1,4,7,10-tetraazacyclododecane-1,4,7-tri(acetic acid)-10-((1,2-ethylenediamine monoamide)acetic acid) trifluroacetate | 944731-76-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 1,4,7,10-tetraazacyclododecane-1,4,7-tri(acetic acid)-10-((1,2-ethylenediamine monoamide)acetic acid) trifluroacetate
• CAS: 944731-76-4
• 化学式: C₂HF₃O₂*C₁₈H₃₄N₆O₇
• 分子量: 560.528
• InChiKey: WKKYQOBMIFJJNU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.83
• 重原子数：
  38.0
• 可旋转键数：
  10.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  217.28
• 氢给体数：
  6.0
• 氢受体数：
  10.0

反应信息

• 作为反应物：
  描述：

  exo-3,6-epoxy-1,2,3,6-tetrahydrophthalic anhydride 、 1,4,7,10-tetraazacyclododecane-1,4,7-tri(acetic acid)-10-((1,2-ethylenediamine monoamide)acetic acid) trifluroacetate 以 水 为溶剂， 反应 0.08h， 以65%的产率得到DOTA-马来酰亚胺
  参考文献：
  名称：

  Bifunctional ligands based on the DOTA-monoamide cage

  摘要：

  本文介绍了获得带有氨基、羟基、醛基和马来酰亚胺基团的 DOTA-单酰胺配体的有效途径。这些官能团可随意与配位笼保持一定间距，很容易与合适的靶向基团发生反应。以这种方式获得的生物共轭物可用于诊断成像和治疗应用。

  DOI：

  10.1039/b715844k
• 作为产物：
  描述：

  轮环藤宁 在 sodium acetate 、 potassium carbonate 作用下， 以 N,N-二甲基乙酰胺 、 乙腈 为溶剂， 反应 173.0h， 生成 1,4,7,10-tetraazacyclododecane-1,4,7-tri(acetic acid)-10-((1,2-ethylenediamine monoamide)acetic acid) trifluroacetate
  参考文献：
  名称：

  DOTA 分支有机框架作为巨大而有效的金属螯合剂

  摘要：

  多核配合物作为临床使用的金属制剂引起了广泛关注。在本文中，我们将 DOTA 作为功能单元和构建连接点，通过逐层组织 DOTA，构建了一系列具有多个螯合孔的 DOTA 分支有机框架（DBOF）。这些巨大的螯合剂得到了很好的表征，揭示了它们的纳米尺寸和柔软的结构。进一步的实验表明，与传统的小型 DOTA 螯合剂相比，它们可以有效地保持丰富的金属离子，并具有更高的动力学稳定性。它们相应的含有 Gd3+、Tb3+ 或两者的多核复合物显示出优异的成像特性、出色的周边修饰可行性和异常的动力学稳定性。这项工作可以很容易地扩展到具有多功能特性的各种同多核配合物和核/壳异质多核配合物的制造。我们期望这种新型巨分子和配体分支策略将为设计和构建用于生物医学应用的高性能和稳定性的下一代多金属试剂开辟一条新途径。

  DOI：

  10.1021/jacs.9b09269

文献信息

• Noninvasive Visualization of Pharmacokinetics, Biodistribution and Tumor Targeting of Poly[N-(2-hydroxypropyl)methacrylamide] in Mice Using Contrast Enhanced MRI
  作者：Yanli Wang、Furong Ye、Eun-Kee Jeong、Yongen Sun、Dennis L. Parker、Zheng-Rong Lu

  DOI：10.1007/s11095-007-9252-1

  日期：2007.6

  To study a non-invasive method of using contrast enhanced magnetic resonance imaging (MRI) to visualize the real-time pharmacokinetics, biodistribution and tumor accumulation of paramagnetically labeled poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) copolymer conjugates with different molecular weights and spacers in tumor-bearing mice. Paramagnetically labeled HPMA copolymer conjugates were synthesized by free radical copolymerization of HPMA with monomers containing a chelating ligand, followed by complexation with Gd(OAc)3. A stable paramagnetic chelate, Gd-DO3A, was conjugated to the copolymers via a degradable spacer GlyPheLeuGly and a non-degradable spacer GlyGly, respectively. The conjugates with molecular weights of 28, 60 and 121 kDa and narrow molecular weight distributions were prepared by fractionation with size exclusion chromatography. The conjugates were injected into athymic nude mice bearing MDA-MB-231 human breast carcinoma xenografts via a tail vein. MR images were acquired before and at various time points after the injection with a 3D FLASH sequence and a 2D spin-echo sequence at 3T. Pharmacokinetics, biodistribution and tumor accumulation of the conjugates were visualized based on the contrast enhancement in the blood, major organs and tumor tissue at various time points. The size effect of the conjugates was analyzed among the conjugates. Contrast enhanced MRI resulted in a real-time, three-dimensional visualization of blood circulation, pharmacokinetics, biodistribution and tumor accumulation of the conjugates, and the size effect on these pharmaceutical properties. HPMA copolymer conjugates with high molecular weight had a prolonged blood circulation time and high passive tumor targeting efficiency. Non-biodegradable HPMA copolymers with molecular weights higher than the threshold of renal filtration demonstrated higher efficiency for tumor drug delivery than biodegradable poly(L-glutamic acid). Contrast enhanced MRI is an effective method for non-invasive visualization of in vivo properties of the paramagnetically labeled polymer conjugates in preclinical studies.

  -operative检查。
• Synthesis and In Vitro Comparison of DOTA, NODAGA and 15-5 Macrocycles as Chelators for the 64Cu-Labelling of Immunoconjugates
  作者：Aurélie Maisonial-Besset、Tiffany Witkowski、Mercedes Quintana、Sophie Besse、Vincent Gaumet、Axel Cordonnier、Cyrille Alliot、Aurélien Vidal、Caroline Denevault-Sabourin、Sébastien Tarrit、Sophie Levesque、Elisabeth Miot-Noirault、Jean-Michel Chezal

  DOI：10.3390/molecules28010075

  日期：——

  The development of 64Cu-based immuno-PET radiotracers requires the use of copper-specific bifunctional chelators (BFCs) that contain functional groups allowing both convenient bioconjugation and stable copper complexes to limit in vivo bioreduction, transmetallation and/or transchelation. The excellent in vivo kinetic inertness of the pentaazamacrocyclic [64Cu]Cu-15-5 complex prompted us to investigate its potential for the 64Cu-labelling of monoclonal antibodies (mAbs), compared with the well-known NODAGA and DOTA chelators. To this end, three NODAGA, DOTA and 15-5-derived BFCs, containing a pendant azadibenzocyclooctyne moiety, were synthesised and a robust methodology was determined to form covalent bonds between them and azide-functionalised trastuzumab, an anti-HER2 mAb, using strain-promoted azide-alkyne cycloaddition. Unlike the DOTA derivative, the NODAGA- and 15-5-mAb conjugates were radiolabelled with 64Cu, obtaining excellent radiochemical yields, under mild conditions. Although all the radioimmunoconjugates showed excellent stability in PBS or mouse serum, [64Cu]Cu-15-5- and [64Cu]Cu-NODAGA-trastuzumab presented higher resistance to transchelation when challenged by EDTA. Finally, the immunoreactive fraction of the radioimmunoconjugates (88–94%) was determined in HER-2 positive BT474 human breast cancer cells, confirming that the bioconjugation and radiolabelling processes implemented had no significant impact on antigen recognition.

  64Cu基免疫PET放射性示踪剂的开发需要使用含有功能基团的铜特异性双功能螯合剂（BFCs），以便进行方便的生物偶联并形成稳定的铜配合物，以限制体内生物还原、金属转移和/或转螯合。五胺大环[64Cu]Cu-15-5配合物的出色体内动力学惰性促使我们研究其与著名的NODAGA和DOTA螯合剂相比，用于标记单克隆抗体（mAbs）的64Cu。为此，合成了三种含有嵌二氮苯并环辛炔基的NODAGA、DOTA和15-5衍生的BFCs，并确定了一种强大的方法，通过应变促进的偶联反应，在其中与带有偶氮基的Trastuzumab进行共价键的形成，这是一种针对HER2的抗体。与DOTA衍生物不同，NODAGA-和15-5-mAb偶联物在温和条件下用64Cu标记，获得了优异的放射化学收率。虽然所有的放射免疫偶联物在PBS或小鼠血清中均表现出良好的稳定性，但当受到EDTA挑战时，[64Cu]Cu-15-5-和[64Cu]Cu-NODAGA-trastuzumab表现出更高的抗转螯合能力。最后，在HER-2阳性BT474人类乳腺癌细胞中确定了放射免疫偶联物的免疫反应性分数（88-94%），确认实施的生物偶联和放射标记过程对抗原识别没有显著影响。