N,N'-ETHYLENE-DI-L-CYSTEINE (EC) COMPLEXES OF GA(III) AND IN(III) - MOLECULAR MODELING, THERMODYNAMIC STABILITY AND IN-VIVO STUDIES

There are several reports in the literature on the evaluation of chela tes containing two nitrogens and two sulfurs (N2S2) as four coordinate ligands (in solution) for gallium and indium radiopharmaceuticals. No thermodynamic stability constants of these ligands were reported, and the stability of these complexes in vivo has been questioned. L,L-Eth ylenedicysteine (EC) is a N2S2 ligand that also contains two carboxyli c acid moieties for complexation of Ga(III) and In(III) in a hexacoord inate environment. The stability constants of Ga- and In-EC have been determined by potentiometric methods. The stability of In-EC was found to be greater than that of Ga-EC, with stability constants (log K's) of 33.0 and 31.5, respectively. A molecular mechanics evaluation of th e Ga- and In-EC complexes support the thermodynamic results. Ga-67- an d In-111-labeled complexes of EC were prepared and analyzed by thin la yer chromatography and electrophoresis. Both complexes were evaluated in biodistribution studies in normal Sprague-Dawley rats. In-111-EC cl eared rapidly through the hepatobiliary system, whereas Ga-67-EC remai ned in the liver at Ih post-injection. Although Ga-67-EC was retained in the liver, suggesting instability of the complex in vivo, Ga-67-EC was Stable in rat plasma in vivo at 2 h post-injection. Because of the high thermodynamic and in vivo stability of In-EC, derivatives of EC may have applications as bifunctional chelates for In-111-labeled prot eins and peptides. More lipophilic analogues of Ga-68-EC may also have potential as myocardial PET imaging agents.