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.

Study of Thermodynamic and Kinetic Stability of Transition Metal and Lanthanide Complexes of DTPA Analogues with a Phosphorus Acid Pendant Arm

“…In the case of [Gd(L 2 )] 2-, the lower basicity of the donor groups results in lower ability of binuclear complex formation (see also the values of stability constants of dinuclear species, For the H 5 dtpa and its various amide derivatives, all the gadolinium() complexes have similar kinetic stability comparing to each other. [26][27][28]] Surprisingly, we found that the gadolinium() complexes with H 5 dtpa-analogues derived on the central nitrogen atom by the phosphorus acid pendant arm are much less kinetically stable with the halflife times about two to three orders of magnitude shorter. This can probably be attributed to a steric strain in the new complexes, which coordination sphere is not so compact and which can be attacked by a proton or by an additional metal ion.…”

“…[27,28] Therefore, the kinetic data had to be acquired by a stopped-flow technique. Dissociation reactions were performed in high excess (10-70×) of the concurrent metal ion (Cu 2+ or Eu 3+ ), ensuring pseudofirst-order reaction conditions, and in buffered solutions (pH in range 3.5-5.7).…”

Stability and Toxicity of Contrast Agents

“…Since the basicity of the amide oxygen increases in the following order, -CO-NH 2 < −CO-NHR < −CO-NR 2 , the decrease in the log K M(L) values is smallest for complexes of DTPA-bis-amides derived from secondary amines (e.g., DTPA-B(BBuA)). It has been argued that this drop in stability does not preclude the use of these complexes in vivo because the stability constants of DTPA-bisamide ligands with endogenous Ca 2+ , Zn 2+ , and Cu 2+ decrease even more dramatically under in vitro conditions [1,30]. However, this argument assumes that the toxicity of these complexes is largely due to transmetallation (competitive removal of the Gd 3+ by one of these endogenous ions) and this may not be the case.…”

“…Formation of dinuclear complexes is even more pronounced for ligands having higher denticity (e.g., EGTA, BAPTA, or TTHA), or for ligands that contain phosphinate or alcoholic OH groups positioned between two iminodiacetate units (BIMP or HPDTA) [63,64]. The formation of dinuclear complexes was first assumed not to occur for DTPA-bisamide derivatives [1] yet dinuclear Cu 2 (L) and Zn 2 (L) species have been reported for DTPA-bisbutylamide and DTPA-bisdibutylamide [30].…”

“…The rates of this type of transmetallation reactions were found to be inversely proportional to the stability constants of the complexes [225]. The kinetics of metal exchange reactions between Gd 3+ complexes of AAZTA, DTPA, and DTPA derivatives in the presence of excess Cu 2+ , Zn 2+ , or Eu 3+ have been investigated more recently [23,30,62,84,226]. Under these conditions, the exchange reactions are pseudo-first-order and the rates can be expressed by Equation (4.8), where k d is a pseudo-first-order rate constant and [Ln(L)] t is the total concentration of the complex:…”