一种新型笼状双功能螯合剂 4-((8-氨基-3,6,10,13,16,19-六氮杂双环[6.6.6]icosane-1-基氨基)甲基)苯甲酸的改进合成及生物评价及其用于 64Cu 放射性药物。
An improved synthesis and biological evaluation of a new cage-like bifunctional chelator, 4-((8-amino-3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane-1-ylamino)methyl)benzoic acid, for 64Cu radiopharmaceuticals.
机构信息
Molecular Imaging Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
出版信息
Nucl Med Biol. 2010 Jan;37(1):57-65. doi: 10.1016/j.nucmedbio.2009.09.001. Epub 2009 Oct 12.
INTRODUCTION
Stable attachment of (64)Cu(2+) to a targeting molecule usually requires the use of a bifunctional chelator (BFC). Sarcophagine (Sar) ligands rapidly coordinate (64)Cu(2+) within the multiple macrocyclic rings comprising the cage structure under mild conditions, providing high stability in vivo. Previously, we have designed a new versatile cage-like BFC Sar ligand, 4-((8-amino-3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane-1-ylamino)methyl)benzoic acid (AmBaSar), for (64)Cu radiopharmaceuticals. Here we report the improved synthesis of AmBaSar, (64)Cu(2+) labeling conditions and its biological evaluation compared with the known BFC 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA).
METHODS
The AmBaSar was synthesized in four steps starting from (1,8-diamine-Sar) cobalt(III) pentachloride ([Co(DiAmSar)]Cl(5)) using an improved synthetic method. The AmBaSar was labeled with (64)Cu(2+) in pH 5.0 ammonium acetate buffer solution at room temperature, followed by analysis and purification with HPLC. The in vitro stability of (64)Cu-AmBaSar complex was evaluated in phosphate buffered saline (PBS), fetal bovine serum and mouse blood. The microPET imaging and biodistribution studies of (64)Cu-AmBaSar were performed in Balb/c mice, and the results were compared with (64)Cu-DOTA.
RESULTS
The AmBaSar was readily prepared and characterized by MS and (1)H NMR. The radiochemical yield of (64)Cu-AmBaSar was >or=98% after 30 min of incubation at 25 degrees C. The (64)Cu-AmBaSar complex was analyzed and purified by HPLC with a retention time of 17.9 min. The radiochemical purity of (64)Cu-AmBaSar was more than 97% after 26 h of incubation in PBS or serum. The biological evaluation of (64)Cu-AmBaSar in normal mouse demonstrated renal clearance as the primary mode of excretion, with improved stability in vivo compared to (64)Cu-DOTA.
CONCLUSIONS
The new cage-like BFC AmBaSar was prepared using a simplified synthetic method. The (64)Cu-AmBaSar complex could be obtained rapidly with high radiochemical yield (>/=98%) under mild conditions. In vitro and in vivo evaluation of AmBaSar demonstrated its promising potential for preparation of (64)Cu radiopharmaceuticals.
简介
将（64）Cu（2+）稳定地附着于靶向分子通常需要使用双功能螯合剂（BFC）。在温和条件下，笼状结构中包含的多个大环迅速使（64）Cu（2+）配位，在体内提供高稳定性。以前，我们设计了一种新的多功能笼状 BFC Sar 配体，4-（（8-氨基-3,6,10,13,16,19-六氮杂双环[6.6.6]二十烷-1-基氨基）甲基）苯甲酸（AmBaSar），用于（64）Cu 放射性药物。在这里，我们报告了 AmBaSar 的改进合成，（64）Cu（2+）标记条件及其与已知 BFC 1,4,7,10-四氮杂环十二烷-N，N'，N“，N”-四乙酸（DOTA）的生物学评价。
方法
从（1,8-二胺-Sar）钴（III）五氯（[Co（DiAmSar）] Cl（5））开始，通过改进的合成方法，分四步合成 AmBaSar。在室温下，在 pH 5.0 的乙酸铵缓冲溶液中用（64）Cu（2+）标记 AmBaSar，然后通过 HPLC 进行分析和纯化。在磷酸盐缓冲盐水（PBS），胎牛血清和小鼠血液中评估（64）Cu-AmBaSar 复合物的体外稳定性。在 Balb/c 小鼠中进行（64）Cu-AmBaSar 的 microPET 成像和生物分布研究，并将结果与（64）Cu-DOTA 进行比较。
结果
AmBaSar 很容易通过 MS 和（1）H NMR 进行制备和表征。在 25℃孵育 30 分钟后，（64）Cu-AmBaSar 的放射化学产率> = 98％。（64）Cu-AmBaSar 复合物通过 HPLC 进行分析和纯化，保留时间为 17.9 分钟。在 PBS 或血清中孵育 26 小时后，（64）Cu-AmBaSar 的放射化学纯度> 97％。（64）Cu-AmBaSar 在正常小鼠中的生物学评价表明，肾脏清除是主要的排泄方式，与（64）Cu-DOTA 相比，体内稳定性得到改善。
结论
使用简化的合成方法制备了新型笼状 BFC AmBaSar。在温和条件下，（64）Cu-AmBaSar 复合物可以快速获得，放射化学产率高（≥98％）。AmBaSar 的体外和体内评价表明，它具有制备（64）Cu 放射性药物的潜在应用前景。
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