DOI: 10.1002/chem.201202930 Dissociation Kinetics of Open-Chain and Macrocyclic GadoliniumACHTUNGTRENNUNG(III)- Aminopolycarboxylate Complexes Related to Magnetic Resonance Imaging: Catalytic Effect of Endogenous Ligands Zsolt Baranyai, [a] Zoltµn Pµlinkµs, [a] Fulvio Uggeri, [b] Alessandro Maiocchi, [b] Silvio Aime, [c] and Erno ˝ Brücher* [a] Introduction Linear and macrocyclic aminopolycarboxylate ligands like DTPA and DOTA (Scheme 1) form complexes of high sta- bility with tripositive metal ions, which are widely used in medical diagnosis and therapy. The most important applica- tions include the radiopharmaceuticals in nuclear medicine, the optical imaging probes, and the magnetic resonance imaging (MRI) contrast agents. [1] The complexes formed with 47 Sc, 67 Ga, and 111 In isotopes are used in single photon emission computed tomography (SPECT), while the 90 Y, 153 Sm, 166 Ho, and 177 Lu complexes are applied in the therapy of cancer. The complexes of Eu 3+ , Tb 3+ , and Yb 3+ attached to sensitizing chromophores are used as fluorescence probes. In MRI experiments the complexes of Gd 3+ are Abstract: The kinetics of the metal ex- change reactions between open-chain GdACHTUNGTRENNUNG(DTPA) 2 and GdACHTUNGTRENNUNG(DTPA-BMA), macrocyclic GdACHTUNGTRENNUNG(DOTA)  and GdACHTUNGTRENNUNG(HP- DO3A) complexes, and Cu 2+ ions were investigated in the presence of endoge- nous citrate, phosphate, carbonate and histidinate ligands in the pH range 6–8 in NaCl (0.15 m) at 25 8C. The rates of the exchange reactions of GdACHTUNGTRENNUNG(DTPA) 2 and GdACHTUNGTRENNUNG(DTPA-BMA) are independent of the Cu 2+ concentration in the pres- ence of citrate and the reactions occur via the dissociation of Gd 3+ complexes catalyzed by the citrate ions. The HCO 3  /CO 3 2 and H 2 PO 4  ions also catalyze the dissociation of complexes. The rates of the dissociation of Gd- ACHTUNGTRENNUNG(DTPA-BMA), catalyzed by the en- dogenous ligands, are about two orders of magnitude higher than those of the GdACHTUNGTRENNUNG(DTPA) 2 . In fact near to physio- logical conditions the bicarbonate and carbonate ions show the largest catalyt- ic effect, that significantly increase the dissociation rate of GdACHTUNGTRENNUNG(DTPA-BMA) and make the higher pH values (when the carbonate ion concentration is higher) a risk-factor for the dissocia- tion of complexes in body fluids. The exchange reactions of GdACHTUNGTRENNUNG(DOTA)  and GdACHTUNGTRENNUNG(HP-DO3A) with Cu 2+ 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 com- plexes. More insights into the interac- tion scheme between GdACHTUNGTRENNUNG(DTPA-BMA) and GdACHTUNGTRENNUNG(DTPA) 2 and endogenous lig- ACHTUNGTRENNUNGands have been obtained by acquiring the 13 C NMR spectra of the corre- sponding diamagnetic YACHTUNGTRENNUNG(III)-com- plexes, indicating the increase of the rates of the intramolecular rearrange- ments in the presence of carbonate and citrate ions. The herein reported results may have implications in the under- standing of the etiology of nephrogenic systemic fibrosis, a rare disease that has been associated to the administra- tion of Gd-containing agents to pa- tients with impaired renal function. Keywords: chelates · exchange re- actions · gadolinium · kinetics · re- action mechanisms [a] Dr. Zs. Baranyai, Z. Pµlinkµs, Prof. E. Brücher Department of Inorganic and Analytical Chemistry University of Debrecen 4010, Debrecen, Egyetem tØr 1 (Hungary) Fax: (+ 36) 52518-660 E-mail: ebrucher@sceince.unideb.hu [b] Dr. F. Uggeri, Dr. A. Maiocchi Bracco Imaging S.p.A. Via E. Folli 50, 20135 Milano (Italy) [c] Prof. S. Aime Dipartimento di Chimica & Molecular Imaging Center Università degli Studi di Torino Via Nizza 52, 10126 Torino (Italy) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201202930. Scheme 1. Formulas of the ligands discussed in this work.  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2012, 18, 16426 – 16435 16426