Modulation of the Prototropic Exchange Rate at the Water Molecule Coordinated to a Gd^III Ion

Abstract

The aim of this work is to assess whether it is possible to control the rate of the prototropic exchange in a class of DTPA bis-amide Gd III complexes.In the last decade much attention has been devoted to the understanding of the determinants of the water-exchange process in Gd III complexes because their successful application as MRI contrast agents is related to the occurrence of a suitable exchange lifetime (τ M ) of the coordinated water.[1Ϫ4] The latter parameter inversely affects the innersphere relaxation term (R 1p is ) and is often the main determinant of the overall relaxivity of a paramagnetic Gd III complex. The R 1p is contribution is given by Equation (1):(1)where [C] is the molar concentration of the paramagnetic agent, q is the number of coordinated water molecules and T 1M is the relaxation time of their protons. Thus, as long as τ M is shorter than T 1M the paramagnetic relaxation effect can be efficiently transferred to the bulk water solvent.Bis-amide derivatives of Gd-DTPA (DTPA ϭ diethylenetriamine pentaacetic acid) display relatively long exchange lifetimes of the coordinated water,[5Ϫ8] therefore their relaxivity is usually smaller than expected. However, such a drawback has been exploited in order to assess the rate of prototropic exchange at the coordinated water molecule. The latter process is pH-dependent and becomes significantly high either at acidic or basic pH, to overcome the ''quenching'' effect of the slow exchanging water, thus allowing the system to raise the relaxivity expected on the basis of its T 1M value.[a] Dipartimento di Chimica IFM, Università di Torino, Via P. Thus, τ M in Equation (1) can be replaced by Equation (2): (2) where k ex is the prototropic exchange rate. Although the prototropic exchange is either acid or base catalysed, its assessment, in the case of bis-amide derivatives of Gd-DTPA, is preferentially pursued under basic conditions because the limited thermodynamic stability of these complexes may cause some release of Gd III ions upon protonation of the acetic arms at acidic pH. Typically the determination of k ex is then carried out by fitting the pH-dependent curve of the relaxivity in the pH range between 3 and 10.The aim of this work is to assess whether it is possible to control the rate of the prototropic exchange in this class of Gd III complexes. Six novel bis-amide derivatives of Gd-DTPA have been synthesised (Scheme 1). These ligands were obtained according to the previously reported procedure [9] based on the reaction of DTPA bis-anhydride with the amine group of the entering R substituent. Compounds 1 and 2 were obtained by hydrolyzing the ester functionalities of 3 and 4, respectively.The corresponding Gd III complexes were obtained by reacting equimolar amounts of any given ligand and GdCl 3 at pH 6. The eventual excess of uncomplexed Gd III ions was precipitated as the hydroxide as the pH of the solution was brought to basic values, and separated by ultracentrifugation.At neutral pH and 298 K, the relaxivity (measured at 20 MHz) shown by...

Towards Targeted MRI: New MRI Contrast Agents for Sialic Acid Detection

“…These values are similar to those reported for Gd 3 + complexes of other DTPA-bisamides. [38,39] The pH dependence of the relaxivities of the complexes increases signficantly at low and high pH values (Figure 1). At pH < 2 both complexes show a steep increase in relaxivity to about 13 s À1 mm…”

“…It has been reported that the prototropic exchange rate is modulated by the overall charge of the complex under basic conditions; exchange is faster for positively charged and slower for negatively charged complexes. [39] This effect has been explained in terms of the ease of access of OH À ions to the coordinated water molecule. It is likely that the activation of prototropic exchange plays a role in the relaxivity enhancement observed for the two complexes GdL 1 and GdL 2 under basic conditions.…”

“…[39] Prototropic exchange can be catalyzed both by H + and by OH À ions. It has been reported that the prototropic exchange rate is modulated by the overall charge of the complex under basic conditions; exchange is faster for positively charged and slower for negatively charged complexes.…”

“…In both cases, the increase in relaxivity observed in the basic pH region (pH > 9) is most likely to be caused by activation of the prototropic exchange mechanism. [39] DTPA-bisamides generally have relatively long exchange lifetimes, t M . The relaxivity of a complex of this size with a fast water exchange rate is usually governed mainly by changes in the rotational correlation time.…”

Substituent Effects on Gd(III)-Based MRI Contrast Agents: Optimizing the Stability and Selectivity of the Complex and the Number of Coordinated Water Molecules1

“…Aime and coworkers have recently been able to modulate the prototropic exchange rate of the coordinated water molecules of several Gd DTPA-BMA analogues by changing the overall charge of the complex. 20 Similarly, Sherry and coworkers have shown that although the lanthanide coordination geometry of their Eu-DOTA analogues does play a role in determining τ M , the identity of the ligand side chains, and particularly the charge and polarity they induce in the complex, can also have a determining effect. 21 .…”