title: 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 degrees C, indicating a relatively slow water exchange. Above 25 degrees 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 approximately 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 (17)O 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 kex 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(L2)(H2O)] and [Gd(L3)(H2O)]+, respectively.
authors.affiliation: Department of Inoragnic and Analytic Chemistry, University of Debrecen, H-4010, Debrecen, Hungary.
authors.forename: Z
authors.initials: Z
authors.lastname: Jaszberényi
authors.forename: E
authors.initials: E
authors.lastname: Tóth
authors.forename: T
authors.initials: T
authors.lastname: Kálai
authors.forename: R
authors.initials: R
authors.lastname: Király
authors.forename: L
authors.initials: L
authors.lastname: Burai
authors.forename: E
authors.initials: E
authors.lastname: Brücher
authors.forename: A E
authors.initials: AE
authors.lastname: Merbach
authors.forename: K
authors.initials: K
authors.lastname: Hideg
mesh_terms: D002614:Chelating Agents / Q000737:chemistry; D003287:Contrast Media / Q000138:chemical synthesis* / Q000378:metabolism; D004355:Drug Stability; D004578:Electron Spin Resonance Spectroscopy; D005682:Gadolinium / Q000737:chemistry*; D019786:Gadolinium DTPA / Q000138:chemical synthesis*; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008024:Ligands; D008279:Magnetic Resonance Imaging; D014867:Water / Q000737:chemistry*
chemical_list: D002614:Chelating Agents; D003287:Contrast Media; D008024:Ligands; D014867:Water; D005682:Gadolinium; D019786:Gadolinium DTPA