Comparative in vivo stability of copper-64-labeled cross-bridged and conventional tetraazamacrocyclic complexes
Comparative in vivo stability of copper-64-labeled cross-bridged and conventional tetraazamacrocyclic complexes
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DOI：
10.1021/jm030383m
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发表时间：
2004-03-11
影响因子：
7.3
通讯作者：
Anderson, CJ
中科院分区：
文献类型：
--
作者：
Boswell, CA;Sun, XK;Anderson, CJ
铜放射性同位素在放射性药物应用中的应用增加了对形成稳定的放射性铜络合物并允许共价结合到生物分子上的双功能螯合剂(BFC)的需求。最常用于将铜放射性核素标记到生物分子上的螯合剂是1，4，8，11-tetraazacyclotetradecane-1，4，8，11-tetraacetic酸(TETA)的类似物；然而，最近的报道表明放射性-铜(II)-TETA络合物在体内不稳定。一类双环四氮杂大环，即乙烯“交桥”环类化合物(CB-Cyclam)，与铜(II)形成高度动力学稳定的络合物，因此在体内可能比它们的非桥联类似物更不容易发生跨螯合反应。在这里，我们报道了一系列铜-标记的大环配合物的相对生物稳定性和由此产生的放射性标记代谢物的鉴定结果。在正常大鼠肝脏的代谢研究表明，4，11-bis(carboxymethyl)1，4，8，11-tetraazabicyclo[6.6.2]hexadecane的铜-络合物(铜--CB-TE2A)在4h时蛋白结合铜-显著低于铜--TETA[13+/-6%vs75+/-9%]。在相应的环素衍生物中也观察到了类似的趋势，4，10-bis(carboxymethyl)-1，4，7，10-tetraazabicyclo[5.5.2]tetradecane的铜-络合物(铜--CB-DO2A)比1，4，7，10-tetraazacyclododecane-1，4，7，10-tetraacetic酸的铜-络合物(铜--DOTA)在4h发生的穿络作用[61+/-14%vs90.3+/-0.5%蛋白质结合的铜-]。这些数据表明，结构增强的交联桥通过减少环素和环烯交叉桥联的铜-络合物中的金属到蛋白质的损失来提高体内的稳定性，并且在这方面，铜--CB-TE2A优于铜--CB-DO2A。这些发现进一步表明，CB-TE2A的双功能螯合衍生物是将铜放射性核素标记到生物分子上用于诊断成像和靶向放射治疗的非常理想的替代方案。
The increased use of copper radioisotopes in radiopharmaceutical applications has created a need for bifunctional chelators (BFCs) that form stable radiocopper complexes and allow covalent attachment to biological molecules. The chelators most commonly utilized for labeling copper radionuclides to biomolecules are analogues of 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA); however, recent reports have communicated the instability of the radio-Cu(II)-TETA complexes in vivo. A class of bicyclic tetraazamacrocycles, the ethylene "crossbridged" cyclam (CB-cyclam) derivatives, form highly kinetically stable complexes with Cu(II) and therefore may be less susceptible to transchelation than their nonbridged analogues in vivo. Herein we report results on the relative biological stabilities and identification of the resulting radiolabeled metabolites of a series of Cu-64-labeled macrocyclic complexes. Metabolism studies in normal rat liver have revealed that the Cu-64 complex of 4,11-bis(carboxymethyl)1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (Cu-64-CB-TE2A) resulted in significantly lower values of protein-associated Cu-64 than Cu-64-TETA [13 +/- 6% vs 75 +/- 9% at 4 h]. A similar trend was observed for the corresponding cyclen derivatives, with the Cu-64 complex of 4,10-bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (Cu-64-CB-DO2A) undergoing less transchelation than the Cu-64 complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Cu-64-DOTA) [61 +/- 14% vs 90.3 +/- 0.5% protein associated Cu-64 at 4 h]. These data indicate that the structurally reinforcing cross-bridge enhances in vivo stability by reducing metal loss to protein in both the cyclam and cyclen cross-bridged Cu-64 complexes and that Cu-64-CB-TE2A is superior to Cu-64-CB-DO2A in that regard. These findings further suggest that a bifunctional chelator derivative of CB-TE2A is a highly desirable alternative for labeling copper radionuclides to biological molecules for diagnostic imaging and targeted radiotherapy.