Open AccessRational Ligand Design Enables pH Control over Aqueous Iron Magnetostructural Dynamics and Relaxometric Properties
Author(s) -
Huan Wang,
Alison Wong,
Luke C. Lewis,
Genevieve R Nemeth,
Veronica Clavijo Jordan,
Jeffrey W. Bacon,
Peter Caravan,
Hannah S. Shafaat,
Eric M. Gale
Publication year - 2020
Publication title -
inorganic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.348
H-Index - 233
eISSN - 1520-510X
pISSN - 0020-1669
DOI - 10.1021/acs.inorgchem.0c02923
Subject(s) - chemistry , deprotonation , dimer , aqueous solution , ligand (biochemistry) , crystallography , titration , denticity , electron paramagnetic resonance , relaxation (psychology) , monomer , nuclear magnetic resonance spectroscopy , inorganic chemistry , stereochemistry , crystal structure , nuclear magnetic resonance , polymer , organic chemistry , ion , social psychology , receptor , psychology , biochemistry , physics
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 p K 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.