Synthesis and complexation properties bis[bis(n-butyl)]-N'-methyl-tris(amide).Kinetic stability and water exchange of its Gd~(3+) complex

摘要

A novel DTPA-tris(amide) derivative ligand,DTPA-N,N"-bis[bis(n-butyl)]-N'-methyl-tris(amide) (H_2L~3) was synthesized.With Gd~(3+),it forms a positively charged [Gd(L~3)]~+ complex,whereas with Cu~(2+) and Zn~(2+) [ML~3],[MHL~3]~+ and [M_2L~3]~(2+) species are formed.The protonation constants of H_2L~3 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)] (H_3L~2),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 Eu~(3+),Cu~(2+) and Zn~(2+).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 10-20 deg C,indicating a relatively slow water exchange.Above 25 deg C,the relaxivities decrease,similarly to other Gd~(3+) DTPA-bis(amide) complexes.The pH dependence of the relaxivities for [Gd(L~3)]~+ shows a minimum at pH approx= 9,thus differs from the behaviour of Gd~(3+)-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)(H_2O)] and [Gd(L~3)(H_2O)]~+,determined from a variable temperature ~(17)O NMR study,are lower than that for [Gd(DTPA)(H_2O)]~(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 ~(17)O NMR study prove a dissociative interchange and a limiting dissociative mechanism for [Gd(L~2)(H_2O)] and [Gd(L~3)(H_2O)]~+,respectively.