Primer on gadolinium chemistry

Abstract

Gadolinium is widely known by all practitioners of magnetic resonance imaging (MRI) but few appreciate the basic solution chemistry of this trivalent lanthanide ion. Given the recent linkage between gadolinium contrast agents and nephrogenic systemic fibrosis, some basic chemistry of this ion must be more widely understood. This short primer on gadolinium chemistry is intended to provide the reader the background principles necessary to understand the basics of chelation chemistry, water hydration numbers, and the differences between thermodynamic stability and kinetic stability or inertness. We illustrate the fundamental importance of kinetic dissociation rates in determining gadolinium toxicity in vivo by presenting new data for a novel europium DOTA-tetraamide complex that is relatively unstable thermodynamically yet extraordinarily inert kinetically and also quite nontoxic. This, plus other literature evidence, forms the basis of the fundamental axiom that it is the kinetic stability of a gadolinium complex, not its thermodynamic stability, that determines its in vivo toxicity. J. Magn. Reson. Imaging 2009;30:1240-1248. (c) 2009 Wiley-Liss, Inc.

Figures

Figure 1

Molecular stick models of Gd(H2O)83+ and Gd(H2O)DTPA2-. Note the one inner-sphere water molecule in Gd(H2O)DTPA2- that is important for MRI contrast. Mixing of DTPA with Gd3+ results in fast formation of a ML complex because of the DTPA ligand is flexible and can “wrap around” the Gd3+ ion very quickly. Water exchange is fast so removal of water molecules from the inner coordination sphere of the Gd3+ does not hinder the rate at which the complex forms.

Figure 2

Chemical structures of the four ligands examined in this paper. Two are derived from linear amines (DTPA and DTPA-BMA) and two are derived from macrocyclic amines (DOTA and DOTA-(gly)4).

Figure 3

Molecular stick models of Gd(H2O)83+ and Gd(H2O)DOTA- and the kinetic intermediate, Gd(H2O)4DOTA-. Although the intermediate, Gd(H2O)4DOTA-, is formed quickly upon mixing DOTA with Gd3+, it takes considerable time for this intermediate to rearrange into the thermodynamically stable product, Gd(H2O)DOTA- (Dotarem).

Figure 4

Pharmacokinetic curves for elimination of EuDOTA-(gly)4- from the blood of rats (male and female, n = 5 in each of four groups) showing no differences between low (0.7 μmol/kg) and high (0.1 mmol/kg) doses.

Figure 5

Biodistribution of EuDOTA-(gly)4- at 30 minutes and 2 hours. The percent initial dose per gram of tissue (%ID/g) is plotted for each tissue. Error bars represent standard deviations.

Figure 6

Modifying the DOTA ligand by introducing one (TRITA) or two (TETA) additional CH2 units (arrows) dramatically lowers the thermodynamic stability of the Gd complex and increases its metal dissociation rate constant. The stability data were reported in (26) and the kinetic data in (27).

Figure 7

Plots of thermodynamic stability constants, dissociation half-times in acid, and incidence of NSF for two linear amine-based agents and two macrocyclic amine-based agents. EuDOTA-(gly)4- is not clinically approved so data on the incidence of NSF for this compound are not available. Incidence data for the other agents were reported in (29).

Figure 7

Plots of thermodynamic stability constants, dissociation half-times in acid, and incidence of NSF for two linear amine-based agents and two macrocyclic amine-based agents. EuDOTA-(gly)4- is not clinically approved so data on the incidence of NSF for this compound are not available. Incidence data for the other agents were reported in (29).

Figure 7

Plots of thermodynamic stability constants, dissociation half-times in acid, and incidence of NSF for two linear amine-based agents and two macrocyclic amine-based agents. EuDOTA-(gly)4- is not clinically approved so data on the incidence of NSF for this compound are not available. Incidence data for the other agents were reported in (29).