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

Abstract

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(L³)]⁺ 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 (L³)²⁻. The kinetic stability of [Gd(L³)]⁺ 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(L³)]⁺, 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(L²)] and [Gd(L³)]⁺ are constant between 10–20 °C, indicating a relatively slow water exchange. Above 25 °C, the relaxivities decrease, similarly to other Gd³⁺ DTPA-bis(amide) complexes. The pH dependence of the relaxivities for [Gd(L³)]⁺ shows a minimum at pH ≈ 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(L²)(H₂O)] and [Gd(L³)(H₂O)]⁺, determined from a variable temperature ¹⁷O 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 DTPA⁵⁻ 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 ¹⁷O NMR study prove a dissociative interchange and a limiting dissociative mechanism for [Gd(L²)(H₂O)] and [Gd(L³)(H₂O)]⁺, respectively.