Radiolabeling and in vivo behavior of copper-64-labeled cross-bridged cyclam ligands
Radiolabeling and in vivo behavior of copper-64-labeled cross-bridged cyclam ligands
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DOI：
10.1021/jm0103817
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发表时间：
2002-01-17
影响因子：
7.3
通讯作者：
Anderson, CJ
中科院分区：
文献类型：
--
作者：
Sun, XK;Wuest, M;Anderson, CJ
大环螯合剂及其金属配合物在生物医学科学中具有广泛的应用，包括放射性药物化学。铜放射性核素在放射性药物中的使用正在增加。已发现大环螯合剂比乙二胺四乙酸 (EDTA) 和二亚乙基三胺五乙酸 (DTPA) 等无环螯合剂具有增强的体内稳定性。目前用于将铜放射性核素标记到生物分子上的螯合剂是 TETA（1,4,8,11-四氮杂环十四烷-1,4,8,11-四乙酸）的类似物；然而，最近的报告证明了放射性 Cu(II)-TETA 复合物体内不稳定性的证据。一类新的结构增强大环化合物，即“交桥”cyclam 衍生物，可与 Cu(II) 形成高度稳定的络合物，在强酸中不易解离。在这里，我们评估了一系列 Cu-64(II) 交桥大环配合物的生物稳定性和体内行为。评估的配体包括母体配体，1,4,8,11-四氮杂双环[6.6.2]十六烷(1)，和三个4,11-双臂衍生物：4,11-双(羧甲基)-1,4,8,11-四氮杂双环[6.6.2]十六烷(2)； 4,11-双(N,N-二乙基-酰氨基甲基)-1,4,8,11-四氮杂双环[6.6.2]十六烷(3)；和4,11-双(酰氨基乙基)-1,4,8,11-四氮杂双环[6.6.2]十六烷(4)。 Copper-64 与配体 1-4 形成高放射化学产率的配合物。 Cu-64-2 配合物呈中性，而 64Cu 配合物 1、3 和 4 带正电。所有复合物在大鼠血清中 24 小时内均未分解。 Sprague-Dawley 大鼠的生物分布实验表明，Cu-64-1、-3 和 -4 被肝脏和肾脏吸收，并在 24 小时内缓慢清除，而 Cu-64-2 从所有组织中快速清除。 Cu-64-2复合物从血液和肝脏中的快速清除以及大鼠肝脏代谢实验表明它在体内高度稳定。 2 的双功能螯合剂是将铜放射性核素标记到生物分子上以进行诊断成像和靶向的重要候选者。放射治疗。
Macrocyclic chelators and their metal complexes have widespread applications in the biomedical sciences, including radiopharmaceutical chemistry. The use of copper radionuclides in radiopharmaceuticals is increasing. Macrocyclic chelators have been found to have enhanced in vivo stability over acyclic chelators such as ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA). The currently used chelators of choice for labeling copper radionuclides to biological molecules are analogues of TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid); however, recent reports have demonstrated evidence of in vivo instability of the radio-Cu(II)-TETA complexes. A new class of structurally reinforced macrocycles, the "cross-bridged" cyclam derivatives, form highly stable complexes with Cu(II) that are resistant to dissociation in strong acid. Here, we evaluate a series of Cu-64(II) cross-bridged macrocyclic complexes for biological stability and in vivo behavior. The ligands evaluated include the parent ligand, 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (1), and three 4,11-dipendant arm derivatives: 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (2); 4,11-bis(N,N-diethyl-amidomethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (3); and 4,11-bis(amidoethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (4). Copper-64 formed complexes with ligands 1-4 in high radiochemical yields. The Cu-64-2 complex was neutral, while 64Cu complexes of 1, 3, and 4 were positively charged. All complexes showed no decomposition in rat serum out to 24 h. Biodistribution experiments in Sprague-Dawley rats indicated that Cu-64-1, -3, and -4 were taken up by the liver and kidney and cleared slowly over 24 h, whereas Cu-64-2 cleared rapidly from all tissues. The rapid clearance of the Cu-64-2 complex from the blood and liver, as well as liver metabolism experiments in rats, suggests that it is highly stable in vivo. A bifunctional chelator of 2 is a significant candidate for labeling copper radionuclides to biological molecules for diagnostic imaging and targeted. radiotherapy.