6-Carboxamido-5,4-Hydroxypyrimidinones:  A New Class of Heterocyclic Ligands and Their Evaluation as Gadolinium Chelating Agents

A previously unexplored class of heterocyclic bidentate chelating groups, 6-carboxamido-5,4-hydroxypyrimidinones (6-substituted-HOPYs), have been synthesized by two routes that provide a flexible entry into this ligand system. These are related to, but distinct from, the hydroxypyridonates and have been characterized in this study as a gadolinium chelating agent for magnetic resonance imaging (MRI) applications. The complex Gd[TrenHOPY] demonstrates high stability and high selectivity relative to other ions of biological interest, such as Zn(II) and Ca(II). These stability constants are comparable to those demonstrated by the previously studied 3,2-pyridinone analogues, however, the 5,4-pyrimidinones are at least an order of magnitude more soluble in water. The proton relaxation properties of Gd[TrenHOPY] in water were measured as a function of magnetic field, pH, and temperature. These results support the description of Gd[TrenHOPY] as a complex with two coordinated water molecules in fast exchange with bulk water. In addition, the influence of exogenous anions and blood serum proteins has been investigated. The favorable contrast agent properties emerging from these studies are discussed.