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 °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 mM bovine serum albumin (BSA) or 10-fold of diamagnetic ion La3+. More importantly, the thermodynamic stability and kinetic inertness of (Gd-DO3A)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 (Gd-DO3A)2–DAB has also been investigated.