Synthesis of a ligand based upon a new entry into the 3-hydroxy-N-alkyl-2(1H)-pyridinone ring system and thermodynamic evaluation of its gadolinium complex

The synthesis of a new, more water soluble derivative of TREN-Me-3,2-HOPO {tris[(3-hydroxy-1-methyl-2-oxo-1,2-didehydropyridine-4-carboxamido)ethyl]amine} is presented. The synthesis starts with the condensation reaction of (N-methoxyethylamino)acetonitrile hydrochloride and oxalyl chloride to give 3,5-dichloro-N-(methoxyethyl)-2(1H)-pyrazinone. The 3-position is readily substituted with a benzyloxy group, and the pyrazinone is converted to ethyl 3-(benzyloxy)-N-(methoxyethyl)-2-(1H)-pyridinone-4-carboxylate by a Diels-Alder cycloaddition with ethyl propiolate. Basic deprotection of the eater followed by activation, coupling to tren, and acidic deprotection of the benzyl groups gives the Ligand TREN-MOE-3,2-HOPO {tris[(3-hydroxy-1-(methoxyethyl)-oxo-1 12-didehydropyridine-4-carboxamido)ethyl]amine}. The gadolinium complex of TREN-MOE-3,2-HOPO was prepared by metathesis, starting from gadolinium chloride. The solubility of the new metal complex is significantly enhanced. The four protonation constants (determined by potentiometry) for TREN-MOE-3,2-HOPO (log K-a1 = 8.08, log K-a2 = 6.85, log K-a3 = 5.81, log K-a4 = 4.98) are virtually identical to those reported for the parent ligand. The stability constants for the gadolinium complex of TREN-MOE-3,2-HOPO determined by potentiometry (log beta(110) = 19.69(2), log beta(111) = 22.80(2)) and by spectrophotometry (log beta(110) = 19.80(1), log beta(111) = 22.58(1), log beta(112) = 25.88(1)) differ slightly from those for the parent ligand; this follows from a change in the complexation model in which a new diprotonated species, [Gd(TREN-MOE-3,2-HOPO)(H)(2)](2+), was included. The presence of this extra species was demonstrated by factor analysis, comparison of spectral data, and nonlinear least-squares refinement. Significant formation of this species is observed between pH 3 and pH 1.5.