, resulting in substantial observed relaxivity change. Controlling Fe(3+) 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.