RELAXOMETRIC INVESTIGATION OF Fe(III) COMPLEXES AND THEIR SUPRAMOLECULAR ADDUCTS

Contrast agents (CAs) are used in 40% of the tens of millions of MRI scans performed each year. Currently, all FDA-approved CAs are Gd(III)-based complexes (GBCAs). Clinical and environmental concerns have renewed the interest in replacing Gd(III) with endogenous ions such as Fe(III). Some recent results indicate that Fe(III) chelates administered at higher doses than GBCAs have achieved similar results in typical clinical applications. Despite these important initial contributions, the effects and mechanisms responsible for the water proton relaxation enhancement induced by Fe(III) complexes and the relationships between the molecular parameters governing their efficacy (relaxivity) and chemical structure are still in their infancy. For example, structural modifications that may facilitate interactions with macromolecules (e.g., human serum albumin, HSA) have been explored in a limited way, which is an intriguing aspect that deserves further investigation. For this reason, we present the 1H and 17O NMR relaxometric characterization of two new Fe(III)-based complexes of ethylenediaminetetraacetic acid (EDTA) derivatives carrying one or two benzyloxymethyl (BOM) functionalities, namely EDTA-BOM and EDTA-BOM2. The presence of the BOM substituents is expected to have a dual effect. Firstly, according to the paramagnetic relaxation theory, an increase in the molecular weight of the complex is associated with increased relaxation at high magnetic fields (≥ 20 MHz, 0.47 T). Secondly, the lipophilic nature of the BOM functionalities may promote a noncovalent interaction with HSA and other substrates, which will be further explored. The formation of these macromolecular adducts leads to a strong increase in relaxivity. In addition, to investigate the behavior of these complexes in supramolecular adducts, the interaction with β-cyclodextrin and poly-β-cyclodextrin is also explored. These complexes might represent an initial platform for the future design of complexes able to combine high efficacy, enhanced stability and inertness and non-covalent binding capability.