GdIII Complexes with Fast Water Exchange and High Thermodynamic Stability: Potential Building Blocks for High‐Relaxivity MRI Contrast Agents

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Abstract
On the basis of structural considerations in the inner sphere of nine‐coordinate, monohydrated GdIII poly(aminocarboxylate) complexes, we succeeded in accelerating the water exchange by inducing steric compression around the water binding site. We modified the common DTPA5− ligand (DTPA=(diethylenetriamine‐N,N,N′,N″,N″‐pentaacetic acid) by replacing one (EPTPA5−) or two (DPTPA5−) ethylene bridges of the backbone by propylene bridges, or one coordinating acetate by a propionate arm (DTTA‐prop5−). The ligand EPTPA5− was additionally functionalized with a nitrobenzyl linker group (EPTPA‐bz‐NO25−) to allow for coupling of the chelate to macromolecules. The water exchange rate, determined from a combined variable‐temperature 17O NMR and EPR study, is two orders of magnitude higher on [Gd(eptpa‐bz‐NO2)(H2O)]2− and [Gd(eptpa)(H2O)]2− than on [Gd(dtpa)(H2O)]2− (k =150×106, 330×106, and 3.3×106 s−1, respectively). This is optimal for attaining maximum proton relaxivities for GdIII‐based, macrocyclic MRI contrast agents. The activation volume of the water exchange, measured by variable‐pressure 17O NMR spectroscopy, evidences a dissociative interchange mechanism for [Gd(eptpa)(H2O)]2− (ΔV ≠=(+6.6±1.0) cm3 mol−1). In contrast to [Gd(eptpa)(H2O)]2−, an interchange mechanism is proved for the macrocyclic [Gd(trita)(H2O)]− (ΔV ≠=(−1.5±1.0) cm3 mol−1), which has one more CH2 group in the macrocycle than the commercial MRI contrast agent [Gd(dota)(H2O)]−, and for which the elongation of the amine backbone also resulted in a remarkably fast water exchange. When one acetate of DTPA5− is substituted by a propionate, the water exchange rate on the GdIII complex increases by a factor of 10 (k =31×106 s−1). The [Gd(dptpa)]2− chelate has no inner‐sphere water molecule. The protonation constants of the EPTPA‐bz‐NO25− and DPTPA5− ligands and the stability constants of their complexes with GdIII, ZnII, CuII and CaII were determined by pH potentiometry. Although the thermodynamic stability of [Gd(eptpa‐bz‐NO2)(H2O)]2− is reduced to a slight extent in comparison with [Gd(dtpa)(H2O)]2−, it is stable enough to be used in medical diagnostics as an MRI contrast agent. Therefore both this chelate and [Gd(trita)(H2O)]− are potential building blocks for the development of high‐relaxivity macromolecular agents.

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