Dissociation Kinetics of Open-Chain and Macrocyclic Gadolinium(III)-Aminopolycarboxylate Complexes Related to Magnetic Resonance Imaging: Catalytic Effect of Endogenous Ligands

The kinetics of the metal exchange reactions between open-chain Gd(DTPA)2- and Gd(DTPA-BMA), macrocyclic Gd(DOTA)- and Gd(HP-DO3A) complexes, and Cu2+ions were investigated in the presence of endogenous citrate, phosphate, carbonate and histidinate ligands in the pH range 6-8 in NaCl (0.15 M) at 25 °C. The rates of the exchange reactions of Gd(DTPA)2- and Gd(DTPA-BMA) are independent of the Cu2+ concentration in the presence of citrate and the reactions occur via the dissociation of Gd3+complexes catalyzed by the citrate ions. The HCO3 -/CO3 2- and H2PO 4 - ions also catalyze the dissociation of complexes. The rates of the dissociation of Gd(DTPA-BMA), catalyzed by the endogenous ligands, are about two orders of magnitude higher than those of the Gd(DTPA) 2-. In fact near to physiological conditions the bicarbonate and carbonate ions show the largest catalytic effect, that significantly increase the dissociation rate of Gd(DTPA-BMA) and make the higher pHvalues (when the carbonate ion concentration is higher) a risk-factor for the dissociation of complexes in body fluids. The exchange reactions of Gd(DOTA)- and Gd(HP-DO3A) with Cu2+ occur through the proton assisted dissociation of complexes in the pH range 3.5-5 and the endogenous ligands do not affect the dissociation rates of complexes. More insights into the interaction scheme between Gd(DTPA-BMA) and Gd(DTPA)2- and endogenous ligands have been obtained by acquiring the 13CNMR spectra of the corresponding diamagnetic Y(III)-complexes, indicating the increase of the rates of the intramolecular rearrangements in the presence of carbonate and citrate ions. The herein reported results may have implications in the understanding of the etiology of nephrogenic systemic fibrosis, a rare disease that has been associated to the administration of Gd-containing agents to patients with impaired renal function. Transmetalation reactions of Gd(DTPA)2- and Gd(DTPA-BMA) with Cu2+ occur through the dissociation of complexes catalyzed by endogenous citrate, phosphate, and carbonate ions. The dissociation of Gd(DTPA-BMA) is catalyzed mainly by CO3 2-ions. The reactions of Gd(DOTA)- and Gd(HP-DO3A) with Cu2+ take place through the proton-assisted dissociation of complexes and the endogenous ligands do not affect the dissociation rates (see figure)