Synthesis of a diaminedithiol bifunctional chelating agent for incorporation of technetium-99m into biomolecules.
Synthesis of a diaminedithiol bifunctional chelating agent for incorporation of technetium-99m into biomolecules.
复制标题
用于将 Technetium-99m 掺入生物分子的二胺二硫醇双功能螯合剂的合成。
DOI：
10.1021/bc00002a007
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发表时间：
1990
影响因子：
4.7
通讯作者：
Lever,SZ
中科院分区：
文献类型：
--
作者：
Baidoo,KE;Lever,SZ
本文报道了一种基于二胺二硫醇（DADT）配体体系的双功能螯合剂（BCA）的合成。经六步合成，总收率16%，得到1，它含有一个硫内酯作为反应部分，它允许直接偶联亲核试剂而不形成副产物。1对苄胺的反应性和随后用锝-99m标记的配体已被评估作为制备各种生物缀合物的模型。偶联和交换标记在温和条件下都能高产率进行，与二乙三胺五乙酸（DTPA）的竞争反应表明锝-99 m-DADT络合物具有良好的上级稳定性。在目前可用的放射性核素中，Tc-99 m（99 mTc）具有最好的显像特性（1，2）。它的高光子产率每分裂确保良好的计数统计和单能光子（140千电子伏）是理想的平面和单光子发射计算机断层扫描（SPECT）仪器。6.02小时的短半衰期和缺乏微粒排放通常导致患者吸收的辐射剂量较低。此外，99 mTc价格便宜，并且以发电机的形式广泛使用。由于这些性质，人们对开发含有这种放射性核素的基于蛋白质的放射性药物有相当大的兴趣。最初的方法依赖于天然蛋白质为还原的锝提供直接稳定性;然而，弱非特异性标记、胶体污染、蛋白质变性和体内标记损失可能是有问题的（2-6）。双功能che-late方法，它提供了某些优势（7-9），已在研究中的标记蛋白质与99 mTc。然而，可与其他放射性核素一起使用的双功能螯合剂（BCA）对99 mTc的成功率有限。例如，尝试利用二亚乙基三胺五乙酸（DTPA）偶联蛋白质（10-13）导致标记产物缺乏足够的体外和体内稳定性
The synthesis of a bifunctional chelating agent (BCA), 1, based on the diaminedithiol (DADT) ligand system, is described. The six-step synthetic sequencehas been accomplished in 16% overall yield, affording 1, which contains a thiolactone as a reactive moiety, which permits direct coupling to nucleo-philes without the formation of byproducts. The reactivity of 1 toward benzylamine and subsequent labeling of the ligand with technetium-99m has beenevaluated as a model for preparation of various bioconjugates. Both coupling and exchange labeling occur in high yield under mild conditions, and competition reactions with diethylenetriaminepentaacetic acid (DTPA) indicate the superior stabil-ity of the technetium-99m-DADT complex. Preparation of BCA 1 thus provides a new avenue into technetium-labeled radiopharmaceuticals.Technetium-99 m (99mTc) possesses the best character-istics for scintigraphic imaging among currently avail-able radionuclides (1, 2). Its high photon yield per dis-integration ensures good counting statistics and its monoen-ergetic photons (140 KeV) are ideally suited for planar and single photon emission computed tomography (SPECT) instrumentation. The short half-life of 6.02 h and lack of particulate emissions generallyresult in a low absorbed radiation dose to patients. In addition, 99mTc is inexpensive and is widely available in generator form. Due to these properties, there is considerable interest in developing protein-based radiopharmaceuticals con-taining this radionuclide. Initial methods relied on the native protein to offer direct stabilization for reduced technetium; however, weak nonspecific labeling, colloidal contamination, protein denaturation, and loss of label in vivo can be problematic (2-6). The bifunctional che-late approach, which provides certain advantages (7-9), has been under investigation for the labeling of proteins with 99mTc. However, the bifunctional chelating agents (BCAs) available for use with otherradionuclides have had only limited success with 99mTc. For example, attempts to utilize diethylenetriaminepentaacetic acid (DTPA) coupled proteins (10-13) result in labeled prod-ucts which lack sufficient in vitro and in vivo stability