(6-(2-fluoroethoxy)pyridin-3-yl)(1-(3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)piperidin-4-yl)methanone

• 分子结构分类: 有机化合物 - 苯类化合物 - 四氢化萘
• 英文名称: (6-(2-fluoroethoxy)pyridin-3-yl)(1-(3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)piperidin-4-yl)methanone
• 英文别名: [6-(2-fluoroethoxy)pyridin-3-yl]-[1-[(2R,3R)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl]piperidin-4-yl]methanone
• 化学式: C₂₃H₂₇FN₂O₃
• 分子量: 398.477
• InChiKey: IVSNCPPNDXXHRP-NHCUHLMSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  62.7
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (6-(2-fluoroethoxy)pyridin-3-yl)(1-(3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)piperidin-4-yl)methanone 在 chiralcel OD column 作用下， 以 正己烷 、 异丙醇 为溶剂， 以8 mg的产率得到(6-(2-fluoroethoxy)pyridin-3-yl)(1-(3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)piperidin-4-yl)methanone
  参考文献：
  名称：

  非人类灵长类动物中三种水泡乙酰胆碱转运蛋白配体的合成，拆分和体外评估以及氟18放射性配体的评估

  摘要：

  水泡乙酰胆碱转运蛋白（VAChT）是用于评估与痴呆症相关的胆碱能功能障碍的可靠生物标志物。我们最近报告了三种新型的，具有选择性的碳11标记的VAChT放射性示踪剂。本文中，我们报告了使用氟乙氧基或氟乙基氨基部分取代甲氧基的三种其他类似物的合成，以及使用Chiralcel OD色谱柱拆分了其外消旋异构体的方法。体外竞争结合试验表明（-）-7对VAChT的效价高（Ki-VAChT = 0.31±0.03 nM），对VAChT相对于σ受体的选择性极好（Ki-σ1= 1869±248 nM，Ki-σ2= 5482±144 nM）。探索了三种不同的放射性标记方法来完成放射性合成。（-）-[18F] 7是通过逐步两锅法成功生产的，三步法，收率适中（11±2％），放射化学纯度高（> 98％）。在非人类灵长类动物中进行的PET成像研究表明，（-）-[18F] 7迅速进入大脑并积累在富含VAChT的纹状体中

  DOI：

  10.1039/c7ob00854f
• 作为产物：
  描述：

  1-Boc-4-[甲氧基(甲基)氨基甲酰]哌嗪 在 正丁基锂 、 碘代三甲硅烷 、 potassium carbonate 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 113.0h， 生成 (6-(2-fluoroethoxy)pyridin-3-yl)(1-(3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)piperidin-4-yl)methanone
  参考文献：
  名称：

  Heteroaromatic and Aniline Derivatives of Piperidines As Potent Ligands for Vesicular Acetylcholine Transporter

  摘要：

  To identify suitable lipophilic compounds having high potency and selectivity for vesicular acetylcholine transporter (VAChT), a heteroaromatic ring or a phenyl group was introduced into the carbonyl-containing scaffold for VAChT ligands. Twenty new compounds with ALogD values between 0.53 and 3.2 were synthesized, and their in vitro binding affinities were assayed. Six of them (19a, 19e, 19g, 19k, and 24a-b) displayed high affinity for VAChT (K-i = 0.93-18 nM for racemates) and moderate to high selectivity for VAChT over sigma(1) and sigma(2) receptors (K-i = 44-4400-fold). These compounds have a methyl or a fluoro substitution that provides the position for incorporating PET radioisotopes C-11 or F-18. Compound (-)-[C-11]24b (K-i = 0.78 nM for VAChT, 1200-fold over sigma receptors) was successfully synthesized and evaluated in vivo in rats and nonhuman primates. The data revealed that (-)-[C-11]24b has highest binding in striatum and has favorable pharmacokinetics in the brain.

  DOI：

  10.1021/jm400664x

文献信息

• Heteroaromatic and Aniline Derivatives of Piperidines As Potent Ligands for Vesicular Acetylcholine Transporter
  作者：Junfeng Li、Xiang Zhang、Zhanbin Zhang、Prashanth K. Padakanti、Hongjun Jin、Jinquan Cui、Aixiao Li、Dexing Zeng、Nigam P. Rath、Hubert Flores、Joel S. Perlmutter、Stanley M. Parsons、Zhude Tu

  DOI：10.1021/jm400664x

  日期：2013.8.8

  To identify suitable lipophilic compounds having high potency and selectivity for vesicular acetylcholine transporter (VAChT), a heteroaromatic ring or a phenyl group was introduced into the carbonyl-containing scaffold for VAChT ligands. Twenty new compounds with ALogD values between 0.53 and 3.2 were synthesized, and their in vitro binding affinities were assayed. Six of them (19a, 19e, 19g, 19k, and 24a-b) displayed high affinity for VAChT (K-i = 0.93-18 nM for racemates) and moderate to high selectivity for VAChT over sigma(1) and sigma(2) receptors (K-i = 44-4400-fold). These compounds have a methyl or a fluoro substitution that provides the position for incorporating PET radioisotopes C-11 or F-18. Compound (-)-[C-11]24b (K-i = 0.78 nM for VAChT, 1200-fold over sigma receptors) was successfully synthesized and evaluated in vivo in rats and nonhuman primates. The data revealed that (-)-[C-11]24b has highest binding in striatum and has favorable pharmacokinetics in the brain.
• Synthesis, resolution, and in vitro evaluation of three vesicular acetylcholine transporter ligands and evaluation of the lead fluorine-18 radioligand in a nonhuman primate
  作者：Xuyi Yue、Hongjun Jin、Hui Liu、Zonghua Luo、Xiang Zhang、Kota Kaneshige、Hubert P. Flores、Joel S. Perlmutter、Stanley M. Parsons、Zhude Tu

  DOI：10.1039/c7ob00854f

  日期：——

  Vesicular acetylcholine transporter (VAChT) is a reliable biomarker for assessing cholinergic dysfunction that is associated dementia. We recently reported three new potent and selective carbon-11 labeled VAChT radiotracers. Herein, we report the synthesis of three additional analogs using a fluoroethoxy or fluoroethylamino moiety substituted for the methoxy group and the resolution of their racemic

  水泡乙酰胆碱转运蛋白（VAChT）是用于评估与痴呆症相关的胆碱能功能障碍的可靠生物标志物。我们最近报告了三种新型的，具有选择性的碳11标记的VAChT放射性示踪剂。本文中，我们报告了使用氟乙氧基或氟乙基氨基部分取代甲氧基的三种其他类似物的合成，以及使用Chiralcel OD色谱柱拆分了其外消旋异构体的方法。体外竞争结合试验表明（-）-7对VAChT的效价高（Ki-VAChT = 0.31±0.03 nM），对VAChT相对于σ受体的选择性极好（Ki-σ1= 1869±248 nM，Ki-σ2= 5482±144 nM）。探索了三种不同的放射性标记方法来完成放射性合成。（-）-[18F] 7是通过逐步两锅法成功生产的，三步法，收率适中（11±2％），放射化学纯度高（> 98％）。在非人类灵长类动物中进行的PET成像研究表明，（-）-[18F] 7迅速进入大脑并积累在富含VAChT的纹状体中