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Mono-, Bi-, and Trinuclear Bis-Hydrated Mn²⁺ Complexes as Potential MRI Contrast Agents

Attila Forgács^†, Martín Regueiro-Figueroa‡, José Luis Barriada§, David Esteban-Gómez‡, Andrés de Blas‡, Teresa Rodríguez-Blas‡, Mauro Botta^*†, and Carlos Platas-Iglesias^*‡

^† Dipartimento di Scienze e Innovazione Tecnologica, Università del Piemonte Orientale “A. Avogadro”, Viale T. Michel 11, 15121 Alessandria, Italy

^‡Grupo QUICOOR, Centro de Investigaciones Cientı́ficas Avanzadas (CICA) and Departamento de Química Fundamental and ^§Departamento de Química Física e Enxeñaría Química I, Universidade da Coruña, Campus da Zapateira, Rúa da Fraga 10, 15008 A Coruña, Spain

Inorg. Chem., 2015, 54 (19), pp 9576–9587

DOI: 10.1021/acs.inorgchem.5b01677

Publication Date (Web): September 23, 2015

Copyright © 2015 American Chemical Society

*E-mail: mauro.botta@uniupo.it., *E-mail: carlos.platas.iglesias@udc.es.

http://pubsdc3.acs.org/doi/10.1021/acs.inorgchem.5b01677 

Synopsis

Bis hydrated di- and trinuclear Mn²⁺ complexes present remarkable relaxivities upon binding to human serum albumin, while the mononuclear analogue shows lower relaxivities due to the displacement of the coordinated water molecules by donor atoms of the protein.

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Abstract

We report a series of ligands containing pentadentate 6,6′-((methylazanediyl)bis(methylene))dipicolinic acid binding units that form mono- (H₂dpama), di- (mX(H₂dpama)₂), and trinuclear (mX(H₂dpama)₃) complexes with Mn²⁺ containing two coordinated water molecules per metal ion, which results in pentagonal bipyramidal coordination around the metal ions. In contrast, the hexadentate ligand 6,6′-((ethane-1,2-diylbis(azanediyl))bis(methylene))dipicolinic acid (H₂bcpe) forms a complex with distorted octahedral coordination around Mn²⁺ that lacks coordinated water molecules. The protonation constants of the ligands and the stability constants of the Mn²⁺, Cu²⁺, and Zn²⁺ complexes were determined using potentiometric and spectrophotometric titrations in 0.15 M NaCl. The pentadentate dpama^2– ligand and the di- and trinucleating mX(dpama)₂^4– and mX(dpama)₃^6–ligands provide metal complexes with stabilities that are very similar to that of the complex with the hexadentate ligand bcpe^2–, with log β₁₀₁ values in the range 10.1–11.6. Cyclic voltammetry experiments on aqueous solutions of the [Mn(bcpe)] complex reveal a quasireversible system with a half-wave potential of +595 mV versus Ag/AgCl. However, [Mn(dpama)] did not suffer oxidation in the range 0.0–1.0 V, revealing a higher resistance toward oxidation. A detailed ¹H NMRD and ¹⁷O NMR study provided insight into the parameters that govern the relaxivity for these systems. The exchange rate of the coordinated water molecules in [Mn(dpama)] is relatively fast, k_ex²⁹⁸ = (3.06 ± 0.16) × 10⁸ s^–1. The trinuclear [mX(Mn(dpama)(H₂O)₂)₃] complex was found to bind human serum albumin with an association constant of 1286 ± 55 M^–1 and a relaxivity of the adduct of 45.2 ± 0.6 mM^–1 s^–1 at 310 K and 20 MHz.