Impact of rigidification on relaxometric properties of a tricyclic tetraazatriacetic gadolinium chelate.

A constrained derivative of Gd-PCTA12, Gd-cyclo-PCTA12, in which one ethylene bridge connecting two nitrogen atoms of the triamine block is replaced by a cyclohexylene bridge, was synthesized and the impact of rigidification was studied by comparing the physicochemical and relaxometric properties of both gadolinium MRI contrast agents, Gd-PCTA12 and Gd-cyclo-PCTA12. The new complex has higher proton relaxivity than the parent compound (r(1) = 6.1 s(-1) mM(-1) at 20 MHz and 310 K). The rigidification of the PCTA12 scaffold proved to have no impact on the inertness towards transmetallation by endogenous ions such as Zn(2+). Moreover, for both contrast agents, the relaxivity was not quenched by endogenous anions. The oxygen-17 NMR study and the NMRD profile demonstrated that the rigidification of the PCTA scaffold had no impact on the electronic relaxation of Gd-cyclo-PCTA12. However, the rigidity of this complex induced an acceleration of the exchange rate of the inner-sphere water molecules as a result of steric crowding around the gadolinium ion. The value of tau(M) (310) thus approached the optimal value required to attain high relaxivity once the chelate is immobilized by covalent or non-covalent binding to macromolecules.