Co(II) and Fe(II) triazole-appended 4,10-diaza-15-crown-5-ether Macrocyclic complexes for CEST MRI applications

Transition metal ion complexes have several advantages as MRI contrast agents including low cost, biological relevance, rich coordination chemistry, tunable magnetic properties, and the potential for smart agents that are responsive to temperature, pH, and redox environment. Here we present triazole-appended azamacrocyclic ligands for Co(II) and Fe(II) complexes towards paraCEST and lipoCEST applications. The triazole pendants are synthesized using ‘click’ chemistry, in particular the azide-alkyne Huisgen cycloaddition reaction. The versatility and specificity of these reactions are particularly useful in synthesizing a variety of analogs and derivatives of triazole-containing ligands. The triazole-NH proton in our Co(II) complex is unsuitable for paraCEST applications at biological pH, but the carboxylic acid derivative produced exceptionally large paramagnetically shifted bulk water ¹H resonances which are important towards the development of lipoCEST agents.