(19R,23S)-tri-tert-butyl-1-(1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)-2-((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)-13,21-dioxo-2,14,20,22-tetraazapentacosane-19,23,25-tricarboxylate | 1382722-19-1

• 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: (19R,23S)-tri-tert-butyl-1-(1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)-2-((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)-13,21-dioxo-2,14,20,22-tetraazapentacosane-19,23,25-tricarboxylate
• 英文别名: (19S,23S)-tri-tert-butyl 1-(1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)-2-((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)-13,21-dioxo-2,14,20,22-tetraazapentacosane-19,23,25-tricarboxylate
• CAS: 1382722-19-1
• 化学式: C₅₅H₉₄N₈O₁₂
• 分子量: 1059.4
• InChiKey: VDHVIMVWIUZABC-YATWDLPUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.4
• 重原子数：
  75.0
• 可旋转键数：
  31.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.76
• 拓扑面积：
  240.61
• 氢给体数：
  3.0
• 氢受体数：
  17.0

反应信息

• 作为反应物：
  描述：

  (NEt4)2[rhenium(I)(bromide)3(carbonyl)3] 、 (19R,23S)-tri-tert-butyl-1-(1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)-2-((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)-13,21-dioxo-2,14,20,22-tetraazapentacosane-19,23,25-tricarboxylate 以 甲醇 为溶剂， 反应 4.0h， 生成
  参考文献：
  名称：

  Synthesis and SAR of 99mTc/Re-labeled small molecule prostate specific membrane antigen inhibitors with novel polar chelates

  摘要：

  Prostate specific membrane antigen (PSMA) is recognized as an attractive molecular target for the development of radiopharmaceuticals to image and potentially treat metastatic prostate cancer. A series of novel Tc-99m/Re-tricarbonyl radiolabeled PSMA inhibitors were therefore synthesized by the attachment of glutamate-urea-lysine (Glu-urea-Lys) and glutamate-urea-glutamate (Glu-urea-Glu) pharmacophore to single amino acid chelate (SAAC) where the SAAC ligand was either bis(pyridin-2-ylmethyl)amino (DPA), bis((1-methyl-1H-imidazol-2-yl)methyl)amino (NMI), bis((1-(carboxymethyl)-1H-imidazol-2-yl)methyl)amino (CIM) or bis((1-(2-(bis(carboxymethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino (TIM). The in vitro binding affinity of the rhenium complexes was evaluated using PSMA-expressing human prostate cancer LNCaP cells. IC50 values ranged from 3.8 +/- 2 to > 2000 nM. A linker between the SAAC chelate and pharmacophore was required for high affinity binding. However, extending the length of the linker did not substantially improve binding. PSMA binding was also influenced by the nature of the SAAC chelate. One of the most potent compounds, 23b (IC50 = 4.8 +/- 2.7 nM), was radiolabeled with technetium tricarbonyl ({Tc-99m(CO)(3)}(+)) to afford the {Tc-99m(CO)(3)}(+) complex in excellent yield and high purity. This effort has led to the identification of a diverse series of promising high affinity {Tc-99m(CO)(3)}(+) radiolabeled PSMA inhibitors. (c) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.09.014
• 作为产物：
  描述：

  tert-butyl 2-(2-formyl-1H-imidazol-1-yl)acetate 在 溶剂黄146 、 三乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 反应 0.5h， 生成 (19R,23S)-tri-tert-butyl-1-(1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)-2-((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)-13,21-dioxo-2,14,20,22-tetraazapentacosane-19,23,25-tricarboxylate
  参考文献：
  名称：

  Synthesis and SAR of 99mTc/Re-labeled small molecule prostate specific membrane antigen inhibitors with novel polar chelates

  摘要：

  Prostate specific membrane antigen (PSMA) is recognized as an attractive molecular target for the development of radiopharmaceuticals to image and potentially treat metastatic prostate cancer. A series of novel Tc-99m/Re-tricarbonyl radiolabeled PSMA inhibitors were therefore synthesized by the attachment of glutamate-urea-lysine (Glu-urea-Lys) and glutamate-urea-glutamate (Glu-urea-Glu) pharmacophore to single amino acid chelate (SAAC) where the SAAC ligand was either bis(pyridin-2-ylmethyl)amino (DPA), bis((1-methyl-1H-imidazol-2-yl)methyl)amino (NMI), bis((1-(carboxymethyl)-1H-imidazol-2-yl)methyl)amino (CIM) or bis((1-(2-(bis(carboxymethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino (TIM). The in vitro binding affinity of the rhenium complexes was evaluated using PSMA-expressing human prostate cancer LNCaP cells. IC50 values ranged from 3.8 +/- 2 to > 2000 nM. A linker between the SAAC chelate and pharmacophore was required for high affinity binding. However, extending the length of the linker did not substantially improve binding. PSMA binding was also influenced by the nature of the SAAC chelate. One of the most potent compounds, 23b (IC50 = 4.8 +/- 2.7 nM), was radiolabeled with technetium tricarbonyl ({Tc-99m(CO)(3)}(+)) to afford the {Tc-99m(CO)(3)}(+) complex in excellent yield and high purity. This effort has led to the identification of a diverse series of promising high affinity {Tc-99m(CO)(3)}(+) radiolabeled PSMA inhibitors. (c) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.09.014

文献信息

• Small molecule inhibitors of PSMA incorporating technetium-99m for imaging prostate cancer: Effects of chelate design on pharmacokinetics
  作者：Kevin P. Maresca、Shawn M. Hillier、Genliang Lu、John C. Marquis、Craig N. Zimmerman、William C. Eckelman、John L. Joyal、John W. Babich

  DOI：10.1016/j.ica.2012.03.002

  日期：2012.7

  molecules and peptides. Here, we designed, synthesized, and evaluated novel polar functionalized imidazole derived SAAC systems (SAAC II) which have been chemically modified to promote overall 99m Tc(CO) 3 L 3 complex hydrophilicity with the intent of reducing non-target effects and enhancing renal clearance of prostate specific membrane antigen (PSMA) targeting small molecules. The 99m Tc-labeled compounds

  摘要用于复合M（CO）3部分（M = Tc / Re）的单氨基酸螯合物（SAAC）系统已成功地纳入了放射性药物的新型合成策略，并已在多种生物学应用中进行了评估。但是，第一代99m Tc（CO）3复合物的亲脂性在作为赖氨酸衍生物或整合入具有生物活性的小分子和肽中进行检查时已导致大量的肝胆吸收。在这里，我们设计，合成和评估了新型极性官能化的咪唑衍生的SAAC系统（SAAC II），该系统经过化学修饰以提高整体99m Tc（CO）3 L 3络合物的亲水性，目的是减少非靶点作用并增强肾脏功能清除针对小分子的前列腺特异性膜抗原（PSMA）。制备，纯化99m Tc标记的化合物，并评估其在LNCaP异种移植小鼠中的稳定性，亲脂性和组织分布。用各种螯合剂制备Glu-脲-Lys-C11类似物以形成（19 R，23 S）-1-（X）-2-（（Y）甲基）-13,21-dioxo-2,14 ，20,22-四氮杂萘烷-19