Effective mitigation of gadolinium deposition using the bidentate hydroxypyridinone ligand Me-3,2-HOPO

Abstract

With the extensive usage of gadolinium-based contrast agents (GBCAs) in magnetic resonance imaging (MRI), gadolinium deposition has been observed in the brain, kidneys, liver, etc., and this is also closely related to the development of nephrogenic systemic fibrosis (NSF) in patients with renal dysfunction. Chelation, thereby promoting the elimination of deposited Gd(III), seems to be promising for alleviating these problems. Despite many ligands suitable for chelation therapy having been studied, the decorporation of transition metals (e.g. iron, copper, lead, etc.) and actinides (e.g. uranium, plutonium, etc.) has long been a primary concern, whereas the study of Gd(III) has been extremely limited. Due to their excellent metal binding abilities in vivo and therapeutic effects toward neurodegenerative diseases, bidentate hydroxypyridinone ligands are expected to be able to remove Gd(III) from the brain, kidneys, bones, and liver. Herein, the Gd(III) decorporation efficacy of a bidentate hydroxypyridinone ligand (Me-3,2-HOPO) has been evaluated. The complexation behavior between Me-3,2-HOPO and Gd(III) in solution and solid states was characterized with the assistance of potentiometric titration and X-ray diffraction techniques, respectively. Solution-based thermodynamic studies illustrate that the dominant species of complex between Gd(III) and Me-3,2-HOPO (HL) is GdL₂⁺ (log β₁₂₀ = 11.8 (3)) at pH 7.4. The structure of the Gd–Me-3,2-HOPO crystal obtained from a room temperature reaction reveals the formation of a Gd(III) dimer that is chelated by four ligands as a result of metal ion hydration and ligand complexation. Cellular Gd(III) removal assays illustrate that Me-3,2-HOPO could effectively reduce final amounts of gadolinium by 77.6% and 66.1% from rat renal proximal tubular epithelial (NRK-52E) cells and alpha mouse liver 12 (AML-12) cells, respectively. Our current results suggest the potential of bidentate HOPO ligands as an effective approach to treat patients suffering from Gd(III) toxicity.