New Chiral Pyclen-Based Gadolinium(III) Complexes: Advancing Stability, Relaxivity, and Water Exchange for Improved Magnetic Resonance Imaging Probes

The safety issues of MRI contrast agents in clinical practice have raised significant concerns, which can lead to adverse effects such as nephrogenic systemic fibrosis and metal deposition in the brain. Herein, we designed two innovative chiral pyclen-based octadentate Gd(III) complexes, Gd-L3 and Gd-L4. Compared to the achiral Gd-L2, these chiral complexes exhibited substantial enhancements in relaxivity, by 52.0% and 36.9%, respectively. They also demonstrated improvements in thermodynamic stability and kinetic inertness. DFT calculations revealed that the strong coordination of pendant arm oxygen atoms with the Gd(III) ion contributes to the observed kinetic inertness. Variable-temperature ¹⁷O NMR measurements showed that Gd-L3 and Gd-L4 possess shorter inner-sphere water residence lifetimes, resulting in water exchange rates approximately twice as high as that of Gd-L2. In vivo imaging and biodistribution studies further highlighted their distinct clearance pathways: Gd-L3 exhibited dual hepatic and renal clearance, whereas Gd-L4 was exclusively cleared via the renal route.