GdIII complexes with fast water exchange and high thermodynamic stability: potential building blocks for high-relaxivity MRI contrast agents.

On the basis of structural considerations in the inner sphere of nine-coordinate, monohydrated Gd(III) poly(aminocarboxylate) complexes, we succeeded in accelerating the water exchange by inducing steric compression around the water binding site. We modified the common DTPA(5-) ligand (DTPA=(diethylenetriamine-N,N,N',N",N"-pentaacetic acid) by replacing one (EPTPA(5-)) or two (DPTPA(5-)) ethylene bridges of the backbone by propylene bridges, or one coordinating acetate by a propionate arm (DTTA-prop(5-)). The ligand EPTPA(5-) was additionally functionalized with a nitrobenzyl linker group (EPTPA-bz-NO(2) (5-)) to allow for coupling of the chelate to macromolecules. The water exchange rate, determined from a combined variable-temperature (17)O NMR and EPR study, is two orders of magnitude higher on Gd(eptpa-bz-NO(2))(H(2)O) and Gd(eptpa)(H(2)O) than on Gd(dtpa)(H(2)O) (k(ex)298=150x10(6), 330x10(6), and 3.3x10(6) s(-1), respectively). This is optimal for attaining maximum proton relaxivities for Gd(III)-based, macrocyclic MRI contrast agents. The activation volume of the water exchange, measured by variable-pressure (17)O NMR spectroscopy, evidences a dissociative interchange mechanism for Gd(eptpa)(H(2)O) (DeltaV(not equal sign)=(+6.6+/-1.0) cm(3) mol(-1)). In contrast to Gd(eptpa)(H(2)O), an interchange mechanism is proved for the macrocyclic Gd(trita)(H(2)O) (DeltaV (not equal sign)=(-1.5+/-1.0) cm(3) mol(-1)), which has one more CH(2) group in the macrocycle than the commercial MRI contrast agent Gd(dota)(H(2)O), and for which the elongation of the amine backbone also resulted in a remarkably fast water exchange. When one acetate of DTPA(5-) is substituted by a propionate, the water exchange rate on the Gd(III) complex increases by a factor of 10 (k(ex)298=31x10(6) s(-1)). The Gd(dptpa) chelate has no inner-sphere water molecule. The protonation constants of the EPTPA-bz-NO(2) (5-) and DPTPA(5-) ligands and the stability constants of their complexes with Gd(III), Zn(II), Cu(II) and Ca(II) were determined by pH potentiometry. Although the thermodynamic stability of Gd(eptpa-bz-NO(2))(H(2)O) is reduced to a slight extent in comparison with Gd(dtpa)(H(2)O), it is stable enough to be used in medical diagnostics as an MRI contrast agent. Therefore both this chelate and Gd(trita)(H(2)O) are potential building blocks for the development of high-relaxivity macromolecular agents.