A benzene-core trinuclear GdIII complex: towards the optimization of relaxivity for MRI contrast agent applications at high magnetic field
A novel ligand, H12L, based on a trimethylbenzene core bearing three methylenediethylenetriamine-N,N,N,N- tetraacetate moieties (–CH2DTTA4–) for Gd3+ chelation has been synthesized, and its trinuclear Gd3+ complex [Gd3L(H2O) 6]3– investigated with respect to MRI contrast agent applications. A multiple-field, variable-temperature 17O NMR and proton relaxivity study on [Gd3L(H2O)6]3– yielded the parameters characterizing water exchange and rotational dynamics. On the basis of the 17O chemical shifts, bishydration of Gd3+ could be evidenced. The water exchange rate, kex298 = 9.0 ± 3.0 s–1 is around twice as high as kex298 of the commercial [Gd(DTPA)(H2O)]2– and comparable to those on analogous Gd3+-DTTA chelates. Despite the relatively small size of the complex, the rotational dynamics had to be described with the Lipari–Szabo approach, by separating global and local motions. The difference between the local and global rotational correlation times, lO298 = 170 ± 10 ps and gO298 = 540 ± 100 ps respectively, shows that [Gd3L(H2O)6]3– is not fully rigid; its flexibility originates from the CH2 linker between the benzene core and the poly(amino carboxylate) moiety. As a consequence of the two inner-sphere water molecules per Gd3+, their close to optimal exchange rate and the appropriate size and limited flexibility of the molecule, [Gd3L(H2O)6]3– has remarkable proton relaxivities when compared with commercial contrast agents, particularly at high magnetic fields (r1 = 21.6, 17.0 and 10.7 mM–1s–1 at 60, 200 and 400 MHz respectively, at 25 °C; r1 is the paramagnetic enhancement of the longitudinal water proton relaxation rate, referred to 1 mM concentration of Gd3+).