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.

Synthesis of homochiral tris(2-alkyl-2-aminoethyl)amine derivatives from chiral alpha-amino aldehydes and their application in the synthesis of water soluble chelators.

A novel synthesis of 3-fold symmetric, homochiral tris(2-alkyl-2-aminoethyl)amine (TREN) derivatives is presented. The synthesis is general in scope, starting from readily prepared chiral alpha-amino aldehydes. The optical purity of the N-BOC protected derivatives of tris(2-methyl-2-aminoethyl)amine and tris(2-hydroxymethyl-2-aminoethyl)amine has been ascertained by polarimetry and chiral NMR chemical shift experiments. An X-ray diffraction study of the L-alanine derivative (tris(2-methyl-2-aminoethyl)amine.3 HCl, L-Ala(3)-TREN) is presented: crystals grown from ether diffusion into methanol are cubic, space group P2(1)3 with unit cell dimensions a = 11.4807(2) A, V = 1513.23(4) A(3), and Z = 4. Attachment of the triserine derived backbone tris(2-hydroxymethyl-2-aminoethyl)amine (L-Ser(3)-TREN) to three 3-hydroxy-1-methyl-2(1H)-pyridinonate (3,2-HOPO) moieties, followed by complexation with Gd(III) gives the complex Gd(L-Ser(3)-TREN-Me-3,2-HOPO)(H(2)O)(2), which is more water soluble than the parent Gd(TREN-Me-3,2-HOPO)(H(2)O)(2) and a promising candidate for magnetic resonance imaging (MRI) applications. Crystals of the chiral ferric complex Fe(L-Ser(3)-TREN-Me-3,2-HOPO) grown from ether/methanol are orthorhombic, space group P2(1)2(1)2(1), with unit cell dimensions a = 13.6290(2) A, b = 18.6117(3) A, c = 30.6789(3) A, V = 7782.0(2) A(3), and Z = 8. The solution conformation of the ferric complex has been investigated by circular dichroism spectroscopy. The coordination chemistry of this new ligand and its iron(III) and gadolinium(III) complexes has been studied by potentiometric and spectrophotometric methods. Compared to the protonation constants of previously studied polydentate 3,2-HOPO-4-carboxamide ligands, the sum of protonation constants (log beta(014)) of L-Ser(3)-TREN-Me-3,2-HOPO (24.78) is more acidic by 1.13 log units than the parent TREN-Me-3,2-HOPO. The formation constants for the iron(III) and gadolinium(III) complexes have been evaluated by spectrophotometric pH titration to be (log K) 26.3(1) and 17.2(2), respectively.