(1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-N-(5-fluoropyridin-2-yl)-2-(3-fluoro-4-[¹¹C]methoxyphenyl)-cyclopropanecarboxamide | 1449429-83-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-N-(5-fluoropyridin-2-yl)-2-(3-fluoro-4-[¹¹C]methoxyphenyl)-cyclopropanecarboxamide
• 英文别名: (1R,2S)-2-[(2,4-dimethylpyrimidin-5-yl)oxymethyl]-2-(3-fluoro-4-(111C)methoxyphenyl)-N-(5-fluoropyridin-2-yl)cyclopropane-1-carboxamide
• CAS: 1449429-83-7
• 化学式: C₂₃H₂₂F₂N₄O₃
• 分子量: 439.438
• InChiKey: PKCHWHMQABQDIP-DWRUBXQFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  32
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  86.2
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  [11C]methyl iodide 、 (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluoro-4-hydroxyphenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.05h， 生成 (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-N-(5-fluoropyridin-2-yl)-2-(3-fluoro-4-[¹¹C]methoxyphenyl)-cyclopropanecarboxamide
  参考文献：
  名称：

  Synthesis and Evaluation of Novel Radioligands for Positron Emission Tomography Imaging of the Orexin-2 Receptor

  摘要：

  Orexin receptors (OXRs) in the brain have been implicated in diverse physiological and neuropsychiatric conditions. Here we describe the design, synthesis, and evaluation of OXR ligands related to (1R,2S)-2-(((2-methyl-4-methoxymethylpyrimidin-5-yl)oxy)methyl)-N-(5-fluoropyri- din-2-yl)-2-(3-fluorophenyl)cyclopropanecarboxamide (9a) applicable to positron emission tomography (PET) imaging. Structural features were incorporated to increase binding affinity for OXRs, to enable carbon-11 radiolabeling and to adjust lipophilicity considered optimal for brain penetration and low nonspecific binding. 9a displayed nanomolar affinity for OXRs, and autoradiography using rat brain sections showed that specific binding of [C-11]9a was distributed primarily to neocortical layer VI and hypothalamus, consistent with reported localizations of orexin-2 receptors (OX(2)Rs). In vivo PET study of [C-11]9a demonstrated moderate uptake of radioactivity into rat and monkey brains under deficiency or blockade of P-glycoprotein, and distribution of PET signals in the brain was in agreement with autoradiographic data. Our approach and findings have provided significant information for development of OX2R PET tracers.

  DOI：

  10.1021/jm400772t

文献信息

• Synthesis and Evaluation of Novel Radioligands for Positron Emission Tomography Imaging of the Orexin-2 Receptor
  作者：Norihito Oi、Michiyuki Suzuki、Taro Terauchi、Masaki Tokunaga、Yosuke Nakatani、Noboru Yamamoto、Toshimitsu Fukumura、Ming-Rong Zhang、Tetsuya Suhara、Makoto Higuchi

  DOI：10.1021/jm400772t

  日期：2013.8.22

  Orexin receptors (OXRs) in the brain have been implicated in diverse physiological and neuropsychiatric conditions. Here we describe the design, synthesis, and evaluation of OXR ligands related to (1R,2S)-2-(((2-methyl-4-methoxymethylpyrimidin-5-yl)oxy)methyl)-N-(5-fluoropyri- din-2-yl)-2-(3-fluorophenyl)cyclopropanecarboxamide (9a) applicable to positron emission tomography (PET) imaging. Structural features were incorporated to increase binding affinity for OXRs, to enable carbon-11 radiolabeling and to adjust lipophilicity considered optimal for brain penetration and low nonspecific binding. 9a displayed nanomolar affinity for OXRs, and autoradiography using rat brain sections showed that specific binding of [C-11]9a was distributed primarily to neocortical layer VI and hypothalamus, consistent with reported localizations of orexin-2 receptors (OX(2)Rs). In vivo PET study of [C-11]9a demonstrated moderate uptake of radioactivity into rat and monkey brains under deficiency or blockade of P-glycoprotein, and distribution of PET signals in the brain was in agreement with autoradiographic data. Our approach and findings have provided significant information for development of OX2R PET tracers.