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

To dissect the contributions to the longitudinal relaxivity (r₁ ) 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 r₁ .

Longitudinal relaxation rates R₁ 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 r₁ values.

In v-SBF or in the presence of HSA, r₁ 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. R₁ versus pH curves in i-SBF indicates that prototropic exchange sizably contributes to the relaxivity of Gd-HP-DO3A and Gd-Phen-DO3A.

The major contributions to r₁ 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 r₁ 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. © 2016 International Society for Magnetic Resonance in Medicine.