Bipyridil-based chelators for Gd(III) complexation: kinetic, structural and relaxation properties

Area of Science:

• Inorganic Chemistry
• Radiochemistry
• Materials Science

Background:

• Nephrogenic systemic fibrosis (NSF) is a serious concern linked to gadolinium (Gd(III))-based MRI contrast agents (CAs).
• Improving the in vivo stability of Gd(III) chelates is crucial to prevent dissociation and mitigate NSF risk.
• Ligand rigidification is a key strategy to enhance the inertness of Gd(III) complexes.

Purpose of the Study:

• To characterize the thermodynamic, kinetic, and structural properties of the Gd(III)-DIPTA complex.
• To evaluate the potential of DIPTA as a chelator for Gd(III) in MRI contrast agents.
• To assess the suitability of the bipyridine backbone for developing stable and safe Gd(III) chelates.

Main Methods:

• Thermodynamic and kinetic stability measurements.
• Luminescence lifetime measurements to determine water coordination (q) and water exchange rates.
• Density Functional Theory (DFT) calculations for structural analysis.
• Comparison with established Gd(III) chelates like Gd(DTPA) and Gd(FENTA).

Main Results:

• The Gd(III)-DIPTA complex exhibits significantly lower inertness (t1/2 = 1.34 h) compared to clinical agents, indicating spontaneous dissociation.
• Relaxivity values are comparable to Gd(FENTA) and higher than Gd(DTPA).
• Luminescence data indicate one inner-sphere water molecule (q=1) with a high water exchange rate (k298ex = 43(5) × 10^6 s^-1).
• DFT calculations suggest a distorted tricapped trigonal prismatic geometry for the Gd(III) complex.

Conclusions:

• The bipyridine backbone of DIPTA is not favorable for enhancing the inertness of Gd(III) chelates.
• Despite comparable relaxivity, the poor kinetic stability of Gd(III)-DIPTA limits its potential as a safe MRI contrast agent.
• Further research should focus on alternative ligand designs to improve the in vivo stability of Gd(III) contrast agents.