Sun Y, Anderson C J, Pajeau T S, Reichert D E, Hancock R D, Motekaitis R J, Martell A E, Welch M J
Department of Chemistry, Texas A&M University, College Station 77843-3255, USA.
J Med Chem. 1996 Jan 19;39(2):458-70. doi: 10.1021/jm9505977.
Complexes of Ga(III) and In(III) radionuclides are widely used in diagnostic imaging. In this study, the following ligands of denticities 4, 5, and 6 respectively were prepared: N,N'-bis-(2,2-dimethyl-2-mercaptoethyl) ethylenediamine (4SS), 1-carboxy-N-N'-bis(2,2-dimethyl-2- mercaptoethyl)ethylenediamine (5SS), and N,N'-bis(2,2- dimethyl-2-mercaptoethyl)ethylenediamine-N,N'-diacetic acid (6SS). Syntheses of the two new ligands, 5SS and 6SS, are described. Equilibrium constants for their In(III) and Ga(III) complexes were determined by both direct and ligand-competitive potentiometric methods. The formation constant (KML = [ML]/[M][L]) of In(III)--6SS in 0.100 M KNO3 at 25.0 degrees C is 10(39.8), and its pM at physiological pH (7.4 with 100% excess of the ligand) is 30.9. These values are higher than those of any other previous reported ligand for In(III). The stability constants of the complexes of 4SS, 5SS, 6SS, and the analogous ligand EDDASS, N,N'-bis(2-mercaptoethyl) ethylenediamine-N,N'-diacetic acid, which does not contain gem-dimethyl groups, are compared. The thermodynamic stabilities of the In(III) complexes of all ligands except 6SS are greater than those of the corresponding Ga(III) complexes. The presence of the geminal dimethyl groups in 6SS increased the stability of the Ga(III) and In(III) complexes over those of EDDASS. The effects of the gem-dimethyl groups on complex stabilities are explained by molecular modeling. The serum stabilities and biodistributions out to 1 h postinjection of 67/68Ga and 111In chelates of 4SS, 5SS, and 6SS were measured and compared with those of EDDASS. The 67/68Ga- and 111In-ligand complexes with more donor atoms showed were more stable in serum, both in vitro and in vivo. The biodistributions of the 67/68Ga- and 111In-ligand complexes exhibited distinct trends. None of the 67/68Ga- and 111In-chelates demonstrated significant heart or brain uptake. The majority of uptake for all compounds was in the liver and kidney. The degree of clearance through the liver corresponded to the thermodynamic stability of the complex. Correlations between in vivo behavior, molecular modeling data, and thermodynamic stability of the complexes are discussed.
镓（III）和铟（III）放射性核素配合物广泛应用于诊断成像。在本研究中，分别制备了以下配位数为4、5和6的配体：N，N'-双（2,2-二甲基-2-巯基乙基）乙二胺（4SS）、1-羧基-N，N'-双（2,2-二甲基-2-巯基乙基）乙二胺（5SS）和N，N'-双（2,2-二甲基-2-巯基乙基）乙二胺-N，N'-二乙酸（6SS）。描述了两种新配体5SS和6SS的合成方法。通过直接电位法和配体竞争电位法测定了它们与铟（III）和镓（III）配合物的平衡常数。在25.0℃、0.100M硝酸钾中，铟（III）-6SS的形成常数（KML = [ML]/[M][L]）为10（39.8），在生理pH值（7.4，配体过量100%）下其pM值为30.9。这些值高于此前报道的任何其他铟（III）配体的值。比较了4SS、5SS、6SS以及不含偕二甲基的类似配体EDDASS（N，N'-双（2-巯基乙基）乙二胺-N，N'-二乙酸）配合物的稳定常数。除6SS外，所有配体的铟（III）配合物的热力学稳定性均高于相应的镓（III）配合物。6SS中偕二甲基的存在使镓（III）和铟（III）配合物的稳定性高于EDDASS。通过分子模拟解释了偕二甲基对配合物稳定性的影响。测定了4SS、5SS和6SS的67/68Ga和11In螯合物在注射后1小时内的血清稳定性和生物分布，并与EDDASS进行了比较。具有更多供体原子的67/68Ga-和111In-配体配合物在体外和体内血清中更稳定。67/68Ga-和111In-配体配合物的生物分布呈现出明显的趋势。67/68Ga-和111In-螯合物均未显示出明显的心脏或脑部摄取。所有化合物的大部分摄取都在肝脏和肾脏。通过肝脏的清除程度与配合物的热力学稳定性相对应。讨论了配合物的体内行为、分子模拟数据和热力学稳定性之间的相关性。
