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The physicochemical characterization of MS‐325 [trisodium {4‐(R)‐[(4,4‐diphenylcyclohexyl)phosphanooxymethyl]‐3,6,9‐triaza‐3,6,9‐tris(methoxycarbonyl)undecanedioato}gadolinium(III)], a new derivative of Gd‐DTPA {Magnevist®: dimeglumin [{3,6,9‐triaza3,6,9‐tris(methoxycarbonyl)undecanedioato}gadolinium(III)], presented as a potentially useful angiographic contrast agent, was carried out in various media. Water solution, protein‐containing solution, phosphorylated metabolites solution, and Zn2+‐containing solution were investigated using different NMR techniques such as water 1H nuclear magnetic relaxation rates, water 17O transverse relaxation rates, and 31P longitudinal relaxation rates of phosphorylated metabolites. The proton relaxivity of MS‐325 in water was found to be higher than that of the parent compound Gd‐DTPA; this can be attributed to the longer rotational correlation time (τR) of the hydrated complex, and possibly to an apparently shorter mean distance (r) between the protons of the coordinated water molecule and the gadolinium ion. The kinetic and thermodynamic stability of MS‐325 in solutions containing phosphorylated metabolites (ATP, phosphocreatine and inorganic phosphate) were measured by 31P relaxation rate analysis and found to be higher than for Gd‐DTPA. Similarly, the Zn2+ transmetallation process studied by proton relaxometry is slower than for the same reference compound. Finally, an analysis of the noncovalent binding of MS‐325 to serum proteins by proton relaxometry showed that MS‐325 interacts with human serum albumin (HSA) and that the association constant of this interaction is equal to 6100 ± 2130 M−1. A peak relaxivity of approx. 50 s−1mM−1 was determined at 25 MHz for the protein‐bound paramagnetic complex. This value is lower than the maximal relaxivity predicted for a paramagnetic center totally immobilized at the surface of the protein.

A convenient synthesis of disodium S-[4-(4-ethoxybenzyl)-3,6,9-tris[(carboxy-kappaO)methyl]-3,6,9-triazaundecandioato)(5-)-kappa(3)N(3)(),N(6)(),N(9)(),kappa(2)O(1)(),O(11)()]gadolinate(2-) (Gd-EOB-DTPA), 1, is reported. This water-soluble complex is presently undergoing phase III clinical trials as a liver-specific contrast agent for magnetic resonance imaging (MRI). The thermodynamic complex stability constant of 1 and the acid dissociation constants of the ligand have been determined as well as the stability constant of the calcium complex Ca-EOB-DTPA (2), which is used as an additive in the pharmaceutical formulation of the contrast agent. The solid-state structure of the ligand S-4-(4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6,9-triazaundecanedioic acid (H(5)EOB-DTPA), 3, has been elucidated in a single crystal X-ray diffraction study. Additionally, HPLC evidence is given that the enantiomerically pure ligand forms two diastereomeric gadolinium complexes in a 65:35 ratio. The kinetics of isomerization of the isolated diastereomers-as dependent on pH and temperature-has been investigated, and thus, the activation energy for the interconversion of these isomers has been estimated to be 75.3 kJ mol(-1). Finally, the structures of the two components of 1 are discussed in terms of four possible diastereomers.

Several Bi(III) complexes are used in medicine as drugs. Bi(DO3A-Bu) has recently been proposed as a nonionic contrast agent in X-ray imaging (H(3)DO3A-Bu = 10-[2,3-dihydroxy-(1-hydroxymethyl)propyl]-1,4,7,10-tetraazacyclododecane-1,4,7,-triacetic acid). The solution equilibria and NMR structure and dynamics of Bi(DO3A-Bu) and of the similar Bi(DOTA)(-) have been investigated (H(4)DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). The stability constants were determined with the study of the competition equilibria between Br(-) ions and the ligands DOTA or DO3A-Bu for the Bi(III) by spectrophotometry. The stability constants, obtained for Bi(DOTA)(-) and Bi(DO3A-Bu), are very high, log K = 30.3 and 26.8, respectively. Potentiometric titrations indicated the dissociation of one of the protons among the three alcoholic OH groups in Bi(DO3A-Bu). The dissociation constant is log K = 7.53 (0.09) indicating that at physiological pH about 50% of the species possess -1 charge. It was shown by (1)H and (13)C NMR spectroscopy that the OH group attached to the middle carbon atom of the "butriol" side chain is coordinated to the Bi(III) and starts to deprotonate at pH > 5.5. The crystal structure of NaBi(DOTA).H(2)O shows an octacoordinated arrangement of the donor atoms around the Bi(III), with no water in the inner sphere. The crystals belong to the centrosymmetric space group C2/c. The temperature dependent (1)H and (13)C NMR spectra indicate that both Bi(DOTA)(-) and Bi(DO3A-Bu)(-) complexes are fluxional. For Bi(DOTA), the Delta(deltadeltadeltadelta) right harpoon over left harpoon Lambda(lambdalambdalambdalambda) fluxionality was identified, and on the basis of the activation parameters, a synchronous motion was suggested for the fluxional motion resulting in the change of ring conformation and of the helicity of the complex. The transition state is supposed to be more symmetrical than the initial state. The deprotonated Bi(DO3A-Bu) has a highly asymmetric NMR structure in solution, and its fluxional motion is slower than that of Bi(DOTA)(-).

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