Synthesis, Cu(II) complexation, 64Cu-labeling and biological evaluation of cross-bridged cyclam chelators with phosphonate pendant arms.
Synthesis, Cu(II) complexation, 64Cu-labeling and biological evaluation of cross-bridged cyclam chelators with phosphonate pendant arms.
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DOI：
10.1039/c1dt11743b
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发表时间：
2012-02-21
期刊：
影响因子：
--
通讯作者：
Anderson CJ
中科院分区：
文献类型：
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作者：
Ferdani R;Stigers DJ;Fiamengo AL;Wei L;Li BT;Golen JA;Rheingold AL;Weisman GR;Wong EH;Anderson CJ
开发了一类新的具有膦酸酯侧基的基于交联环素的大环化合物。 1,4,8,11-四氮杂环十四烷-1,8-二（甲膦酸）（CB-TE2P, 1）和 1,4,8,11-四氮杂环十四烷-1-（甲膦酸）-8-（甲羧酸）（CB-TE1A1P, 2）已被合成，并且已被证明在室温下很容易形成中性铜（II）络合物，作为相应的二价阴离子。两种配合物均表现出对脱金属的高动力学惰性，并且晶体结构证实铜（II）离子完全封装在每个大环的裂隙状结构内。 CB-TE2P (1) 和 CB-TE1A1P (2) 均可在室温下用 64Cu 进行放射性标记，反应时间不到 1 小时，比活性 >1mCi/μg，这对于跨桥环己酰胺衍生物而言是前所未有的。通过使用健康雄性 Lewis 大鼠进行生物分布研究，研究了 64Cu-CB-TE2P 和 64Cu-CB-TE1A1P 的体内行为。与其他铜螯合剂（包括 CB-TE2A、NOTA 和 Diamsar）相比，这两种新化合物均显示出快速清除率，并且在非靶器官/组织中的积累相似或较低。
A new class of cross-bridged cyclam-based macrocycles featuring phosphonate pendant groups has been developed. 1,4,8,11-tetraazacyclotetradecane-1,8-di(methanephosphonic acid) (CB-TE2P, 1) and 1,4,8,11-tetraazacyclotetradecane-1-(methanephosphonic acid)-8-(methanecarboxylic acid) (CB-TE1A1P, 2) have been synthesized and have been shown to readily form neutral copper (II) complexes at room temperature as the corresponding dianions. Both complexes showed high kinetic inertness to demetallation and crystal structures confirmed complete encapsulation of copper (II) ion within each macrocycle’s cleft-like structure. Unprecedented for cross-bridged cyclam derivatives, both CB-TE2P (1) and CB-TE1A1P (2) can be radiolabeled with 64Cu at room temperature in less than 1 hour with specific activities >1mCi/μg. The in vivo behavior of both 64Cu-CB-TE2P and 64Cu-CB-TE1A1P were investigated through biodistribution studies using healthy, male, Lewis rats. Both new compounds showed rapid clearance with similar or lower accumulation in non-target organs/tissues when compared to other copper chelators including CB-TE2A, NOTA and Diamsar.