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Structural optimization of Zn(II)-activated magnetic resonance imaging probes.

ABSTRACT: We report the structural optimization and mechanistic investigation of a series of bioactivated magnetic resonance imaging contrast agents that transform from low relaxivity to high relaxivity in the presence of Zn(II). The change in relaxivity results from a structural transformation of the complex that alters the coordination environment about the Gd(III) center. Here, we have performed a series of systematic modifications to determine the structure that provides the optimal change in relaxivity in response to the presence of Zn(II). Relaxivity measurements in the presence and absence of Zn(II) were used in conjunction with measurements regarding water access (namely, number of water molecules bound) to the Gd(III) center and temperature-dependent (13)C NMR spectroscopy to determine how the coordination environment about the Gd(III) center is affected by the distance between the Zn(II)-binding domain and the Gd(III) chelate, the number of functional groups on the Zn(II)-binding domain, and the presence of Zn(II). The results of this study provide valuable insight into the design principles for future bioactivated magnetic resonance probes.

SUBMITTER: Matosziuk LM

PROVIDER: S-EPMC3805786 | biostudies-other | 2013 Nov

REPOSITORIES: biostudies-other

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Structural optimization of Zn(II)-activated magnetic resonance imaging probes.

Matosziuk Lauren M LM Leibowitz Jonathan H JH Heffern Marie C MC MacRenaris Keith W KW Ratner Mark A MA Meade Thomas J TJ

Inorganic chemistry 20130618 21

We report the structural optimization and mechanistic investigation of a series of bioactivated magnetic resonance imaging contrast agents that transform from low relaxivity to high relaxivity in the presence of Zn(II). The change in relaxivity results from a structural transformation of the complex that alters the coordination environment about the Gd(III) center. Here, we have performed a series of systematic modifications to determine the structure that provides the optimal change in relaxivi ...[more]

PMID: 23777423

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Project description:A library of 10 Mn-containing complexes capable of switching reversibly between the Mn(II) and Mn(III) oxidation states was prepared and evaluated for potential usage as MRI reporters of tissue redox activity. We synthesized N-(2-hydroxybenzyl)-N,N',N'-ethylenediaminetriacetic acid (HBET) and N-(2-hydroxybenzyl-N,N',N'-trans-1,2-cyclohexylenediaminetriacetic acid (CyHBET) ligands functionalized (-H, -OMe, -NO2) at the 5-position of the aromatic ring. The Mn(II) complexes of all ligands and the Mn(III) complexes of the 5-H and 5-NO2 functionalized ligands were synthesized and isolated, but the Mn(III) complexes with the 5-OMe functionalized ligands were unstable. (1)H relaxivity of the 10 isolable complexes was measured at pH 7.4 and 37 °C, 1.4 T. Thermodynamic stability, pH-dependent complex speciation, hydration state, water exchange kinetics of the Mn(II) complexes, and pseudo-first order reduction kinetics of the Mn(III) complexes were studied using a combination of pH-potentiometry, UV-vis spectroscopy, and (1)H and (17)O NMR measurements. The effects of ligand structural and electronic modifications on the Mn(II/III) redox couple were studied by cyclic voltammetry. The Mn(II) complexes are potent relaxation agents as compared to the corresponding Mn(III) species with [Mn(II)(CyHBET)(H2O)](2-) exhibiting a 7.5-fold higher relaxivity (3.3 mM(-1) s(-1)) than the oxidized form (0.4 mM(-1) s(-1)). At pH 7.4, Mn(II) exists as a mixture of fully deprotonated (ML) and monoprotonated (HML) complexes and Mn(II) complex stability decreases as the ligands become more electron-releasing (pMn for 10 μM [Mn(II)(CyHBET-R')(H2O)](2-) decreases from 7.6 to 6.2 as R' goes from -NO2 to -OMe, respectively). HML speciation increases as the electron-releasing nature of the phenolato-O donor increases. The presence of a water coligand is maintained upon conversion from HML to ML, but the water exchange rate of ML is faster by up to 2 orders of magnitude (k(ex)(310) for H[Mn(II)(CyHBET)(H2O)](-) and [Mn(II)(CyHBET)(H2O)](2-) are 1.2 × 10(8) and 1.0 × 10(10) s(-1), respectively). The Mn(II/III) redox potential can be tuned over a range of 0.30 V (E(1/2) = 0.27-0.57 V) through electronic modifications to the 5-substituent of the aromatic ligand component. However, care must be taken in tuning the ligand electronics to avoid Mn(III)-ligand autoredox. Taken together, these results serve to establish criteria for optimizing Mn(III) versus Mn(II) relaxivity differentials, complex stability, and Mn(II/III) redox potential.

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Structural optimization of Zn(II)-activated magnetic resonance imaging probes.

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Structural optimization of Zn(II)-activated magnetic resonance imaging probes.

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