N-[[2-[dideuterio(fluoro)methoxy]-5-methoxyphenyl]methyl]-N-(5-fluoro-2-phenoxyphenyl)acetamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-[[2-[dideuterio(fluoro)methoxy]-5-methoxyphenyl]methyl]-N-(5-fluoro-2-phenoxyphenyl)acetamide
• 化学式: C₂₃H₂₁F₂NO₄
• 分子量: 415.405
• InChiKey: HNCYVWMTXRPXGY-DOBBINOXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  30
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  48
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  N-(5-fluoro-2-phenoxyphenyl)-N-(2-(iodomethoxy-d2)-5-methoxybenzyl)acetamide 在 四丁基氟化铵 作用下， 以 四氢呋喃 为溶剂， 反应 8.0h， 以70%的产率得到N-[[2-[dideuterio(fluoro)methoxy]-5-methoxyphenyl]methyl]-N-(5-fluoro-2-phenoxyphenyl)acetamide
  参考文献：
  名称：

  Synthesis and evaluation of N-(5-fluoro-2-phenoxyphenyl)-N-(2-[18F]fluoromethoxy-d2-5-methoxybenzyl)acetamide: a deuterium-substituted radioligand for peripheral benzodiazepine receptor

  摘要：

  N-(5-Fluoro-2-phenoxyphenyl)-N-(2-[F-18]fluoromethoxy-d(2)-5-methoxybenzyl)acetamide ([F-18]2) is a potent ligand (IC50: 1.71 nM) for peripheral benzodiazepine receptor (PBR). However, in vivo evaluation on rodents and primates showed that this ligand was unstable and rapidly metabolized to [F-18]F- by defluorination of the [F-18]fluoromethyl moiety. In this study, we designed a deuterium-substituted analogue, N-(5-fluoro-2-phenoxyphenyl)-N-(2-[F-18]fluoromethoxy-d2-5-methoxybenzyI)acetamide ([F-18]5) as a radioligand for PBR to reduce the in vivo metabolic rate of the non-deuterated [F-18]2. The design principle was based on the hypothesis that the deuterium substitution may reduce the rate of defluorination initiated by cleavage of the C-H bond without altering the binding affinity for PBR. The non-radioactive 5 was prepared by reacting diiodomethane-d(2) (CD2I2, 6) with a phenol precursor 7, followed by treatment with tetrabutylammonium fluoride. The ligand [F-18]5 was synthesized by the alkylation of 7 with [F-18]fluoromethyl iodide-d(2) ([F-18]FCD2I, [F-18]9). Compound 5 displayed a similar in vitro affinity to PBR (IC50: 1.90nM) with 2. In vivo evaluation demonstrated that [F-18]5 was metabolized by defluorination to [F-18]F- as a main radioactive component, but its metabolic rate was slower than that of [F-18]2 in the brain of mice. The deuterium substitution decreased the radioactivity level of[F-18]5 in the bone of mouse, augmented by 1 the percentage of specific binding to PBR in the rat brain determined by ex vivo autoradiography. However, the PET image of [F-18]5 for monkey brain showed high radioactivity in the brain and skull, suggesting a possible species difference between rodents and primates. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2004.11.058

文献信息

• Synthesis and evaluation of N-(5-fluoro-2-phenoxyphenyl)-N-(2-[18F]fluoromethoxy-d2-5-methoxybenzyl)acetamide: a deuterium-substituted radioligand for peripheral benzodiazepine receptor
  作者：Ming-Rong Zhang、Jun Maeda、Takehito Ito、Takashi Okauchi、Masanao Ogawa、Junko Noguchi、Tetsuya Suhara、Christer Halldin、Kazutoshi Suzuki

  DOI：10.1016/j.bmc.2004.11.058

  日期：2005.3.1

  N-(5-Fluoro-2-phenoxyphenyl)-N-(2-[F-18]fluoromethoxy-d(2)-5-methoxybenzyl)acetamide ([F-18]2) is a potent ligand (IC50: 1.71 nM) for peripheral benzodiazepine receptor (PBR). However, in vivo evaluation on rodents and primates showed that this ligand was unstable and rapidly metabolized to [F-18]F- by defluorination of the [F-18]fluoromethyl moiety. In this study, we designed a deuterium-substituted analogue, N-(5-fluoro-2-phenoxyphenyl)-N-(2-[F-18]fluoromethoxy-d2-5-methoxybenzyI)acetamide ([F-18]5) as a radioligand for PBR to reduce the in vivo metabolic rate of the non-deuterated [F-18]2. The design principle was based on the hypothesis that the deuterium substitution may reduce the rate of defluorination initiated by cleavage of the C-H bond without altering the binding affinity for PBR. The non-radioactive 5 was prepared by reacting diiodomethane-d(2) (CD2I2, 6) with a phenol precursor 7, followed by treatment with tetrabutylammonium fluoride. The ligand [F-18]5 was synthesized by the alkylation of 7 with [F-18]fluoromethyl iodide-d(2) ([F-18]FCD2I, [F-18]9). Compound 5 displayed a similar in vitro affinity to PBR (IC50: 1.90nM) with 2. In vivo evaluation demonstrated that [F-18]5 was metabolized by defluorination to [F-18]F- as a main radioactive component, but its metabolic rate was slower than that of [F-18]2 in the brain of mice. The deuterium substitution decreased the radioactivity level of[F-18]5 in the bone of mouse, augmented by 1 the percentage of specific binding to PBR in the rat brain determined by ex vivo autoradiography. However, the PET image of [F-18]5 for monkey brain showed high radioactivity in the brain and skull, suggesting a possible species difference between rodents and primates. (C) 2004 Elsevier Ltd. All rights reserved.