1-Nitroelacridar | 1300732-04-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 1-Nitroelacridar
• 英文别名: N-(4-(2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl)phenyl)-5-methoxy-1-nitroacridone-4-carboxamide；N-[4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]-5-methoxy-1-nitro-9-oxo-10H-acridine-4-carboxamide
• CAS: 1300732-04-0
• 化学式: C₃₄H₃₂N₄O₇
• 分子量: 608.651
• InChiKey: HZYNNUAOHOLDPY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  45
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  135
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  1-Nitroelacridar 在 Kryptofix222[18F]钾盐 作用下， 以 二甲基亚砜 为溶剂， 反应 1.0h， 生成 1-[18F]fluoroelacridar
  参考文献：
  名称：

  Radiosynthesis and in vivo evaluation of 1-[18F]fluoroelacridar as a positron emission tomography tracer for P-glycoprotein and breast cancer resistance protein

  摘要：

  Aim of this study was to label the potent dual P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) inhibitor elacridar (1) with F-18 to provide a positron emission tomography (PET) radiotracer to visualize Pgp and BCRP. A series of new 1- and 2-halogen- and nitro-substituted derivatives of 1 (4a-e) was synthesized as precursor molecules and reference compounds for radiolabelling and shown to display comparable in vitro potency to 1 in increasing rhodamine 123 accumulation in a cell line overexpressing human Pgp (MDCKII-MDR1). 1-[F-18]fluoroelacridar ([F-18]4b) was synthesized in a decay-corrected radiochemical yield of 1.7 +/- 0.9% by a 1-step no-carrier added nucleophilic aromatic F-18-substitution of 1-nitro precursor 4c. Small-animal PET imaging of [F-18]4b was performed in naive rats, before and after administration of unlabelled 1 (5 mg/kg, n = 3), as well as in wild-type and Mdr1a/b((-/-)) Bcrp1((-/-)) mice (n = 3). In PET experiments in rats, administration of unlabelled 1 increased brain activity uptake by a factor of 9.5 (p = 0.0002, 2-tailed Student's t-test), whereas blood activity levels remained unchanged. In Mdr1a/b((-/-)) Bcrp1((-/-)) mice, the mean brain-to-blood ratio of activity at 60 min after tracer injection was 7.6 times higher as compared to wild-type animals (p = 0.0002). HPLC analysis of rat brain tissue extracts collected at 40 min after injection of [F-18]4b revealed that 93 +/- 7% of total radioactivity in brain was in the form of unchanged [F-18] 4b. In conclusion, the in vivo behavior of [F-18]4b was found to be similar to previously described [C-11]1 suggesting transport of [F-18]4b by Pgp and/or BCRP at the rodent BBB. However, low radiochemical yields and a significant degree of in vivo defluorination will limit the utility of [F-18]4b as a PET tracer. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.02.039
• 作为产物：
  描述：

  2-溴-4-硝基苯甲酸 在 铜 、 potassium carbonate 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 三乙胺 、 三氯氧磷 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 7.5h， 生成 1-Nitroelacridar
  参考文献：
  名称：

  Radiosynthesis and in vivo evaluation of 1-[18F]fluoroelacridar as a positron emission tomography tracer for P-glycoprotein and breast cancer resistance protein

  摘要：

  Aim of this study was to label the potent dual P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) inhibitor elacridar (1) with F-18 to provide a positron emission tomography (PET) radiotracer to visualize Pgp and BCRP. A series of new 1- and 2-halogen- and nitro-substituted derivatives of 1 (4a-e) was synthesized as precursor molecules and reference compounds for radiolabelling and shown to display comparable in vitro potency to 1 in increasing rhodamine 123 accumulation in a cell line overexpressing human Pgp (MDCKII-MDR1). 1-[F-18]fluoroelacridar ([F-18]4b) was synthesized in a decay-corrected radiochemical yield of 1.7 +/- 0.9% by a 1-step no-carrier added nucleophilic aromatic F-18-substitution of 1-nitro precursor 4c. Small-animal PET imaging of [F-18]4b was performed in naive rats, before and after administration of unlabelled 1 (5 mg/kg, n = 3), as well as in wild-type and Mdr1a/b((-/-)) Bcrp1((-/-)) mice (n = 3). In PET experiments in rats, administration of unlabelled 1 increased brain activity uptake by a factor of 9.5 (p = 0.0002, 2-tailed Student's t-test), whereas blood activity levels remained unchanged. In Mdr1a/b((-/-)) Bcrp1((-/-)) mice, the mean brain-to-blood ratio of activity at 60 min after tracer injection was 7.6 times higher as compared to wild-type animals (p = 0.0002). HPLC analysis of rat brain tissue extracts collected at 40 min after injection of [F-18]4b revealed that 93 +/- 7% of total radioactivity in brain was in the form of unchanged [F-18] 4b. In conclusion, the in vivo behavior of [F-18]4b was found to be similar to previously described [C-11]1 suggesting transport of [F-18]4b by Pgp and/or BCRP at the rodent BBB. However, low radiochemical yields and a significant degree of in vivo defluorination will limit the utility of [F-18]4b as a PET tracer. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.02.039

文献信息

• Radiosynthesis and in vivo evaluation of 1-[18F]fluoroelacridar as a positron emission tomography tracer for P-glycoprotein and breast cancer resistance protein
  作者：Bernd Dörner、Claudia Kuntner、Jens P. Bankstahl、Thomas Wanek、Marion Bankstahl、Johann Stanek、Julia Müllauer、Florian Bauer、Severin Mairinger、Wolfgang Löscher、Donald W. Miller、Peter Chiba、Markus Müller、Thomas Erker、Oliver Langer

  DOI：10.1016/j.bmc.2011.02.039

  日期：2011.4

  Aim of this study was to label the potent dual P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) inhibitor elacridar (1) with F-18 to provide a positron emission tomography (PET) radiotracer to visualize Pgp and BCRP. A series of new 1- and 2-halogen- and nitro-substituted derivatives of 1 (4a-e) was synthesized as precursor molecules and reference compounds for radiolabelling and shown to display comparable in vitro potency to 1 in increasing rhodamine 123 accumulation in a cell line overexpressing human Pgp (MDCKII-MDR1). 1-[F-18]fluoroelacridar ([F-18]4b) was synthesized in a decay-corrected radiochemical yield of 1.7 +/- 0.9% by a 1-step no-carrier added nucleophilic aromatic F-18-substitution of 1-nitro precursor 4c. Small-animal PET imaging of [F-18]4b was performed in naive rats, before and after administration of unlabelled 1 (5 mg/kg, n = 3), as well as in wild-type and Mdr1a/b((-/-)) Bcrp1((-/-)) mice (n = 3). In PET experiments in rats, administration of unlabelled 1 increased brain activity uptake by a factor of 9.5 (p = 0.0002, 2-tailed Student's t-test), whereas blood activity levels remained unchanged. In Mdr1a/b((-/-)) Bcrp1((-/-)) mice, the mean brain-to-blood ratio of activity at 60 min after tracer injection was 7.6 times higher as compared to wild-type animals (p = 0.0002). HPLC analysis of rat brain tissue extracts collected at 40 min after injection of [F-18]4b revealed that 93 +/- 7% of total radioactivity in brain was in the form of unchanged [F-18] 4b. In conclusion, the in vivo behavior of [F-18]4b was found to be similar to previously described [C-11]1 suggesting transport of [F-18]4b by Pgp and/or BCRP at the rodent BBB. However, low radiochemical yields and a significant degree of in vivo defluorination will limit the utility of [F-18]4b as a PET tracer. (C) 2011 Elsevier Ltd. All rights reserved.