Synthesis, equilibrium and kinetic properties of Gd3+ complexes of three DTPA-bis(amide) derivatives containing stable nitroxide free radical substituents

Two new DTPA-bis(amide) derivatives containing stable nitroxide free radicals, H3L2 and H3L3, were synthesized. The complexation properties of L-2 and L-3 with Gd3+ were compared with those of H3L1, synthesized earlier. The sums of the protonation constants SigmalogK(i)(H) of the DTPA-bis(amide) derivative ligands with stable nitroxide free radicals are somewhat higher than that for DTPA-bis(methylamide) (H3L4). The ligands L-1, L-2, and L-3 form complexes with a metal-to-ligand ratio of 1:1 with Gd3+, (GdL), while the species formed with Zn2+ are ZnL, ZnHL, ZnH2L, and Zn2L, The formation of the dinuclear complex Zn2L results in a lower selectivity of the ligands for Gd3+ over Zn2+ than was assumed for L-4. The relaxivities of the complexes GdL1, GdL2, and GdL3 are close to the sums of the relaxivities of the complex GdL4 and of the free ligands L-1, L-2, and L-3. The relaxivities of GdL1, GdL2, and GdL3 are practically independent of temperature in the 7-30 degreesC range, which is probably a result of the relatively long lifetime of the water molecules in the inner spheres of the [GdL(H2O)] complexes. The kinetic stabilities of the Gd3+ complexes were characterized by the rates of the exchange reactions taking place between the complexes GdL and Lu3+ or Zn2+. 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 Gd3+ complex and Lu3+ or Zn2+, which occurs with the formation of a dinuclear intermediate, GdLM. The exchange reactions proceed about five times more rapidly with Zn2+ than with Lu3+, indicating the importance of the formation of an intermediate containing an N-Zn2+ bond, which is stronger than the N-Lu3+ bond in an intermediate with similar structure. The exchange reactions of the complex GdL3 formed with the disubstituted ligand L-3 are significantly slower than those of the complexes of the monosubstituted ligands L-1 and L-2. (C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.