Novel Fe(III)-based MRI diagnostic probes as a sustainable and environmentally friendly alternative to the current use of Gd(III) complexes

Gadolinium-based contrast agents (GBCAs) are widely used in MRI due to their effectiveness in enhancing image quality. However, growing attention to their potential long-term environmental impact has prompted interest in alternative metals, such as Fe (HI). Alongside the development of a green synthesis route for a Gd(lll) complex, this work focused on Fe(lll)-polycarboxylate systems, particularly monohydrated EDTA and CDTA derivatives. A series of Fe(lll)-CDTAamide complexes were synthesized to investigate how structural modifications influence different parameters as thermodynamic stability, water exchange process, and relaxivity. Comprehensive relaxometric studies (1H NMRD and 170 trasverse relaxation rate and shift at 11.7 T) demonstrated that these Fe(lll) complexes retain excellent relaxivity. However, the introduction of amide groups, which favor the formation of neutral complexes, reduces kinetic inertness, even though they maintain high thermodynamic stability. To explore the role of hydrophobicity, amphiphilic ligands were also studied. Some derivatives, such as St-EDTA, exhibited promising self-assembly behavior and strong binding to HSA. Our studies on Fe(lll)-(EDTA-BOMx) complexes underscore the necessity of a deeper understanding of electronic relaxation mechanisms in Fe(lll) systems. Unlike Gd(lll) and Mn(ll) complexes, where these processes are better characterized, Fe(lll) complexes present unique challenges. Since electronic relaxation significantly impacts relaxivity, gaining further insight into these mechanisms is essential to refine theoretical models and enhance the predictive accuracy of relaxivity optimization. These advances will be pivotal for the design of next-generation Fe(lll)-based MRI agents with improved safety, stability, and diagnostic performance.