New Bisaqua Picolinate-Based Gadolinium Complexes as MRI Contrast Agents with Substantial High-Field Relaxivities

Two new tripodal heptadentate ligands, H4dpaba (N,N'-bis[(6-carboxypyridin-2-yl)methyl]aspartic acid) and H3mpatcn(1,4-bis(methoxycarbonyl)-7-[(6-carboxypyridin-2-yl)methyl]-1,4,7-triazacyclononane), which bear one or two picolinate pendant arms, have been synthesised. Their lanthanide complexes have been characterised by NMR and fluorescence spectroscopy and potentiometry. Both ligands gave rise to water soluble 1:1 complexes with an increased thermodynamic stability (pGddpaba = 13.3, pGdmpatcn = 11.8, with pGdL = log[Gd]free at pH 7.4, [Gd]total = 1 mu M and [L]total = 10 mu M) with respect to the analogous bisaqua complex [Gd(tpaa)(H2O)2] [H3tpaa = alpha,alpha',alpha''itrilotri(6-methyl-2-pyridinecarboxylic acid), pGdtpaa = 11.2). The two inner-sphere water molecules confer sizeable relaxivities (r1) to the complexes at high field at physiological pH: r1 = 8.90 and r1 = 7.35 mM1s1 have been measured in HOD at 200 MHz for [Gd(dpaba)(HOD)2] and [Gd(mpatcn)(HOD)2], respectively. Their relaxometric properties have been investigated by NMRD (Nuclear Magnetic Relaxation Dispersion) and 17O NMR spectroscopy. The formation of ternary complexes with physiological anions, such as acetate, hydrogen carbonate, hydrogen phosphate and citrate, has been monitored by 1H NMR spectroscopy at 200 MHz and pH 7.4. The addition of a large excess (0.6 M) of acetate, hydrogen phosphate and citrate led to the formation monoaqua ternary complexes. Even under these conditions, the average relaxivity remains higher or similar than most currently used contrast agents. Only hydrogen carbonate interacts strongly with the complexes and coordinates in a bidentate mode by displacing both water molecules to induce a twofold decrease in the relaxivity. Both complexes interact with serum albumin to form a macromolecular adduct with increased relaxivity. In particular, a twofold increase of relaxivity has been measured for [Gd(dpaba)(H2O)2] in bovine serum, which suggests that anion binding does not significantly affect the relaxivity under these conditions.