Picolinate-Containing Macrocyclic Mn²⁺ Complexes as Potential MRI Contrast Agents

Abstract

We report the synthesis of the ligand Hnompa (6-((1,4,7-triazacyclononan-1-yl)methyl)picolinic acid) and a detailed characterization of the Mn(2+) complexes formed by this ligand and the related ligands Hdompa (6-((1,4,7,10-tetraazacyclododecan-1-yl)methyl)picolinic acid) and Htempa (6-((1,4,8,11-tetraazacyclotetradecan-1-yl)methyl)picolinic acid). These ligands form thermodynamically stable complexes in aqueous solution with stability constants of logKMnL = 10.28(1) (nompa), 14.48(1) (dompa), and 12.53(1) (tempa). A detailed study of the dissociation kinetics of these Mn(2+) complexes indicates that the decomplexation reaction at about neutral pH occurs mainly following a spontaneous dissociation mechanism. The X-ray structure of [Mn2(nompa)2(H2O)2](ClO4)2 shows that the Mn(2+) ion is seven-coordinate in the solid state, being directly bound to five donor atoms of the ligand, the oxygen atom of a coordinated water molecule and an oxygen atom of a neighboring nompa(-) ligand acting as a bridging bidentate carboxylate group (μ-η(1)-carboxylate). Nuclear magnetic relaxation dispersion ((1)H NMRD) profiles and (17)O NMR chemical shifts and transverse relaxation rates of aqueous solutions of [Mn(nompa)](+) indicate that the Mn(2+) ion is six-coordinate in solution by the pentadentate ligand and one inner-sphere water molecule. The analysis of the (1)H NMRD and (17)O NMR data provides a very high water exchange rate of the inner-sphere water molecule (kex(298) = 2.8 × 10(9) s(-1)) and an unusually high value of the (17)O hyperfine coupling constant of the coordinated water molecule (AO/ℏ = 73.3 ± 0.6 rad s(-1)). DFT calculations performed on the [Mn(nompa)(H2O)](+)·2H2O system (TPSSh model) provide a AO/ℏ value in excellent agreement with the one obtained experimentally.