Two multinuclear GdIII macrocyclic complexes as contrast agents with high relaxivity and stability using rigid linkers

Two macrocyclic chelating MRI agents (Gd-DO3A)(3)-TAB and (Gd-DO3A)(2)-DAB have been successfully synthesized by appending three and two Gd-DO3A moieties upon the acetylbenzene derivatives, respectively. The longitudinal relaxivity of (Gd-DO3A)(3)-TAB measured at 20 MHz, 37 degrees C and pH 7.0 is 6.1 mMGd(-1) s(-1), 74% higher than that of the mononuclear clinical agent [Gd(DOTA)(H2O)]. A 30% or 16% increase in relaxivity was observed upon addition of 0.72 mMbovine serum albumin (BSA) or 10-fold of diamagnetic ion La3+. More importantly, the thermodynamic stability and kinetic inertness of (GdDO3A)(3)-TAB are comparable to or better than that of [Gd(DTPA)(H2O)](2). The luminescence lifetime study on the corresponding (Eu-DO3A)3-TAB analog demonstrated that the agent had one inner-sphere water coordinated to the Eu3+ center within the complex. The cytotoxicity study indicated that the toxicity of the agent was low with IC50 = 18 mM. In addition, the characterization of its dinuclear analog (GdDO3A)(2)-DAB has also been investigated. (C) 2013 Elsevier B.V. All rights reserved.