Relaxivity Modulation of Gd-HPDO3A-like Complexes by Introducing Polar and Protic Peripheral Groups

Molecules. 2024 Sep 30;29(19):4663. doi: 10.3390/molecules29194663.

Abstract

In the last three decades, high-relaxivity Magnetic Resonance Imaging (MRI) contrast agents (CAs) have been intensively sought, aiming at a reduction in the clinically injected dose while maintaining the safety of the CA and obtaining the same pathological information. Thus, four new Gd(III) complexes based on modified 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (HP-DO3A) macrocyclic structure were designed and synthesized by introducing further polar and protic functional groups (amides, phosphonates, and diols) adjacent to the metal-coordinated hydroxyl group. A detailed 1H NMR relaxometric analysis allowed us to investigate the effect of these functional groups on the relaxivity, which showed a 20-60% increase (at 0.5 T, 298 K, and pH 7.4) with respect to that of clinically approved CAs. The contribution of the water molecules H-bonded to these peripheral functional groups on the relaxivity was evaluated in terms of the second sphere effect or prototropic exchange of labile protons.

Keywords: Gd(III) complexes; functional groups; macrocyclic chelators; relaxometry.

Grants and funding

L.T. acknowledges the financial support of the EU (Next Generation EU) and the Italian Ministry of University and Research for the PRIN 2022 project (PNRR M4C2, ID 20224B4285) “Design of paramagnetic metal complexes for improved MRI-guided drug-release applications”.