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

Molnár, Enikő and Camus, Nathalie and Patinec, Véronique and Rolla, Gabriele A. and Botta, Mauro and Tircsó, Gyula and Kálmán, Ferenc K. and Fodor, Tamás and Tripier, Raphaël and Platas-Iglesias, Carlos (2014) Picolinate-Containing Macrocyclic Mn2+ Complexes as Potential MRI Contrast Agents. Inorganic Chemistry, 53 (10). pp. 5136-5149. ISSN 0020-1669

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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 Mn2+ 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 Mn2+ 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 Mn2+ 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–η1-carboxylate). Nuclear magnetic relaxation dispersion (1H NMRD) profiles and 17O NMR chemical shifts and transverse relaxation rates of aqueous solutions of [Mn(nompa)]+ indicate that the Mn2+ ion is six-coordinate in solution by the pentadentate ligand and one inner-sphere water molecule. The analysis of the 1H NMRD and 17O NMR data provides a very high water exchange rate of the inner-sphere water molecule (kex298 = 2.8 × 109 s–1) and an unusually high value of the 17O 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.

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