Development of new MRI contrast agents based on β- and α-cyclodextrins, regio-functionalized with pyridine-carboxylate and pyridyne-phosphonate ligands

Magnetic Resonance Imaging is one of the most important and non-invasive tools for clinical diagnostics and biomedical researches. Nevertheless, this modality suffers from intrinsic low sensitivity. To overcome this limitation, contrast agents, mostly based on polyamino-carboxylate complexes of gadolinium are used. The aim of this project was to design new Gd(III)-based contrast agents using β- and α-cyclodextrins (CD), known to generate high relaxivity, functionalized with pyridine-carboxylate and pyridine-phosphonate ligands, known for their good affinity with the lanthanide cations. Here we first investigated the regio-functionalization of the β-CD on the primary face to access to scaffold called Lβ with four pyridine-carboxylate ligands. To develop an efficient and reproducible synthesis, HPLC analysis was implemented. Then, using these conditions, carboxylate- and phosphonate-ester, precursors to access α-CD ligands Lα and Lα', were synthesized. The carboxylate-ester de-protection step successfully afforded the ligand noted La contrary to the de-protection of phosphonate ester which still have to be explored. Characterizations of these complicated Gd-ligands systems (Gd-Lα et Gd-Lβ) were reported. Their stability and relaxivity were measured and very good relaxivities were obtained (25 mM^-1s^-1 ≤ r1 ≤ 40 mM^-1s^-1). These new structures open the way to an improvement in term of stability. (author)