title: N,N'-ethylene-di-L-cysteine (EC) complexes of Ga(III) and In(III): molecular modeling, thermodynamic stability and in vivo studies.
abstract: There are several reports in the literature on the evaluation of chelates 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-Ethylenedicysteine (EC) is a N2S2 ligand that also contains two carboxylic acid moieties for complexation of Ga(III) and In(III) in a hexacoordinate 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 the Ga- and In-EC complexes support the thermodynamic results. 67Ga- and 111In-labeled complexes of EC were prepared and analyzed by thin layer chromatography and electrophoresis. Both complexes were evaluated in biodistribution studies in normal Sprague-Dawley rats. 111In-EC cleared rapidly through the hepatobiliary system, whereas 67Ga-EC remained in the liver at 1 h post-injection. Although 67Ga-EC was retained in the liver, suggesting instability of the complex in vivo. 67Ga-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 111In-labeled proteins and peptides. More lipophilic analogues of 68Ga-EC may also have potential as myocardial PET imaging agents.
authors.affiliation: Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Anderson
authors.forename: C S
authors.initials: CS
authors.lastname: John
authors.forename: Y J
authors.initials: YJ
authors.lastname: Li
authors.forename: R D
authors.initials: RD
authors.lastname: Hancock
authors.forename: T J
authors.initials: TJ
authors.lastname: McCarthy
authors.forename: A E
authors.initials: AE
authors.lastname: Martell
authors.forename: M J
authors.initials: MJ
authors.lastname: Welch
mesh_terms: D000818:Animals; D003545:Cysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004355:Drug Stability; D005260:Female; D005710:Gallium Radioisotopes / Q000493:pharmacokinetics; D007202:Indicators and Reagents; D007205:Indium Radioisotopes / Q000493:pharmacokinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011199:Potentiometry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013816:Thermodynamics; D014018:Tissue Distribution
chemical_list: D005710:Gallium Radioisotopes; D007202:Indicators and Reagents; D007205:Indium Radioisotopes; D009942:Organometallic Compounds; C093928:gallium-ethylenedicysteine; C093929:indium-ethylenedicysteine; D003545:Cysteine