A benzene-core trinuclear GdIII complex: towards the optimization of relaxivity for MRI contrast agent applications at high magnetic field

Abstract

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, k_ex²⁹⁸ = 9.0 ± 3.0 s⁻¹ is around twice as high as k_ex²⁹⁸ 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, τ_lO²⁹⁸ = 170 ± 10 ps and τ_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⁺).