Mono-, Bi-, and Trinuclear Bis-Hydrated Mn(2+) Complexes as Potential MRI Contrast Agents

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, (Formula presented.) = (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.