5-[(3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl))propyl]-1-hydroxy-5,6,7,8-tetrahydronaphthalene | 1165451-08-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: 5-[(3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl))propyl]-1-hydroxy-5,6,7,8-tetrahydronaphthalene
• 英文别名: 5-[3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-5,6,7,8-tetrahydro-naphthalen-1-ol；5-(3-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)propyl)-5,6,7,8-tetrahydronaphthalen-1-ol；5-[3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)propyl]-5,6,7,8-tetrahydronaphthalen-1-ol
• CAS: 1165451-08-0
• 化学式: C₂₄H₃₁NO₃
• 分子量: 381.515
• InChiKey: XLAGIXYAZDSULN-UHFFFAOYSA-N

物化性质

• 沸点：
  530.2±50.0 °C(Predicted)
• 密度：
  1.121±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  41.9
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  [11C]methyl iodide 、 5-[(3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl))propyl]-1-hydroxy-5,6,7,8-tetrahydronaphthalene 在 sodium hydroxide 作用下， 以 二甲基亚砜 为溶剂， 生成 6,7-Dimethoxy-2-[3-(5-[11C]methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-propyl]-1,2,3,4-tetrahydro-isoquinoline
  参考文献：
  名称：

  Synthesis and Preclinical Evaluation of Novel PET Probes for P-Glycoprotein Function and Expression

  摘要：

  P-glycoprotein (P-gp) is an ATP-dependent efflux pump protecting the body against xenobiotics. A P-gp substrate (7) and an inhibitor (6) were labeled with C-11, resulting in potential tracers of P-gp function and expression. Methods: 6 and 7 were labeled using (CH3I)-C-11. C-11-verapamil was prepared as published previously, using C-11-methyl triflate. MicroPET scans (with arterial sampling) and biodistribution studies were performed in rats pretreated with saline, cyclosporin A (CsA, 50 mg/kg), or cold 6 (15 mg/kg). Results: The radiochemical yields of C-11-6 and C-11-7 were approximately 30% with a total synthesis time of 45 min. Cerebral distribution volumes (DV) of C-11-6 (2,35 +/- 0.11) and C-11-7 (1.86 +/- 0.15) in saline-treated rats were higher than or C-11-verapamil (0.64 +/- 0.12). DVs of C-11-7 and C-11-verapamil were significantly increased by CsA (to 5.26 +/- 0.14 and 5.85 +/- 0.32, respectively). The DV of C-11-6 was reduced by cold 6 (to 1.65 +/- 0.03). Its uptake was also reduced (up to 67%) in several peripheral organs that express P-gp. Conclusions: C-11-7 is a novel tracer of P-gp function with higher baseline uptake than C-11-verapamil. Upregulation of P-gp function in response to treatment (which is hard to detect with C-11-verapamil) may be detectable using C-11-7 and PET. Because C-11-6 shows specific binding in target organs, this compound is the First PET tracer allowing measurement of P-gp expression.

  DOI：

  10.1021/jm900485a
• 作为产物：
  描述：

  6,7-二甲氧基-1,2,3,4-四氢异喹啉 在 palladium on activated charcoal 、 氢气 、 sodium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 5-[(3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl))propyl]-1-hydroxy-5,6,7,8-tetrahydronaphthalene
  参考文献：
  名称：

  Comparison of In Vitro Assays in Selecting Radiotracers for In Vivo P-Glycoprotein PET Imaging

  摘要：

  对血脑屏障中的 P-糖蛋白（P-gp）进行正电子发射断层扫描（PET）成像，对于 P-gp 受影响的神经系统疾病（如阿尔茨海默病）非常重要。成像研究中使用的放射性示踪剂的浓度非常小，只有纳摩尔级，而体外检测这些示踪剂时，通常是在微摩尔浓度下进行的，因此体内和体外数据往往不一致。我们已获得[11C]维拉帕米、(R)-N-[18F]氟乙基维拉帕米、(R)-O-[18F]氟乙基-去甲维拉帕米、[18F]MC225 和 [18F]MC224 的体内啮齿动物 PET 数据，本研究还包括两种新分子[18F]MC198 和 [18F]KE64 。为了提高体外检测的预测价值，我们用氚标记了所有示踪剂，并在 MDCKII-MDR1 细胞中以三种不同的浓度（0.01、1 和 50 µM）进行了双向底物转运检测，还用 P-gp 抑制剂进行了抑制检测。作为比较，我们在 Caco-2 细胞中使用了浓度为 10 µM 的非放射性分子进行转运试验，在 MDCKII-MDR1 细胞中使用了钙黄绿素-AM 进行抑制试验。所有 P-gp 底物的转运都与剂量有关。在最高浓度（50 µM）下，P-gp 饱和度与 P-gp 抑制剂处理后的情况相似。双向转运试验在 0.01 µM 浓度时获得了最佳体内相关性。仅靠转运试验或钙蓝蛋白-AM 试验中的一个微摩尔浓度不足以正确预测底物 P-gp PET 配体的体内浓度。

  DOI：

  10.3390/ph10030076

文献信息

• Synthesis and Preclinical Evaluation of Three Novel Fluorine-18 Labeled Radiopharmaceuticals for P-Glycoprotein PET Imaging at the Blood–Brain Barrier
  作者：Heli Savolainen、Mariangela Cantore、Nicola A. Colabufo、Philip H. Elsinga、Albert D. Windhorst、Gert Luurtsema

  DOI：10.1021/mp5008103

  日期：2015.7.6

  function, many positron emission tomography (PET) radiopharmaceuticals have been developed. Most P-gp radiopharmaceuticals are labeled with carbon-11, while labeling with fluorine-18 would increase their applicability due to longer half-life. Here we present the synthesis and in vivo evaluation of three novel fluorine-18 labeled radiopharmaceuticals: 4-((6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-y

  P-糖蛋白（P-gp）以及血脑屏障（BBB）上的其他转运蛋白限制了许多药物进入大脑。在几种神经系统疾病中发现了P-gp功能的改变。为了研究P-gp功能，已经开发了许多正电子发射断层扫描（PET）放射性药物。大多数P-gp放射性药物都用碳11标记，而氟18标记则由于更长的半衰期而增加了其适用性。在这里，我们介绍三种新型氟18标记的放射性药物的合成和体内评价：4-（（6,7-二甲氧基-3,4-二氢异喹啉-2（1 H）-基）甲基）-2-（4-氟苯基）恶唑（1a），2-联苯基-4-基-2-氟乙氧基-6,7-二甲氧基-1,2,3,4-四氢-异喹啉（2）和5-（1-（2-氟乙氧基））-[3-（6,7-二甲氧基-3,4-二氢-1 H-异喹啉-2-基）-丙基] -5,6,7 ，8-四氢萘（3）。该化合物在体外被表征为P-gp底物，并使用Mdr1a / b （-/-） Bcrp1 （-/-）和野生型小鼠来评估体内底物的潜力。与（R）-[
• [EN] 6,7-DIOXYALKYLTETRAHYDROISOQUINOLINE COMPOUNDS<br/>[FR] COMPOSÉS DE 6,7-DIOXYALKYLTÉTRAHYDROISOQUINOLINE
  申请人：STICHTING TECH WETENSCHAPP

  公开号：WO2015194954A1

  公开（公告）日：2015-12-23

  The present invention relates to a 6,7-dioxyalkyltetrahydroisoquinoline compound, or a salt or solvate thereof according to formula I: (formula I), (I) wherein R represents hydrogen or a fluorinated alkyl group, and R2 and R3 independently represents hydrogen or an alkyl group.

  本发明涉及一种6,7-二氧烷基四氢异喹啉化合物，或者根据式I的盐或溶剂化合物：（式I），其中R代表氢或氟化烷基，而R2和R3独立地代表氢或烷基。
• Comparison of In Vitro Assays in Selecting Radiotracers for In Vivo P-Glycoprotein PET Imaging
  作者：Renske Raaphorst、Heli Savolainen、Mariangela Cantore、Evita van de Steeg、Aren van Waarde、Nicola Colabufo、Philip Elsinga、Adriaan Lammertsma、Albert Windhorst、Gert Luurtsema

  DOI：10.3390/ph10030076

  日期：——

  Positron emission tomography (PET) imaging of P-glycoprotein (P-gp) in the blood-brain barrier can be important in neurological diseases where P-gp is affected, such as Alzheimer´s disease. Radiotracers used in the imaging studies are present at very small, nanomolar, concentration, whereas in vitro assays where these tracers are characterized, are usually performed at micromolar concentration, causing often discrepant in vivo and in vitro data. We had in vivo rodent PET data of [11C]verapamil, (R)-N-[18F]fluoroethylverapamil, (R)-O-[18F]fluoroethyl-norverapamil, [18F]MC225 and [18F]MC224 and we included also two new molecules [18F]MC198 and [18F]KE64 in this study. To improve the predictive value of in vitro assays, we labeled all the tracers with tritium and performed bidirectional substrate transport assay in MDCKII-MDR1 cells at three different concentrations (0.01, 1 and 50 µM) and also inhibition assay with P-gp inhibitors. As a comparison, we used non-radioactive molecules in transport assay in Caco-2 cells at a concentration of 10 µM and in calcein-AM inhibition assay in MDCKII-MDR1 cells. All the P-gp substrates were transported dose-dependently. At the highest concentration (50 µM), P-gp was saturated in a similar way as after treatment with P-gp inhibitors. Best in vivo correlation was obtained with the bidirectional transport assay at a concentration of 0.01 µM. One micromolar concentration in a transport assay or calcein-AM assay alone is not sufficient for correct in vivo prediction of substrate P-gp PET ligands.

  对血脑屏障中的 P-糖蛋白（P-gp）进行正电子发射断层扫描（PET）成像，对于 P-gp 受影响的神经系统疾病（如阿尔茨海默病）非常重要。成像研究中使用的放射性示踪剂的浓度非常小，只有纳摩尔级，而体外检测这些示踪剂时，通常是在微摩尔浓度下进行的，因此体内和体外数据往往不一致。我们已获得[11C]维拉帕米、(R)-N-[18F]氟乙基维拉帕米、(R)-O-[18F]氟乙基-去甲维拉帕米、[18F]MC225 和 [18F]MC224 的体内啮齿动物 PET 数据，本研究还包括两种新分子[18F]MC198 和 [18F]KE64 。为了提高体外检测的预测价值，我们用氚标记了所有示踪剂，并在 MDCKII-MDR1 细胞中以三种不同的浓度（0.01、1 和 50 µM）进行了双向底物转运检测，还用 P-gp 抑制剂进行了抑制检测。作为比较，我们在 Caco-2 细胞中使用了浓度为 10 µM 的非放射性分子进行转运试验，在 MDCKII-MDR1 细胞中使用了钙黄绿素-AM 进行抑制试验。所有 P-gp 底物的转运都与剂量有关。在最高浓度（50 µM）下，P-gp 饱和度与 P-gp 抑制剂处理后的情况相似。双向转运试验在 0.01 µM 浓度时获得了最佳体内相关性。仅靠转运试验或钙蓝蛋白-AM 试验中的一个微摩尔浓度不足以正确预测底物 P-gp PET 配体的体内浓度。
• Synthesis and Preclinical Evaluation of Novel PET Probes for P-Glycoprotein Function and Expression
  作者：Aren van Waarde、Nisha K. Ramakrishnan、Anna A. Rybczynska、Philip H. Elsinga、Francesco Berardi、Johan R. de Jong、Chantal Kwizera、Roberto Perrone、Mariangela Cantore、Jurgen W. A. Sijbesma、Rudi A. Dierckx、Nicola A. Colabufo

  DOI：10.1021/jm900485a

  日期：2009.7.23

  P-glycoprotein (P-gp) is an ATP-dependent efflux pump protecting the body against xenobiotics. A P-gp substrate (7) and an inhibitor (6) were labeled with C-11, resulting in potential tracers of P-gp function and expression. Methods: 6 and 7 were labeled using (CH3I)-C-11. C-11-verapamil was prepared as published previously, using C-11-methyl triflate. MicroPET scans (with arterial sampling) and biodistribution studies were performed in rats pretreated with saline, cyclosporin A (CsA, 50 mg/kg), or cold 6 (15 mg/kg). Results: The radiochemical yields of C-11-6 and C-11-7 were approximately 30% with a total synthesis time of 45 min. Cerebral distribution volumes (DV) of C-11-6 (2,35 +/- 0.11) and C-11-7 (1.86 +/- 0.15) in saline-treated rats were higher than or C-11-verapamil (0.64 +/- 0.12). DVs of C-11-7 and C-11-verapamil were significantly increased by CsA (to 5.26 +/- 0.14 and 5.85 +/- 0.32, respectively). The DV of C-11-6 was reduced by cold 6 (to 1.65 +/- 0.03). Its uptake was also reduced (up to 67%) in several peripheral organs that express P-gp. Conclusions: C-11-7 is a novel tracer of P-gp function with higher baseline uptake than C-11-verapamil. Upregulation of P-gp function in response to treatment (which is hard to detect with C-11-verapamil) may be detectable using C-11-7 and PET. Because C-11-6 shows specific binding in target organs, this compound is the First PET tracer allowing measurement of P-gp expression.