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.

Effects of exposure to gadolinium on the development of geographically and phylogenetically distant sea urchins species

“…Pharmaceuticals are designed to specifically act on biological systems and that's the reason of their high toxicity; Gd ions (Gd 3þ ) toxicity appears to be associated with its action as a blocker of Ca 2þ channels because its ionic radius is nearly equal to that of divalent Ca 2þ (Sherry et al, 2009). Some studies suggested that Gd ion concentrations in the micromolar range (between 1 and 200 mM)…”

“…Since the 1980s, chelates of Gd have been used as contrast agents for magnetic resonance imaging (MRI) and were considered safe for humans (Niendorf et al, 1991) until they were linked to nephrogenic systemic fibrosis (NSF) disease (Cowper et al, 2000;Grobner, 2006). Gd 3þ toxicity appears to be associated with its action as a blocker of Ca 2þ channels because its ionic radius is nearly equal to that of divalent Ca 2þ (Sherry et al, 2009). Gd chelates are stable complexes and are not metabolized and so they enter the environment unchanged (Kümmerer and Helmers, 2000).…”

Gadolinium retention after administration of contrast agents based on linear chelators and the recommendations of the European Medicines Agency

“…In the linear chelates the gadolinium ion is bound to an open-chain ligand, while in the macrocyclic chelates the gadolinium ion is bound inside a cubic chemical structure. These differences in the chemical structure of the ligands explain the difference in thermodynamic and kinetic stability, whereby the non-ionic linear chelates are the least stable and the ionic macrocyclic chelates are the most stable [3]. The free gadolinium ion is mostly hydrated in biological systems, and this Gd(H 2 O) 8 3+ ion is toxic because of its chemical similarities to Ca 2+ , which is an important factor for proper functioning of many processes in the human body such as contraction of the heart muscle and smooth muscle cells, and nerve transmission.…”

Using Remote Substituents to Control Solution Structure and Anion Binding in Lanthanide Complexes

“…[6] Their large size and high ionic character means that kinetically stable lanthanide complexes must be derived from rigid ligands, typically azamacrocycles, bearing hard donor atoms such as oxygen and nitrogen. In such systems, the arrangement of donor atoms around the lanthanide is defined in large part by the structure of the ligand.…”