Synthesis and complexation properties of DTPA-N,N ''-bis[bis(n-butyl)]-N '-methyl-tris(amide). Kinetic stability and water exchange of its Gd3+ complex

摘要

A novel DTPA-tris(amide) derivative ligand, DTPA-N,N"-bis [bis(n-butyl)] -N-methyl-tris(amide) (H2L3) was synthesized. With Gd3+, it forms a positively charged [Gd(L-3)](+) complex, whereas with Cu2+ and Zn2+ [ML3], [MHL3](+) and [M2L3](2+) species are formed. The protonation constants of H2L3 and the stability constants of the complexes were determined by pH potentiometry. The stability constants are lower than those for DTPA-N,N"-bis [bis(n-butyl) amide)] (H3L2), due to the lower negative charge and reduced basicity of the amine nitrogens in (L-3)(2-). The kinetic stability of [Gd(L-3)](+) was characterised by the rates of metal exchange reactions with Eu3+, Cu2+ and Zn2+. The exchange reactions, which occur via proton and metal ion assisted dissociation of [Gd(L-3)](+), are significantly slower than for [Gd(DTPA)](2-), since the amide groups cannot be protonated and interact only weakly with the attacking metal ions. The relaxivities of [Gd(L-2)] and [Gd(L-3)](+) are constant between 10-20degreesC, indicating a relatively slow water exchange. Above 25degreesC, the relaxivities decrease, similarly to other Gd3+ DTPA-bis(amide) complexes. The pH dependence of the relaxivities for [Gd(L-3)](+) shows a minimum at pH approximate to 9, thus differs from the behaviour of Gd3+-DTPA-bis(amides) which have constant relaxivities at pH 3-8 and an increase below and above. The water exchange rates for [Gd(L-2) (H2O)] and [Gd(L-3) (H2O)](+), determined from a variable temperature O-17 NMR study, are lower than that for [Gd(DTPA) (H2O)](2-). This is a consequence of the lower negative charge and decreased steric crowding at the water binding site in amides as compared to carboxylate analogues. Substitution of the third acetate of DTPA(5-) with an amide, however, results in a less pronounced decrease in k(ex) than substitution of the first two acetates. The activation volumes derived from a variable pressure O-17 NMR study prove a dissociative interchange and a limiting dissociative mechanism for [Gd(L-2) (H2O)] and [Gd(L-3) (H2O)](+), respectively.