Toward optimized high-relaxivity MRI agents: Thermodynamic selectivity of hydroxypyridonate/catecholate ligands

The thermodynamic selectivity for Gd³⁺ relative to Ca ²⁺, Zn²⁺, and Fe³⁺ of two ligands of potential interest as magnetic resonance imaging (MRI) contrast agents has been determined by NMR spectroscopy and potentiometric and spectrophotometric titration. The two hexadentate ligands TREN-6-Me-3,2-HOPO (H₃L2) and TREN-bisHOPO-TAM-EA (H₄L3) incorporate 2,3-dihydroxypyridonate and 2,3-dihydroxyterephthalamide moieties. They were chosen to span a range of basicity while maintaining a structural motif similar to that of the parent ligand, TREN-1-Me-3,2-HOPO (H₃L1), in order to investigate the effect of the ligand basicity on its selectivity. The 1:1 stability constants (β₁₁₀) at 25 °C and 0.1 M KCI are as follows. L2: Gd ³⁺, 20.3; Ca²⁺, 7.4; Zn²⁺, 11.9; Fe ³⁺, 27.9. L3: Gd³⁺, 24.3; Ca²⁺, 5.2; Zn ²⁺, 14.6; Fe³⁺, 35.1. At physiological pH, the selectivity of the ligand for Gd³⁺ over Ca²⁺ increases with the basicity of the ligand and decreases for Gd³⁺ over Fe³⁺. These trends are consistent with the relative acidities of the various metal ions;- more basic ligands favor harder metals with a higher charge-to-radius ratio. The stabilities of the Zn²⁺ complexes do not correlate with basicity and are thought to be more influenced by geometric factors. The selectivities of these ligands are superior to those of the octadentate poly(aminocarboxylate) ligands that are currently used as MRI contrast agents in diagnostic medicine.