R-(-)-1-azabicyclo[2.2.2]oct-3-yl R-(-)-α-(1-fluoropent-5-yl)-α-hydroxy-α-phenylacetate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 奎宁环
• 英文名称: R-(-)-1-azabicyclo[2.2.2]oct-3-yl R-(-)-α-(1-fluoropent-5-yl)-α-hydroxy-α-phenylacetate
• 英文别名: [(3R)-1-azabicyclo[2.2.2]octan-3-yl] (2R)-7-fluoro-2-hydroxy-2-phenylheptanoate
• 化学式: C₂₀H₂₈FNO₃
• 分子量: 349.446
• InChiKey: OQVRGLGAPZVYFG-AZUAARDMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  25
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  49.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  1,5-二碘戊烷 在 氢氧化钾 、 正丁基锂 、 硫酸 、 四丁基氟化铵 、 水 、 sodium 、 六甲基二硅氮烷 作用下， 以 四氢呋喃 、 甲醇 、 乙腈 、 苯 为溶剂， 反应 64.5h， 生成 R-(-)-1-azabicyclo[2.2.2]oct-3-yl R-(-)-α-(1-fluoropent-5-yl)-α-hydroxy-α-phenylacetate
  参考文献：
  名称：

  Resolution, in vitro and in vivo evaluation of fluorine-18-labeled isomers of 1-azabicyclo[2.2.2]oct-3-ylα-(1-fluoropent-5-yl)α-hydroxy-α-phenylacetate (FQNPe) as new PET candidates for the imaging of muscarinic-cholinergic receptor

  摘要：

  l-Azabicyclo[2.2.2]oct-3-yl alpha-(1-fluoropent-5-yl)-alpha-hydroxy-alpha-phenylacetate (FQNPe, 2), an analogue of 1-azabicyclo[2.2.2]oct-3-yl alpha,alpha-(diphenyl)-alpha-hydroxyacetate (QNB), was resolved into its four stereoisomers. In vitro binding assays of the stereoisomers of 2 demonstrated that while the (S,S)-isomer did not have significant receptor binding, the other stereoisomers of 2 bound with high affinity to the various mAChR subtypes [K-i, nM: m1, (R,R), 0.33; (R,S), 1.4; (S,R), 3.8; m2, (R,R), 0.1; (R,S), 4.2; (S,R), < 75% binding; m3, (R,R), 0.34; (R,S), 3.1; (S,R), 7.6]. The (R,R)- and (R,S)stereoisomers of 2 were radiolabeled with fluorine-18 via a two step procedure in radiochemical yields of 12-21% (n=2) and 9% (decayed corrected to beginning of synthesis), respectively. In vivo biodistribution studies demonstrated significant uptake of [F-18]-(R,R)-2 in cerebral mAChR-rich regions of rat brains up to 3 h post injection. Low accumulation of fluorine-18 in the bone indicated that [F-18]-(R,R)-2 displayed significant in vivo stability. In contrast. [F-18]-(R,S)-2 demonstrated rapid washout from all cerebral regions. Preinjection of (R)-QNB (3 mg/kg) 1 h prior to the injection of [F-18]-(R,R)-2 blocked the uptake of activity in cerebral regions by approximately 90% while the preinjection of haloperidol (3 mg/kg) 1 h prior to the injection of [F-18]-(R;R)2 demonstrated no statistically significant effect on the binding of the radiotracer. An ex vivo metabolic study utilizing [F-18]-(R,R)-2 demonstrated that greater than 96% of the organic soluble radioactivity which localized in the brain and heart at 1 h post-injection migrated on TLC with the same mobility as the parent. Although [F-18]-(R,R)-2 did not demonstrate a desired in vitro or in vivo mAChR subtype selectivity, these results suggest that the introduction of a fluoroalkyl group in various benzylic analogues of QNB is an attractive radiolabeling moiety for further evaluation in the design of selective PET mAChR imaging ligands.

  DOI：

  10.1002/(sici)1099-1344(1998080)41:8<681::aid-jlcr131>3.0.co;2-q

文献信息

• Resolution, in vitro and in vivo evaluation of fluorine-18-labeled isomers of 1-azabicyclo[2.2.2]oct-3-ylα-(1-fluoropent-5-yl)α-hydroxy-α-phenylacetate (FQNPe) as new PET candidates for the imaging of muscarinic-cholinergic receptor
  作者：H. Luo、A. L. Beets、M. J. McAllister、M. Greenbaum、D. W. McPherson、F. F. Knapp

  DOI：10.1002/(sici)1099-1344(1998080)41:8<681::aid-jlcr131>3.0.co;2-q

  日期：1998.8

  l-Azabicyclo[2.2.2]oct-3-yl alpha-(1-fluoropent-5-yl)-alpha-hydroxy-alpha-phenylacetate (FQNPe, 2), an analogue of 1-azabicyclo[2.2.2]oct-3-yl alpha,alpha-(diphenyl)-alpha-hydroxyacetate (QNB), was resolved into its four stereoisomers. In vitro binding assays of the stereoisomers of 2 demonstrated that while the (S,S)-isomer did not have significant receptor binding, the other stereoisomers of 2 bound with high affinity to the various mAChR subtypes [K-i, nM: m1, (R,R), 0.33; (R,S), 1.4; (S,R), 3.8; m2, (R,R), 0.1; (R,S), 4.2; (S,R), < 75% binding; m3, (R,R), 0.34; (R,S), 3.1; (S,R), 7.6]. The (R,R)- and (R,S)stereoisomers of 2 were radiolabeled with fluorine-18 via a two step procedure in radiochemical yields of 12-21% (n=2) and 9% (decayed corrected to beginning of synthesis), respectively. In vivo biodistribution studies demonstrated significant uptake of [F-18]-(R,R)-2 in cerebral mAChR-rich regions of rat brains up to 3 h post injection. Low accumulation of fluorine-18 in the bone indicated that [F-18]-(R,R)-2 displayed significant in vivo stability. In contrast. [F-18]-(R,S)-2 demonstrated rapid washout from all cerebral regions. Preinjection of (R)-QNB (3 mg/kg) 1 h prior to the injection of [F-18]-(R,R)-2 blocked the uptake of activity in cerebral regions by approximately 90% while the preinjection of haloperidol (3 mg/kg) 1 h prior to the injection of [F-18]-(R;R)2 demonstrated no statistically significant effect on the binding of the radiotracer. An ex vivo metabolic study utilizing [F-18]-(R,R)-2 demonstrated that greater than 96% of the organic soluble radioactivity which localized in the brain and heart at 1 h post-injection migrated on TLC with the same mobility as the parent. Although [F-18]-(R,R)-2 did not demonstrate a desired in vitro or in vivo mAChR subtype selectivity, these results suggest that the introduction of a fluoroalkyl group in various benzylic analogues of QNB is an attractive radiolabeling moiety for further evaluation in the design of selective PET mAChR imaging ligands.