A seven-coordinate Mn(ii) complex with a pyridine-based 15-membered macrocyclic ligand containing one acetate pendant arm: structure, stability and relaxation properties

Abstract

A new 15-membered pyridine-based macrocyclic ligand containing one acetate pendant arm (N-carboxymethyl-3,12,18-triaza-6,9-dioxabicyclo[12.3.1]octadeca-1(18),14,16-triene, L1) was synthesized and its Mn(II) complex MnL1 was investigated in the context of MRI contrast agent development. The X-ray molecular structure of MnL1 confirmed a coordination number of seven with an axially compressed pentagonal bipyramidal geometry and one coordination site available for an inner-sphere water molecule. The protonation constants of L1 and the stability constants of Mn(II), Zn(II), Cu(II) and Ca(II) complexes were determined by potentiometry, and revealed higher thermodynamic stabilities in comparison with complexes of 15-pyN₃O₂, the parent macrocycle without an acetate pendant arm. The MnL1 complex is fully formed at physiological pH 7.4, but it shows fast dissociation kinetics, as followed by relaxometry in the presence of an excess of Zn(II). The short dissociation half-life estimated for physiological pH (ca. 3 minutes) is related to fast spontaneous dissociation of the non-protonated complex. At lower pH values, the proton-assisted dissociation pathway becomes important, while the Zn(II) concentration has no effect on the dissociation rate. ¹⁷O NMR and ¹H NMRD data indicated the presence of one inner-sphere water molecule with a rather slow exchange (k²⁹⁸_ex = 4.5 × 10⁶ s⁻¹) and provided information about other microscopic parameters governing relaxation. The relaxivity (r₁ = 2.45 mM⁻¹ s⁻¹ at 20 MHz, 25 °C) corresponds to typical values for monohydrated Mn(II) chelates. Overall, the acetate pendant arm in L1 has a beneficial effect with respect to 15-pyN₃O₂ in increasing the thermodynamic stability and kinetic inertness of its Mn(II) complex, but leads to a reduced number of inner-sphere water molecules and thus lower relaxivity.