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, we investigated the Mn2+ complexes of two 12-membered, pyridine-containing 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 number of 6 for Mn2+ in their complexes. In aqueous solution, these pentadentate ligands allow one free coordination site for a water molecule. Potentiometric titration data indicated a higher basicity for H2L2 than that for HL1, related to the electron-donating effect of the negatively charged phosphonate group. According to the protonation sequence determined by H-1 and (31) pH-NMR titrations, the first 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 physiological pH and 1:1 metal to ligand ratio. The kinetic inertness was studied via reaction with excess of Zn2+ under various pHs. The dissociation of MnL2 is instantaneous (at pH 6). For MnL1), the dissociation is very fast (k(obs) = 1-12 x 10(3) s(-1)), much faster than that for MnDOTA, MnNOTA, or the Mn2+ complex of the 15-membered analogue. It proceeds exclusively via the dissociation of the monoprotonated complex, without any influence of Zn2+. In aqueous solution, both complexes are air-sensitive leading to Mn3+ species, as evidenced by UV-vis and H-1 NMRD measurements and X-ray crystallography. Cyclic voltammetry gave low oxidation peak potentials (E-ox = 0.73 V for MnL1 and E-ox, = 0.68 V for MnL2), in accordance with air-oxidation. The parameters governing the relaxivity of the Mn2+ complexes were determined from variable-temperature O-17 NMR and H-1 NMRD data. The water exchange is extremely fast, k(ex) = 3.03 and 1.77 X 10(9) s(-1) for MnL1 and MnL2, respectively. Variable-pressure O-17 NMR measurements have been performed to assess the water exchange mechanism on MnL1 and MnL2 as well as on other Mn2+ complexes. The negative activation volumes for both MnL1 and MnL2 complexes confirmed an associative mechanism of the water exchange as expected for a hexacoordinated Mn2+ ion. The hydration number of q = 1 was confirmed for both complexes by O-17 chemical shifts. A relaxometric titration with phosphate, carbonate or citrate excluded the replacement of the coordinated water molecule by these small endogenous anions.