2,2,2-trifluoro-N-[4-(6-iodoimidazo[1,2-a]pyridin-2-yl)phenyl]-N-methylacetamide | 683768-15-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 2,2,2-trifluoro-N-[4-(6-iodoimidazo[1,2-a]pyridin-2-yl)phenyl]-N-methylacetamide
• CAS: 683768-15-2
• 化学式: C₁₆H₁₁F₃IN₃O
• 分子量: 445.183
• InChiKey: ZUBQIDLHPBLRGL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.13
• 重原子数：
  24.0
• 可旋转键数：
  2.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  37.61
• 氢给体数：
  0.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  2,2,2-trifluoro-N-[4-(6-iodoimidazo[1,2-a]pyridin-2-yl)phenyl]-N-methylacetamide 在 potassium carbonate 作用下， 以 甲醇 、 乙腈 为溶剂， 反应 1.17h， 生成 N-(2-fluoroethyl)-4-(6-iodoimidazo[1,2-a]pyridin-2-yl)-N-methylaniline
  参考文献：
  名称：

  Synthesis and Evaluation of Two ¹⁸F-Labeled 6-Iodo-2-(4‘-N,N-dimethylamino)phenylimidazo[1,2-a]pyridine Derivatives as Prospective Radioligands for β-Amyloid in Alzheimer's Disease

  摘要：

  This study evaluated F-18-labeled IMPY [6-iodo-2-(4'-N,N-dimethylamino)phenylimidazo[1,2-a]pyridine] derivatives as agents for imaging beta-amyloid plaque with positron emission tomography (PET). The precursor for radiolabeling and reference compounds was synthesized in up to five steps from commercially accessible starting materials. One of the two N-methyl groups of IMPY was substituted with either a 3-fluoropropyl (FPM-IMPY) or a 2-fluoroethyl (FEM-IMPY) group. FPM-IMPY and FEM-IMPY were found to have moderate affinity for Abeta-aggregates with K-i = 27 +/- 8 and 40 +/- 5 nM, respectively. A "one-pot" method for F-18-2-fluoroethylation and F-18-3-fluoropropylation of the precursor was developed. The overall decay-corrected radiochemical yields were 26-51%. In PET experiments with normal mouse, high uptake of activity was obtained in the brain after iv injection of each probe: 6.4% ID/g for [F-18]FEM-IMPY at 1.2 min, and 5.7% ID/g for [F-18]FPM-IMPY at 0.8 min. These values were similar to those of [I-123/I-123]IMPY (7.2% ID/g at 2 min). Polar and nonpolar radioactive metabolites were observed in both plasma and brain homogenates after injection of [F-18]FEM or [F-18]FPM-IMPY. In contrast to the single-exponential washout of [I-123/I-123]IMPY, the washouts of brain activity for the two fluorinated analogues were biphasic, with an initial rapid phase over 20 min and a subsequent much slower phase. Residual brain activity at 2 h, which may represent polar metabolites trapped in the brain, was 4.5% ID/g for [F-18] FEM-IMPY and 2.1% ID/g for [F-18]FPM-IMPY. Substantial skull uptake of [F-18]fluoride was also clearly observed. With a view to slow the metabolism of [F-18]FEM-IMPY, an analogue was prepared with deuteriums substituted for the four ethyl hydrogens. However, D-4-[F-18]FEM-IMPY showed the same brain uptake and clearance as the protio analogue. Metabolism of the [F-18]FEM-IMPY was appreciably slower in rhesus monkey than in mouse. Autoradiography of postmortem brain sections of human Alzheimer's disease patients with [F-18]FEM-IMPY showed high displaceable uptake in gray matter and low nonspecific binding in the white matter. This study demonstrates that the IMPY derivatives have favorable in vivo brain pharmacokinetics and a moderate affinity for imaging beta-amyloid plaques; however, further improvements are needed to reduce radioactive metabolites, increase binding affinity, and reduce lipophilicity.

  DOI：

  10.1021/jm030477w
• 作为产物：
  描述：

  2-氨基-5-碘吡啶 、 N-[4-(2-bromoacetyl)phenyl]-2,2,2-trifluoro-N-methylacetamide 在 碳酸氢钠 作用下， 以 乙醇 为溶剂， 反应 6.0h， 生成 2,2,2-trifluoro-N-[4-(6-iodoimidazo[1,2-a]pyridin-2-yl)phenyl]-N-methylacetamide
  参考文献：
  名称：

  Synthesis and Evaluation of Two ¹⁸F-Labeled 6-Iodo-2-(4‘-N,N-dimethylamino)phenylimidazo[1,2-a]pyridine Derivatives as Prospective Radioligands for β-Amyloid in Alzheimer's Disease

  摘要：

  This study evaluated F-18-labeled IMPY [6-iodo-2-(4'-N,N-dimethylamino)phenylimidazo[1,2-a]pyridine] derivatives as agents for imaging beta-amyloid plaque with positron emission tomography (PET). The precursor for radiolabeling and reference compounds was synthesized in up to five steps from commercially accessible starting materials. One of the two N-methyl groups of IMPY was substituted with either a 3-fluoropropyl (FPM-IMPY) or a 2-fluoroethyl (FEM-IMPY) group. FPM-IMPY and FEM-IMPY were found to have moderate affinity for Abeta-aggregates with K-i = 27 +/- 8 and 40 +/- 5 nM, respectively. A "one-pot" method for F-18-2-fluoroethylation and F-18-3-fluoropropylation of the precursor was developed. The overall decay-corrected radiochemical yields were 26-51%. In PET experiments with normal mouse, high uptake of activity was obtained in the brain after iv injection of each probe: 6.4% ID/g for [F-18]FEM-IMPY at 1.2 min, and 5.7% ID/g for [F-18]FPM-IMPY at 0.8 min. These values were similar to those of [I-123/I-123]IMPY (7.2% ID/g at 2 min). Polar and nonpolar radioactive metabolites were observed in both plasma and brain homogenates after injection of [F-18]FEM or [F-18]FPM-IMPY. In contrast to the single-exponential washout of [I-123/I-123]IMPY, the washouts of brain activity for the two fluorinated analogues were biphasic, with an initial rapid phase over 20 min and a subsequent much slower phase. Residual brain activity at 2 h, which may represent polar metabolites trapped in the brain, was 4.5% ID/g for [F-18] FEM-IMPY and 2.1% ID/g for [F-18]FPM-IMPY. Substantial skull uptake of [F-18]fluoride was also clearly observed. With a view to slow the metabolism of [F-18]FEM-IMPY, an analogue was prepared with deuteriums substituted for the four ethyl hydrogens. However, D-4-[F-18]FEM-IMPY showed the same brain uptake and clearance as the protio analogue. Metabolism of the [F-18]FEM-IMPY was appreciably slower in rhesus monkey than in mouse. Autoradiography of postmortem brain sections of human Alzheimer's disease patients with [F-18]FEM-IMPY showed high displaceable uptake in gray matter and low nonspecific binding in the white matter. This study demonstrates that the IMPY derivatives have favorable in vivo brain pharmacokinetics and a moderate affinity for imaging beta-amyloid plaques; however, further improvements are needed to reduce radioactive metabolites, increase binding affinity, and reduce lipophilicity.

  DOI：

  10.1021/jm030477w