Synthesis, Equilibrium and Kinetic Properties of Gd 3+ Complexes of Three DTPA‐Bis(Amide) Derivatives Containing Stable Nitroxide Free Radical Substituents

Two new DTPA‐bis(amide) derivatives containing stable nitroxide free radicals, H 3 L 2 and H 3 L 3 , were synthesized. The complexation properties of L 2 and L 3 with Gd 3+ were compared with those of H 3 L 1 , synthesized earlier. The sums of the protonation constants Σlog K i H of the DTPA‐bis(amide) derivative ligands with stable nitroxide free radicals are somewhat higher than that for DTPA‐bis(methylamide) (H 3 L 4 ). The ligands L 1 , L 2 , and L 3 form complexes with a metal‐to‐ligand ratio of 1:1 with Gd 3+ (GdL), while the species formed with Zn 2+ are ZnL, ZnHL, ZnH 2 L, and Zn 2 L. The formation of the dinuclear complex Zn 2 L results in a lower selectivity of the ligands for Gd 3+ over Zn 2+ than was assumed for L 4 . The relaxivities of the complexes GdL 1 , GdL 2 , and GdL 3 are close to the sums of the relaxivities of the complex GdL 4 and of the free ligands L 1 , L 2 , and L 3 . The relaxivities of GdL 1 , GdL 2 , and GdL 3 are practically independent of temperature in the 7−30 °C range, which is probably a result of the relatively long lifetime of the water molecules in the inner spheres of the [GdL(H 2 O)] complexes. The kinetic stabilities of the Gd 3+ complexes were characterized by the rates of the exchange reactions taking place between the complexes GdL and Lu 3+ or Zn 2+ . The reactions occur through the proton‐assisted dissociation of the complexes, with the formation of a protonated intermediate. Another pathway is the direct reaction between the Gd 3+ complex and Lu 3+ or Zn 2+ , which occurs with the formation of a dinuclear intermediate, GdLM. The exchange reactions proceed about five times more rapidly with Zn 2+ than with Lu 3+ , indicating the importance of the formation of an intermediate containing an N−Zn 2+ bond, which is stronger than the N−Lu 3+ bond in an intermediate with similar structure. The exchange reactions of the complex GdL 3 formed with the disubstituted ligand L 3 are significantly slower than those of the complexes of the monosubstituted ligands L 1 and L 2 . (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)