Characterization of the Proton Exchange Processes Between [Gd(DOTP)]⁵⁻ with Meglumine, D-Glucamine, and Dimeglumine

Currently applied Gd(III)-based MRI contrast agents (GBCAs) are metal complexes mainly formed with macrocyclic amino-polycarboxylate ligands like DOTA and its derivatives (DOTA: 1,4,7,10-tetrazacyclododecane- 1,4,7,10-tetraacetic acid). Efficiency of the Gd(III) complexes is characterized by their relaxivity (r1 = the increase in the longitudinal relaxation rate of water protons by a 1 mM GBCA solution). It was shown that the Gd(III)-complexes with the labile proton/s on the coordinated functions can significantly enhance the relaxation of the bulk water protons (r1) via proton exchange processes.1 Moreover, the proton exchange contribution of the Gd(III)-complexes is directly proportional to the number of mobile protons on the coordinated functional group/s. Among the possible functionalities, the phosphonate group in DOTP ligand has very basic protonation site, which might carry the proton/s to the proximity of the Gd(III) ion in the resulting [Gd(DOTP)]5- complex. According to the detailed thermodynamic and structural studies of Gd(III)- and Ln(III)-complex with DOTP ligand, the Ln(III)-ion is coordinated by 4 amino N and 4 phosphonate O- donor atoms, whereas the non-coordinated basic phosphonate-O- donor atoms can be protonated (-P-OH) and acts as a source of protons for the exchange with the solvent water protons. The structural studies of [Ln(DOTP)]5- complexes reveal the lack of the inner-sphere water molecule allowing the investigation and the development of the pure proton-exchange based relaxation agent.