2,2'-(7-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7-triazonane-1,4-diyl)diacetic acid | 1338231-09-6

• 物质功能分类: 有机原料 - 杂环化合物
• 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: 2,2'-(7-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7-triazonane-1,4-diyl)diacetic acid
• 英文别名: NOTA-NHS；NOTA-NHS ester；2-[4-(carboxymethyl)-7-[2-(2,5-dioxopyrrolidin-1-yl)oxy-2-oxoethyl]-1,4,7-triazonan-1-yl]acetic acid
• CAS: 1338231-09-6
• 化学式: C₁₆H₂₄N₄O₈
• 分子量: 400.389
• InChiKey: UYDHNYKGXODDAV-UHFFFAOYSA-N

物化性质

• 沸点：
  622.7±65.0 °C(Predicted)
• 密度：
  1.50±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -6.2
• 重原子数：
  28
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  148
• 氢给体数：
  2
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  1,2二硬酯酸-3磷脂酰乙醇胺 、 2,2'-(7-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7-triazonane-1,4-diyl)diacetic acid 在 三乙胺 作用下， 以 甲醇 、 氯仿 为溶剂， 反应 5.0h， 以80%的产率得到
  参考文献：
  名称：

  Development of⁶⁸Ga-labelled ultrasound microbubbles for whole-body PET imaging

  摘要：

  我们报告了一种快速高效的方法，用一种简便的连接方法将超声微泡（MB）剂与由发生器产生的PET同位素进行标记，该连接方法是通过一种trans-环辛烯修饰的磷脂和一种新的⁶⁸Ga-HBED-CC-四氮唑示踪剂之间的连接来实现的。这种方法为体内MBs的跟踪提供了可行的解决方案。

  DOI：

  10.1039/c9sc00684b

文献信息

• An Efficient Method for Labeling Single Domain Antibody Fragments with ¹⁸F Using Tetrazine-<i>Trans</i>-Cyclooctene Ligation and a Renal Brush Border Enzyme-Cleavable Linker
  作者：Zhengyuan Zhou、Nick Devoogdt、Michael R. Zalutsky、Ganesan Vaidyanathan

  DOI：10.1021/acs.bioconjchem.8b00699

  日期：2018.12.19

  Single domain antibody fragments (sdAbs) labeled with 18F have shown promise for assessing the status of oncological targets such as the human epidermal growth factor receptor 2 (HER2) by positron emission tomography (PET). Earlier, we evaluated two residualizing prosthetic agents for 18F-labeling of anti-HER2 sdAbs; however, these methods resulted in poor labeling yields and high uptake of 18F activity in the kidneys. To potentially mitigate these limitations, we have now developed an 18F labeling method that utilizes the trans-cyclooctene (TCO)-tetrazine (Tz)-based inverse-electron demand Diels–Alder reaction (IEDDAR) in tandem with a renal brush border enzyme-cleavable glycine-lysine (GK) linker in the prosthetic moiety. The HER2-targeted sdAb 2Rs15d was derivatized with TCO-GK-PEG4-NHS or TCO-PEG4-NHS, which lacks the cleavable linker. As an additional control, the non HER2-specific sdAb R3B23 was derivatized with TCO-GK-PEG4-NHS. The resultant sdAb conjugates were labeled with 18F by IEDDAR using [18F]AlF-NOTA-PEG4-methyltetrazine. As a positive control, the 2Rs15d sdAb was radioiodinated using the well-characterized residualizing prosthetic agent, N-succinimidyl 4-guanidinomethyl-3-[125I]iodobenzoate ([125I]SGMIB). Synthesis of [18F]AlF-NOTA-Tz-TCO-GK-2Rs15d was achieved with an overall radiochemical yield (RCY) of 17.8 ± 1.5% (n = 5) in 90 min, a significant improvement over prior methods (3–4% in 2–3 h). In vitro assays indicated that [18F]AlF-NOTA-Tz-TCO-GK-2Rs15d bound with high affinity and immunoreactivity to HER2. In normal mice, when normalized to coinjected [125I]SGMIB-2Rs15d, the kidney uptake of [18F]AlF-NOTA-Tz-TCO-GK-2Rs15d was 15- and 28-fold lower (P < 0.001) than that seen for the noncleavable control ([18F]AlF-NOTA-Tz-TCO-2Rs15d) at 1 and 3 h, respectively. Uptake of [18F]AlF-NOTA-Tz-TCO-GK-2Rs15d in HER2-expressing SKOV-3 ovarian carcinoma xenografts implanted in athymic mice was about 80% of that seen for coinjected [125I]SGMIB-2Rs15d. On the other hand, kidney uptake was 5–6-fold lower, and as a result, tumor-to-kidney ratios were 4-fold higher for [18F]AlF-NOTA-Tz-TCO-GK-2Rs15d than those for [125I]SGMIB-2Rs15d. SKOV-3 xenografts were clearly delineated even at 1 h after administration of [18F]AlF-NOTA-Tz-TCO-GK-2Rs15d by Micro-PET/CT imaging with even higher contrast observed thereafter. In conclusion, this strategy warrants further evaluation for labeling small proteins such as sdAbs because it offers the benefits of good radiochemical yields and enhanced tumor-to-normal tissue ratios, particularly in the kidney.

  带有 18F 标记的单域抗体片段 (sdAbs) 已显示出通过正电子发射断层扫描 (PET) 评估人表皮生长因子受体 2 (HER2) 等肿瘤学靶点状态的潜力。早期，我们评估了两种残余化辅基用于 18F 标记抗 HER2 sdAbs;然而，这些方法导致标记产率较低且肾脏中 18F 活性摄取较高。为了潜在地缓解这些局限性，我们现在开发了一种 18F 标记方法，该方法利用反式-环辛烯 (TCO)-四嗪 (Tz) 基反电子需求的 Diels-Alder 反应 (IEDDAR) 与肾刷状缘酶可切割的甘氨酸-赖氨酸 (GK) 连接子相结合的策略。HER2 靶向的 sdAb 2Rs15d 被衍生化为 TCO-GK-PEG4-NHS 或不含可切割连接子的 TCO-PEG4-NHS。作为额外对照，非 HER2 特异性的 sdAb R3B23 被衍生化为 TCO-GK-PEG4-NHS。所得的 sdAb 偶联物通过使用 [18F]AlF-NOTA-PEG4-甲基四嗪的 IEDDAR 反应进行 18F 标记。作为阳性对照，2Rs15d sdAb 通过使用广为人知的残余化辅基 N-琥珀酰亚胺基 4-胍基甲基-3-[125I]碘苯甲酸 ([125I]SGMIB) 进行放射碘标记。[18F]AlF-NOTA-Tz-TCO-GK-2Rs15d 的合成在 90 分钟内实现了 17.8 ± 1.5%（n = 5）的总放射化学产率 (RCY)，这相对于先前方法（2-3 小时内的 3-4%）有了显著改进。体外实验表明，[18F]AlF-NOTA-Tz-TCO-GK-2Rs15d 对 HER2 具有高亲和力和免疫反应性。在正常小鼠中，当相对于共注射的 [125I]SGMIB-2Rs15d 进行归一化时，[18F]AlF-NOTA-Tz-TCO-GK-2Rs15d 在 1 和 3 小时时的肾脏摄取分别比不可切割对照组（[18F]AlF-NOTA-Tz-TCO-2Rs15d）低 15 倍和 28 倍（P < 0.001）。在无胸腺小鼠中植入的 HER2 表达的 SKOV-3 卵巢癌异种移植模型中，[18F]AlF-NOTA-Tz-TCO-GK-2Rs15d 的摄取约为共注射的 [125I]SGMIB-2Rs15d 的 80%。另一方面，肾脏摄取低 5-6 倍，因此肿瘤与肾脏比率比 [125I]SGMIB-2Rs15d 高 4 倍。即使在注射 [18F]AlF-NOTA-Tz-TCO-GK-2Rs15d 1 小时后，SKOV-3 异种移植体也能通过 Micro-PET/CT 成像清晰地描绘出来，随后观察到更高的对比度。总之，这种方法值得进一步评估用于标记小蛋白如 sdAbs，因为它提供了良好的放射化学产率和增强的肿瘤与正常组织比率，特别是在肾脏方面。
• [EN] DESIGN AND DEVELOPMENT OF NEUROKININ-1 RECEPTOR-BINDING AGENT DELIVERY CONJUGATES<br/>[FR] CONCEPTION ET DÉVELOPPEMENT DE CONJUGUÉS DE LIBÉRATION D'AGENT DE LIAISON AU RÉCEPTEUR DE LA NEUROKININE-
  申请人：PURDUE RESEARCH FOUNDATION

  公开号：WO2016025322A1

  公开（公告）日：2016-02-18

  Neurokinin-1 (NK-1) receptor-binding agent delivery conjugates, compositions comprising NK-1 receptor-binding agent delivery conjugates, and methods for making and administering NK-1 receptor-binding agent delivery conjugates are provided. A conjugate may include an NK-1 receptor-binding moiety, a linker group containing at least one linker selected from the group of a releasable linker and a spacer linker, and an active agent linked to the linker group. The active agent may be selected from the group of fluorophore-containing compounds, radionuclide-containing compounds, and therapeutic agents for treatment of tumor cells characterized by over-expression of the NK-1 receptor.

  提供了神经激肽-1（NK-1）受体结合剂传递共轭物、包含NK-1受体结合剂传递共轭物的组合物，以及制备和给予NK-1受体结合剂传递共轭物的方法。一个共轭物可能包括一个NK-1受体结合基团，一个含有至少一个可释放连接物和间隔连接物中的一种连接物的连接基团，以及连接到连接基团的活性剂。活性剂可从含有荧光物质的化合物、含有放射性核素的化合物以及用于治疗表达过量NK-1受体的肿瘤细胞的治疗剂组中选择。
• 一种干扰素刺激蛋白靶向化合物、其放射性标记物、及它们的制备方法与应用
  申请人：厦门大学

  公开号：CN112920172B

  公开（公告）日：2022-03-22

  本发明提供一类二聚的酰胺基苯并咪唑化合物，其结构如下式(I)所示；其中，R0为n取0‑5的整数。本发明还提供基于所述二聚的酰胺基苯并咪唑化合物的一类具有抗肿瘤活性的化合物和一类干扰素刺激蛋白靶向的放射性核素标记化合物。本发明所述二聚的酰胺基苯并咪唑化合物对干扰素刺激蛋白具有高亲和力和高特异性，本发明所述的具有抗肿瘤活性的化合物在体外具有激活STING通路的特性，本发明所述的放射性核素标记化合物不仅靶与非靶摄取对比明显，而且可通过引入不同性质的核素改变脂溶性，极大地拓宽了应用场景，可以跟治疗核素联用进行肿瘤治疗，甚至可用于免疫治疗。
• [EN] NUCLEAR IMAGING AND RADIOTHERAPEUTICS AGENTS TARGETING CARBONIC ANHYDRASE IX AND USES THEREOF<br/>[FR] AGENTS D'IMAGERIE NUCLÉAIRE ET RADIOTHÉRAPIQUES CIBLANT L'ANHYDRASE CARBONIQUE IX ET LEURS UTILISATIONS
  申请人：UNIV JOHNS HOPKINS

  公开号：WO2016196628A1

  公开（公告）日：2016-12-08

  Highly potent and selective radionuclide-based imaging and therapy agents targeting carbonic anhydrase IX with minimum non-specific organ uptake are disclosed. Methods of imaging and/or treating carbonic anhydrase IX-expressing cells or tumors also are disclosed.

  揭示了针对碳酸酐酶IX的高效选择性放射性同位素成像和治疗剂，具有最小的非特异性器官摄取。还揭示了成像和/或治疗表达碳酸酐酶IX的细胞或肿瘤的方法。
• ANTI-MACROPHAGE MANNOSE RECEPTOR SINGLE VARIABLE DOMAINS FOR USE IN CARDIOVASCULAR DISEASES
  申请人：VIB VZW

  公开号：US20160024213A1

  公开（公告）日：2016-01-28

  The disclosure relates to the field of cardiovascular diseases. In particular, immunoglobulin single variable domains directed against macrophage mannose receptor (MMR) are provided that can be used in the diagnosis, prognosis and/or monitoring of cardiovascular diseases or as therapeutics. Also, the anti-macrophage mannose receptor (MMR) immunoglobulin single variable domains of the disclosure are useful at different stages of cardiovascular diseases, including post-infarction cardiovascular events. Further, the anti-macrophage mannose receptor (MMR) immunoglobulin single variable domains of the disclosure are particularly useful for the in vivo targeting and/or imaging of vulnerable atherosclerotic plaques.

  本公开涉及心血管疾病领域。具体而言，提供了针对巨噬细胞甘露糖受体（MMR）的免疫球蛋白单变量结构域，可用于心血管疾病的诊断、预后和/或监测，或作为治疗药物。此外，本公开的抗巨噬细胞甘露糖受体（MMR）免疫球蛋白单变量结构域在心血管疾病的不同阶段中均有用处，包括心梗后的心血管事件。此外，本公开的抗巨噬细胞甘露糖受体（MMR）免疫球蛋白单变量结构域特别适用于体内靶向和/或成像易受损斑块。