Enzyme Control Over Ferric Iron Magnetostructural Properties

Abstract

Fe 3 + complexes in aqueous solution can exist as discrete mononuclear species or multinuclear magnetically coupled species. Stimuli-driven change to Fe 3 + speciation represents a powerful mechanistic basis for magnetic resonance sensor technology, but ligand design strategies to exert precision control of aqueous Fe 3 + magnetostructural properties are entirely underexplored. In pursuit of this objective, we rationally designed a ligand to strongly favor a dinuclear μoxo-bridged and antiferromagnetically coupled complex, but which undergoes carboxylesterase mediated transformation to a mononuclear high-spin Fe 3 + chelate resulting in substantial T 1 -relaxivity increase. The data communicated demonstrate proof of concept for a novel and effective strategy to exert biochemical control over aqueous Fe 3 + magnetic, structural, and relaxometric properties.

Redox-Responsive MRI Probes Based on First-Row Transition-Metal Complexes

“…The iron complexes were used to image inflammation in the pancreas (pancreatitis), which was induced artificially by addition of lipopolysaccharide (LPS) (Figure ). Gale’s group has used analogous Fe­(III) complexes with mixed acetate and nitrogen heterocycle pendants to switch between mononuclear Fe­(III) complexes with an inner-sphere water and μ-hydroxy-bridged dinuclear Fe­(III) complexes of lowered relaxivity through either enzymatic or pH-driven reactions.…”

Fe(III) T1 MRI Probes Containing Phenolate or Hydroxypyridine-Appended Triamine Chelates and a Coordination Site for Bound Water

“…There are, however, significant hurdles to overcome in the chemistry of Fe(III)-based MRI probes including the propensity of Fe(III) six-coordinate complexes to have inner-sphere water ligands that exchange too slowly to contribute optimally to relaxivity 7,11 and for these water ligands to form hydroxide or bridging oxide complexes at neutral pH which generally reduces the relaxivity of the probe. 2,12,13 As a result of these challenges, the number of Fe(III) complexes that have been reported for in vivo MRI studies remains limited. 2,14 Similar to gadolinium-based contrast agents, high-spin Fe(III) complexes shorten the T 1 relaxation times of water protons through inner-sphere, second-sphere, and outer-sphere water interactions.…”

“…22 On the other hand, some applications rely on the redox properties of Fe(III)/Fe(II) for the development of agents that register inflammation by oxidation to an Fe(III) T 1 agent. 12,23,24 Several complexes studied as redox-responsive iron-based agents feature a trans-diaminocyclohexane scaffold appended with pyridyl or imidazole donor groups. 12,13 Fe(III) complexes of macrocyclic ligands featuring triazacyclononane (TACN) are a more recently developed class of T 1 MRI probes.…”

“…12,23,24 Several complexes studied as redox-responsive iron-based agents feature a trans-diaminocyclohexane scaffold appended with pyridyl or imidazole donor groups. 12,13 Fe(III) complexes of macrocyclic ligands featuring triazacyclononane (TACN) are a more recently developed class of T 1 MRI probes. 7 These macrocycles may be appended with hydroxypropyl or phosphonate groups.…”

“…Moreover, the human body has biological pathways that regulate iron to maintain homeostasis and limit bioaccumulation. There are, however, significant hurdles to overcome in the chemistry of Fe­(III)-based MRI probes including the propensity of Fe­(III) six-coordinate complexes to have inner-sphere water ligands that exchange too slowly to contribute optimally to relaxivity , and for these water ligands to form hydroxide or bridging oxide complexes at neutral pH which generally reduces the relaxivity of the probe. ,, As a result of these challenges, the number of Fe­(III) complexes that have been reported for in vivo MRI studies remains limited. , …”