[¹¹C]N-methyl lansoprazole | 1400589-76-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: [¹¹C]N-methyl lansoprazole
• 英文别名: [11C]-N-Methyl Lansoprazole；1-(111C)methyl-2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl]benzimidazole
• CAS: 1400589-76-5
• 化学式: C₁₇H₁₆F₃N₃O₂S
• 分子量: 382.383
• InChiKey: OSFITLUTZVXDRB-JVVVGQRLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  76.2
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  、 兰索拉唑 反应 0.08h， 生成 [¹¹C]N-methyl lansoprazole
  参考文献：
  名称：

  High Affinity Radiopharmaceuticals Based Upon Lansoprazole for PET Imaging of Aggregated Tau in Alzheimer’s Disease and Progressive Supranuclear Palsy: Synthesis, Preclinical Evaluation, and Lead Selection

  摘要：

  Abnormally aggregated tau is the hallmark pathology of tauopathy neurodegenerative disorders and is a target for development of both diagnostic tools and therapeutic strategies across the tauopathy disease spectrum. Development of carbon-11- or fluorine-18-labeled radiotracers with appropriate affinity and specificity for tau would allow noninvasive quantification of tau burden using positron emission tomography (PET) imaging. We have synthesized [(18)F]lansoprazole, [(11)C]N-methyl lansoprazole, and [(18)F]N-methyl lansoprazole and identified them as high affinity radiotracers for tau with low to subnanomolar binding affinities. Herein, we report radiosyntheses and extensive preclinical evaluation with the aim of selecting a lead radiotracer for translation into human PET imaging trials. We demonstrate that [(18)F]N-methyl lansoprazole, on account of the favorable half-life of fluorine-18 and its rapid brain entry in nonhuman primates, favorable kinetics, low white matter binding, and selectivity for binding to tau over amyloid, is the lead compound for progression into clinical trials.

  DOI：

  10.1021/cn500103u

文献信息

• Evaluation of [¹¹C]<i>N</i>-Methyl Lansoprazole as a Radiopharmaceutical for PET Imaging of Tau Neurofibrillary Tangles
  作者：Xia Shao、Garrett M. Carpenter、Timothy J. Desmond、Phillip Sherman、Carole A. Quesada、Maria Fawaz、Allen F. Brooks、Michael R. Kilbourn、Roger L. Albin、Kirk A. Frey、Peter J. H. Scott

  DOI：10.1021/ml300216t

  日期：2012.11.8

  [C-11]N-Methyl lansoprazole ([C-11]NML, 3) was synthesized and evaluated as a radiopharmaceutical for quantifying tau neurofibrillary tangle (NFT) burden using positron emission tomography (PET) imaging. [C-11]NML was synthesized from commercially available lansoprazole in 4.6% radiochemical yield (noncorrected RCY, based upon [C-11]MeI), 99% radiochemical purity, and 16095 Ci/mmol specific activity (n = 5). Log P was determined to be 2.18. A lack of brain uptake in rodent inicroPET imaging revealed [C-11]NML to be a,substrate for the rodent permeability-glycoprotein 1 (PGP) transporter, but this could be overcome by, pretreating with cyclosporin A to block the PGP. Contrastingly, [C-11]NML was not found to be a substrate for the primate PGP, and microPET imaging in rhesus revealed [C-11]NML uptake in the healthy primate brain of similar to 1600 nCi/cc maximum at 3 min followed by rapid egress to 500 nCi/cc. Comparative autoradiography between wild type rats and transgenic rats expressing human tau (hTau +/+) revealed 12% higher uptake of [C-11]NML in the cortex of brains expressing human tau. Further autoradiography with tau positive brain samples from progressive supranuclear palsy (PSP) patients revealed colocalization of [C-11]NML with tau NFTs identified using modified Bielschowsky staining. Finally, saturation binding experiments with heparin-induced tau confirmed K-d and Bmax values of [C-11]NML as 700 pM and 0.214 fmol/mu g, respectively.
• High Affinity Radiopharmaceuticals Based Upon Lansoprazole for PET Imaging of Aggregated Tau in Alzheimer’s Disease and Progressive Supranuclear Palsy: Synthesis, Preclinical Evaluation, and Lead Selection
  作者：Maria V. Fawaz、Allen F. Brooks、Melissa E. Rodnick、Garrett M. Carpenter、Xia Shao、Timothy J. Desmond、Phillip Sherman、Carole A. Quesada、Brian G. Hockley、Michael R. Kilbourn、Roger L. Albin、Kirk A. Frey、Peter J. H. Scott

  DOI：10.1021/cn500103u

  日期：2014.8.20

  Abnormally aggregated tau is the hallmark pathology of tauopathy neurodegenerative disorders and is a target for development of both diagnostic tools and therapeutic strategies across the tauopathy disease spectrum. Development of carbon-11- or fluorine-18-labeled radiotracers with appropriate affinity and specificity for tau would allow noninvasive quantification of tau burden using positron emission tomography (PET) imaging. We have synthesized [(18)F]lansoprazole, [(11)C]N-methyl lansoprazole, and [(18)F]N-methyl lansoprazole and identified them as high affinity radiotracers for tau with low to subnanomolar binding affinities. Herein, we report radiosyntheses and extensive preclinical evaluation with the aim of selecting a lead radiotracer for translation into human PET imaging trials. We demonstrate that [(18)F]N-methyl lansoprazole, on account of the favorable half-life of fluorine-18 and its rapid brain entry in nonhuman primates, favorable kinetics, low white matter binding, and selectivity for binding to tau over amyloid, is the lead compound for progression into clinical trials.