Rational Design, Development, and Stability Assessment of a Macrocyclic Four-Hydroxamate-Bearing Bifunctional Chelating Agent for 89Zr
Rational Design, Development, and Stability Assessment of a Macrocyclic Four-Hydroxamate-Bearing Bifunctional Chelating Agent for 89Zr
复制标题
DOI：
10.1002/cmdc.201700377
复制
发表时间：
2017-09-21
期刊：
影响因子：
3.4
通讯作者：
Waengler, Carmen
中科院分区：
文献类型：
--
作者：
Seibold, Uwe;Waengler, Bjoern;Waengler, Carmen
锆-89是一种正电子发射放射性核素，对正电子发射断层扫描（PET）的医学成像应用具有很高的兴趣。为了将这种放射性金属引入生物活性靶向载体，通常使用螯合剂去铁胺B （DFO）。然而，已知DFO形成的Zr-89配合物体内稳定性有限。本文描述了一种新的大环四羟基酸螯合剂的合理设计和化学开发-1,10,19,28-四羟基-1,5,10,14,19,23,28,32-八氧杂环己六康坦-2,6,11,15,20,24,29,33-辛酮（CTH36）用于Zr4+的稳定络合。为此，我们首先进行了计算研究，以确定最佳的螯合剂几何形状，然后我们开发了不同的合成途径，以达到目标结构。采用高效液相法合成目标螯合剂的效果最好。为了实现与生物分子的高效和化学选择性偶联，还开发了四氮修饰的CTH36变体。以模型肽TCO-c（RGDfK）为例，证明了该功能化螯合剂具有良好的偶联特性。我们确定了CTH36及其生物偶联物的最佳Zr-89放射性标记参数，发现在非常温和的反应条件下，Zr-89放射性标记可以有效地进行。最后，我们对Zr-89-CHT36-c（RGDfK）和Zr-89-DFO-c（RGDfK）进行了络合稳定性对比试验，结果表明新开发的螯合剂CTH36的络合稳定性有所提高。
Zirconium-89 is a positron-emitting radionuclide of high interest for medical imaging applications with positron emission tomography (PET). For the introduction of this radiometal into biologically active targeting vectors, the chelating agent desferrioxamine B (DFO) is commonly applied. However, DFO is known to form Zr-89 complexes of limited in vivo stability. Herein we describe the rational design and chemical development of a new macrocyclic four-hydroxamate-bearing chelating agent-1,10,19,28-tetrahydroxy-1,5,10,14,19,23,28,32-octaazacyclohexatriacontan-2,6,11,15,20,24,29,33-octaone (CTH36)for the stable complexation of Zr4+. For this purpose, we first performed computational studies to determine the optimal chelator geometry before we developed different synthesis pathways toward the target structures. The best results were obtained using an efficient solution-phase-based synthesis strategy toward the target chelating agent. To enable efficient and chemoselective conjugation to biomolecules, a tetrazine-modified variant of CTH36 was also developed. The excellent conjugation characteristics of the so-functionalized chelator were demonstrated on the example of the model peptide TCO-c(RGDfK). We determined the optimal Zr-89 radiolabeling parameters for CTH36 as well as its bioconjugate, and found that Zr-89 radiolabeling proceeds efficiently under very mild reaction conditions. Finally, we performed comparative complex stability tests for Zr-89-CHT36-c(RGDfK) and Zr-89-DFO-c(RGDfK), showing improved complex stability for the newly developed chelator CTH36.