7-[2-(2-fluoroethoxy)ethoxy]-1-methyl-9H-β-carboline

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 哈马拉生物碱
• 英文名称: 7-[2-(2-fluoroethoxy)ethoxy]-1-methyl-9H-β-carboline
• 英文别名: FHAR；7-[2-(2-fluoroethoxy)ethoxy]-1-methyl-9H-pyrido[3,4-b]indole
• 化学式: C₁₆H₁₇FN₂O₂
• 分子量: 288.322
• InChiKey: NVQCTWFZHWDJFW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  21
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  47.1
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  7-[2-(2-fluoroethoxy)ethoxy]-1-methyl-9H-β-carboline 在 [¹⁸F]fluoride 、 potassium carbonate 作用下， 以 乙醇 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 0.25h， 生成 7-[2-(2-[18F]fluoroethoxy)ethoxy]-1-methyl-9H-β-carboline
  参考文献：
  名称：

  使用商业平台自动合成 18F 标记的灭蚊胺、伏洛唑和哈明类似物

  摘要：

  三个 18F 标记的 PET 示踪剂，2-[18F] 氟乙基 1-[(1R)-1-苯基乙基]-1H-咪唑-5-羧酸 ([18F]FETO)，6-[(S)-(4-氯苯基)-(1H)-1,2,4-三唑-1-基)甲基]-1-(2-[18F]氟乙基)-1H-苯并三唑([18F]FVOZ)和7-[2-(2- [18F]氟乙氧基）乙氧基]-1-9H-β-咔啉（[18F]FHAR）是使用自动化商业平台TRACERLab FXFN通过一步亲核氟化合成的。在 70-75 分钟的合成时间后，标记的产物获得了 16-20% 的孤立衰减校正的放射化学产率。在所有情况下，放射化学和化学纯度均超过98%。使用商业平台的合成可能使这些示踪剂更容易用于临床研究。版权所有 © 2010 John Wiley & Sons, Ltd.

  DOI：

  10.1002/jlcr.1742
• 作为产物：
  描述：

  哈尔酚 在 四丁基氟化铵 、 potassium carbonate 作用下， 以 四氢呋喃 、 二甲基亚砜 、 丙酮 为溶剂， 反应 3.0h， 生成 7-[2-(2-fluoroethoxy)ethoxy]-1-methyl-9H-β-carboline
  参考文献：
  名称：

  Selective binding to monoamine oxidase A: In vitro and in vivo evaluation of 18F-labeled β-carboline derivatives

  摘要：

  In this study we synthesized four different F-18-labeling precursors for the visualization of the monoamino oxidase A using harmol derivatives. Whereas two are for prosthetic group labeling using [F-18]fluoro-d(2)-methyl tosylate and 2-[F-18]fluoroethyl-tosylate, the other three precursors are for direct nucleophilic F-18-labeling. Additionally the corresponding reference compounds were synthesized. The syntheses of [F-18]fluoro-d(2)-methyl-harmol and 2-[F-18] fluoroethyl-harmol were carried out using harmol as starting material. For direct nucleophilic F-18-labeling of the tracers carrying oligoethyled spacers (PEG), a toluenesulfonyl leaving group was employed. The radiolabeling, purification and formulation for each tracer was optimized and evaluated in vitro and in vivo. Stability tests in human serum showed that all tracers were stable over the observation period of 60 min. mu PET studies using of the synthesized tracers revealed that the tracers carrying PEG spacers showed no sufficient brain uptake. Consequently, the F-18-fuoro alkylated tracers [F-18] fluoro-d2-methyl-harmol and 2-[F-18]fluoroethyl-harmol were further evaluated showing SUVs in the brain of 1.0 +/- 0.2 g/mL and 3.4 +/- 0.5 g/mL after 45 min, respectively. In blockade studies the selectivity and specificity of both tracers were demonstrated. However, for [F-18]fluoro-d(2)-methyl-harmol a rapid washout from the brain was also observed. In vitro binding assays revealed that 2-[F-18] fluoroethyl-harmol (IC50 = 0.54 +/- 0.06 nM) has a higher affinity than the F-18-fluoro-d(2)-methylated ligand (IC50 = 12.2 +/- 0.6 nM), making 2-[F-18] fluoroethyl-harmol superior to the other evaluated compounds and a promising tracer for PET imaging of the MAO A. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2014.11.040

文献信息

• Synthesis andin vitro evaluation of18F-β-carboline alkaloids as PET ligands
  作者：Elisabeth Blom、Farhad Karimi、Olof Eriksson、Håkan Hall、Bengt Långström

  DOI：10.1002/jlcr.1519

  日期：2008.5

  A one-step 18F-labelling strategy was used to prepare four 18F-labelled analogues of 7-methoxy-1-methyl-9H-β-carboline (harmine): 7-(2-[18F]fluoroethoxy)-1-methyl-9H-β-carboline (5), 7-(3-[18F]fluoro-propoxy)-1-methyl-9H-β-carboline (6), 7-[2-(2-[18F]fluoroethoxy)ethoxy]-1-methyl-9H-β-carboline (7), and 7-2-[2-(2-[18F]fluoroethoxy)ethoxy]-ethoxy}-1-methyl-9H-β-carboline (8). These were synthesized as potential positron emission tomography ligands for monoamine oxidase A (MAO-A). A solution of pure labelled compound in buffer was obtained in <70 min from end of radionuclide production, with a decay-corrected yield of up to 23%. The average specific binding to MAO-A in rat brain, determined by autoradiography experiments, was highest for compounds 7 and 8 (89±2 and 96±1%, respectively), which was obtained at <1 nM radioligand concentration. Copyright © 2008 John Wiley & Sons, Ltd.

  采用一步 18F 标记策略制备了四种 18F 标记的 7-甲氧基-1-甲基-9H-β-咔啉（harmine）类似物：7-(2-[18F]fluoroethoxy)-1-methyl-9H-β-carboline (5), 7-(3-[18F]fluoro-propoxy)-1-methyl-9H-β-carboline (6), 7-[2-(2-[18F]fluoroethoxy)ethoxy]-1-methyl-9H-β-carboline (7), and 7-2-[2-(2-[18F]fluoroethoxy)ethoxy]-ethoxy}-1-methyl-9H-β-carboline (8).这些化合物是作为单胺氧化酶 A（MAO-A）的潜在正电子发射断层扫描配体合成的。从放射性核素生产结束算起，在 70 分钟内就能得到缓冲液中的纯标记化合物溶液，衰变校正产率高达 23%。通过自显影实验测定，化合物 7 和 8 与大鼠大脑中 MAO-A 的平均特异性结合率最高（分别为 89±2% 和 96±1%），在放射性配体浓度小于 1 nM 时即可获得。Copyright © 2008 John Wiley & Sons, Ltd. All Rights Reserved.
• Automated synthesis of¹⁸F-labelled analogs of metomidate, vorozole and harmine using commercial platform
  作者：Obaidur Rahman、Maria Erlandsson、Elisabeth Blom、Bengt Långström

  DOI：10.1002/jlcr.1742

  日期：——

  Three 18F-labelled PET tracers, 2-[18F]fluoroethyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate ([18F]FETO), 6-[(S)-(4-chlorophenyl)-(1H)-1,2,4-triazol-1-yl)methyl]-1-(2-[18F]fluoroethyl)-1H-benzotriazole ([18F]FVOZ) and 7-[2-(2-[18F]fluoroethoxy)ethoxy]-1-9H-β-carboline ([18F]FHAR) were synthesized by a one-step nucleophilic fluorination using the automated commercial platform TRACERLab FXFN

  三个 18F 标记的 PET 示踪剂，2-[18F] 氟乙基 1-[(1R)-1-苯基乙基]-1H-咪唑-5-羧酸 ([18F]FETO)，6-[(S)-(4-氯苯基)-(1H)-1,2,4-三唑-1-基)甲基]-1-(2-[18F]氟乙基)-1H-苯并三唑([18F]FVOZ)和7-[2-(2- [18F]氟乙氧基）乙氧基]-1-9H-β-咔啉（[18F]FHAR）是使用自动化商业平台TRACERLab FXFN通过一步亲核氟化合成的。在 70-75 分钟的合成时间后，标记的产物获得了 16-20% 的孤立衰减校正的放射化学产率。在所有情况下，放射化学和化学纯度均超过98%。使用商业平台的合成可能使这些示踪剂更容易用于临床研究。版权所有 © 2010 John Wiley & Sons, Ltd.
• Novel Imaging Agents for Detecting Neurological Dysfunction
  申请人：Kolb Hartmuth C.

  公开号：US20110046378A1

  公开（公告）日：2011-02-24

  Disclosed here in are compounds and methods of diagnosing Alzheimer's Disease or a predisposition thereto in a mammal, the method comprising administering to the mammal a diagnostically effective amount of a radiolabeled compound, wherein the compound is selected from the group consisting of radiolabeled flavones, coumarins, carbazoles, quinolinones, chromenones, imidazoles and triazoles derivatives, allowing the compound to distribute into the brain tissue, and imaging the brain tissue, wherein an increase in binding of the compound to the brain tissue compared to a normal control level of binding indicates that the mammal is suffering from or is at risk of developing Alzheimer's Disease

  本文披露了一种诊断哺乳动物阿尔茨海默病或其易感性的化合物和方法，该方法包括向哺乳动物施用诊断有效量的放射性标记化合物，所述化合物选自放射性标记的黄酮类、香豆素类、咔唑类、喹啉酮类、香豆素酮类、咪唑类和三唑类衍生物组，使化合物分布到脑组织中，并成像脑组织，其中与正常结合水平相比，化合物与脑组织的结合增加表明该哺乳动物正在患有或有发展阿尔茨海默病的风险。
• NOVEL IMAGING AGENTS FOR DETECTING NEUROLOGICAL DYSFUNCTION
  申请人：Kolb Hartmuth C.

  公开号：US20110091382A1

  公开（公告）日：2011-04-21

  Disclosed here in are compounds and methods of diagnosing Alzheimer's Disease or a predisposition thereto in a mammal, the method comprising administering to the mammal a diagnostically effective amount of a radiolabeled compound, wherein the compound is selected from the group consisting of radiolabeled flavones, coumarins, carbazoles, quinolinones, chromenones, imidazoles and triazoles derivatives, allowing the compound to distribute into the brain tissue, and imaging the brain tissue, wherein an increase in binding of the compound to the brain tissue compared to a normal control level of binding indicates that the mammal is suffering from or is at risk of developing Alzheimer's Disease.

  本文披露了一种在哺乳动物中诊断阿尔茨海默病或其易感性的化合物和方法，该方法包括向哺乳动物中投与一种放射性标记化合物的诊断有效量，所述化合物选自放射性标记的黄酮，香豆素，咔唑，喹啉酮，香豆酮，咪唑和三唑衍生物组中的一种，使该化合物分布到脑组织中，并成像脑组织，其中与正常控制水平的结合相比，化合物与脑组织的结合增加表明该哺乳动物正在患有或有发展阿尔茨海默病的风险。
• US8318132B2
  申请人：——

  公开号：US8318132B2

  公开（公告）日：2012-11-27