Toward Optimized High-Relaxivity MRI Agents:  The Effect of Ligand Basicity on the Thermodynamic Stability of Hexadentate Hydroxypyridonate/Catecholate Gadolinium(III) Complexes

Abstract

The thermodynamic stabilities of the Gd(III) complexes of five hexadentate ligands, which incorporate the 2,3-dihydroxyterephthalamide and 2,3-hydroxypyridonate chelating moieties, have been determined by potentiometric and spectrophotometric titration. The ligands were chosen to span a range of basicities while maintaining a similar tripodal structural motif, facilitating a study of the effect of ligand basicity on the thermodynamic stability of the Gd(III) complexes. The relative stability of the five complexes is found to be highly pH dependent, with the most acidic ligands forming the most stable complexes at low pH and more basic ligands forming more stable complexes at high pH. The most stable Gd(III) complex at a physiological pH of 7.4 is formed with a ligand of intermediate basicity and is of stability comparable to that of Gd(III) complexes that feature eight-coordinate amino-carboxylate ligands and are currently used as magnetic resonance imaging contrast agents in diagnostic medicine. A single-crystal X-ray structure of the intermediate compound 3-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid ethyl ester is described: This compound crystallizes in the triclinic space group P1 with a = 7.4801(3) A, b = 8.0671(3) A, c = 8.3457(4) A, alpha = 72.242(2) degrees, beta = 80.693(2) degrees, gamma = 69.943(3) degrees, V = 449.60(3) A(3), Z = 2, and R = 0.042.

A Macrocyclic Chelator That Selectively Binds Ln4+ over Ln3+ by a Factor of 1029

“…An analog for L is the hexadentate ligand TREN-TAM3, which has a log β110 > 17 with Gd 3+ . 153 Even though L has the same TAM binding units, it is difficult to predict its stability with a +3 lanthanide ion given the difference in coordination number and the entirely different topology of the ligands. To obtain a quantitative assessment of the selectivity of L for +4 over +3 metal ions, its stability with an Ln 3+ ion was investigated as a surrogate for Ce 3+ .…”

Optimized Relaxivity and Stability of [Gd(H(2,2)-1,2-HOPO)(H2O)]- for Use as an MRI Contrast Agent1

“…13 The protonation constants 3 illustrate the acidity of 1 compared to 3,2-HOPO chelates. 14 The four acidic protonation steps are associated with deprotonation of the 1,2-HOPO moieties while the tertiary nitrogen atoms represent the two basic protonation sites.…”

High‐Relaxivity MRI Contrast Agents: Where Coordination Chemistry Meets Medical Imaging

“…[55][56][57] The final important effect is that the Lewis basicities of the HOPO oxygen donor atoms are an optimal match for Gd III , resulting in strong binding. [45,55,56] Scaffold A significant factor in chelate stability is the ligand cap scaffold. The TREN scaffold has been found to provide the highest chelate stability for hexadentate HOPO ligands.…”