Macrocyclic paramagnetic agents for MRI: Determinants of relaxivity and strategies for their improvement

Purpose To dissect the contributions to the longitudinal relaxivity (r 1 ) of two commercial contrast agents (CAs), Gd‐DOTA and Gd‐HP‐DO3A, and to synthesize/characterize a novel macrocyclic agent (Gd‐Phen‐DO3A) having superior r 1 . Methods Longitudinal relaxation rates R 1 of the CAs in saline with/without human serum albumin (HSA), ionized simulated body fluid (i‐SBF), viscous simulated body fluid (v‐SBF), and human plasma were measured. Results have been interpreted to evince the main determinants to the observed r 1 values. Results In v‐SBF or in the presence of HSA, r 1 is enhanced for all complexes, reflecting the viscosity increase and a weak interaction with proteins. The CAs further differentiate in plasma, with a relaxivity increase (versus saline) of approximately 1, 1.5, and 2.5 mM −1 s −1 for Gd‐DOTA, Gd‐HPDO3A, and Gd‐Phen‐DO3A, respectively. R 1 versus pH curves in i‐SBF indicates that prototropic exchange sizably contributes to the relaxivity of Gd‐HP‐DO3A and Gd‐Phen‐DO3A. Conclusion The major contributions to r 1 in the physiological environment have been highlighted, namely, increased viscosity, complex‐protein interaction, and prototropic exchange. The control of these terms allows the design of novel macrocyclic structures with enhanced r 1 as a result of an improved interaction with plasma's macromolecules and the shift of the prototropic exchange to physiological pH. Magn Reson Med 78:1523–1532, 2017.