Ternary Gd(III)L-HSA adducts: evidence for the replacement of inner-sphere water molecules by coordinating groups of the protein. Implications for the design of contrast agents for MRI

• Published in: Journal of biological inorganic chemistry 2000-08, Vol.5 (4), p.488-497
• Main Authors: Aime, S, Gianolio, E, Terreno, E, Giovenzana, G B, Pagliarin, R, Sisti, M, Palmisano, G, Botta, M, Lowe, M P, Parker, D
• Format: Article
• Language: English
• Subjects: beta-Cyclodextrins; Contrast Media - chemical synthesis; Contrast Media - metabolism; Cyclodextrins - chemistry; Cyclodextrins - metabolism; Gadolinium - chemistry; Heterocyclic Compounds, 1-Ring - chemical synthesis; Heterocyclic Compounds, 1-Ring - chemistry; Heterocyclic Compounds, 1-Ring - metabolism; Humans; Ligands; Luminescent Measurements; Magnetic Resonance Imaging - methods; Metalloproteins - chemical synthesis; Metalloproteins - chemistry; Molecular Structure; Organophosphonates - chemical synthesis; Organophosphonates - chemistry; Organophosphonates - metabolism; Protein Binding; Serum Albumin - chemistry; Temperature; Water - chemistry
• ISSN: 0949-8257; 1432-1327
• DOI: 10.1007/pl00021449

Two novel gadolinium(III) chelates based on the structure of the heptadentate macrocyclic 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) ligand have been synthesized and their relaxometric and luminescent properties thoroughly investigated. They contain two water molecules in the inner coordination sphere in fast exchange with the bulk solvent and bear either a p-bromobenzyl or a p-phosphonatomethylbenzanilido substituent for promoting further interaction with macromolecular substrates. Upon interaction with human serum albumin the expected relaxation enhancement is not observed owing to displacement of the two inner-sphere water molecules of the complexes by a donor atom (likely from a carboxylate group) on the protein and possibly the phosphate anion of the buffered solution, respectively. We modeled the observed behavior by measuring the decrease of the relaxation rate of the water protons upon addition of malonate anion to aqueous solutions of the complexes. Conversely, no change in the hydratation state of the Gd(III) center for both complexes has been observed when the substrate for the formation of the macromolecular adduct is represented by poly-beta-cyclodextrin.