A Solid-Phase Approach to Chiral C2-Substituted Cyclen and DOTA-Like Lanthanoid Ligands.

Magnetic resonance imaging (MRI) is a powerful diagnostic modality that relies on Gd+3-based contrast agents (GBCAs) to enhance image quality and provide detailed anatomical and functional information. The continued demand for safer and more effective contrast agents has stimulated the development of efficient synthetic routes to macrocyclic gadolinium chelators. In this work, we describe a straightforward synthetic approach to chiral C2-substituted 1,4,7,10-tetraazacyclododecane (cyclen) derivatives 1-3, obtained through BH3-mediated reduction of cyclic peptoid precursors. These compounds were subsequently converted into the corresponding DOTA-type ligands, S-Me-DOTA, S-Bn-DOTA, and S-iBu-DOTA, and their Gd+3 complexes were evaluated as MRI contrast agents through relaxivity measurements in water and human plasma. In addition, structural characterization of [Eu-S-Bn-DOTA]- by 1H NMR spectroscopy revealed the predominance of the square antiprismatic (SAP) Λ(δδδδ)/corner coordination isomer in solution. This work demonstrates the utility of cyclic peptoids as versatile precursors to chiral C-substituted DOTA ligands and provides an alternative route for the development of novel MRI contrast agents.