Mn2+ Complexes with 12-Membered Pyridine Based Macrocycles Bearing Carboxylate or Phosphonate Pendant Arm: Crystallographic, Thermodynamic, Kinetic, Redox, and 1H/17O Relaxation Studies

Mn2+ complexes represent an alternative to Gd3+ chelates which are widely used contrast agents in magnetic resonance imaging. In this perspective, the authors studied the Mn2+ complexes of two 12-membered, pyridine-contg. macrocyclic ligands bearing one pendant arm with a carboxylic acid (HL1, 6-carboxymethyl-3,6,9,15-tetraazabicyclo[9.3.1] pentadeca-1(15),11,13-triene) or a phosphonic acid function (H2L2, 6-dihydroxyphosphorylmethyl-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene). Both ligands were synthesized using nosyl or tosyl amino-protecting groups (starting from diethylenetriamine or tosylaziridine). The x-ray crystal structures confirmed a coordination no. of 6 for Mn2+ in their complexes. In aq. soln., these pentadentate ligands allow one free coordination site for a H2O mol. Potentiometric titrn. data indicated a higher basicity for H2L2 than that for HL1, related to the electron-donating effect of the neg. charged phosphonate group. According to the protonation sequence detd. by 1H and 31P pH-NMR titrns., the 1st two protons are attached to macrocyclic amino groups whereas the subsequent protonation steps occur on the pendant arm. Both ligands form thermodynamically stable complexes with Mn2+, with full complexation at physiol. pH and 1:1 metal to ligand ratio. The kinetic inertness was studied via reaction with excess of Zn2+ under various pHs. The dissocn. of MnL2 is instantaneous (at pH 6). For MnL1, the dissocn. is very fast (kobs = 1-12 × 103 s-1), much faster than that for MnDOTA, MnNOTA, or the Mn2+ complex of the 15-membered analog. It proceeds exclusively via the dissocn. of the monoprotonated complex, without any influence of Zn2+. In aq. soln., both complexes are air-sensitive leading to Mn3+ species, as evidenced by UV-visible and 1H NMRD measurements and x-ray crystallog. Cyclic voltammetry gave low oxidn. peak potentials (Eox = 0.73 V for MnL1 and Eox = 0.68 V for MnL2), in accordance with air-oxidn. The parameters governing the relaxivity of the Mn2+ complexes were detd. from variable-temp. 17O NMR and 1H NMRD data. The H2O exchange is extremely fast, kex = 3.03 and 1.77 × 109 s-1 for MnL1 and MnL2, resp. Variable-pressure 17O NMR measurements were performed to assess the H2O exchange mechanism on MnL1 and MnL2 as well as on other Mn2+ complexes. The neg. activation vols. for both MnL1 and MnL2 complexes confirmed an associative mechanism of the H2O exchange as expected for a hexacoordinated Mn2+ ion. The hydration no. of q = 1 was confirmed for both complexes by 17O chem. shifts. A relaxometric titrn. with phosphate, carbonate or citrate excluded the replacement of the coordinated H2O mol. by these small endogenous anions