AMG 580：一种新型小分子磷酸二酯酶10A（PDE10A）正电子发射断层显像剂
AMG 580: a novel small molecule phosphodiesterase 10A (PDE10A) positron emission tomography tracer.
作者信息
Chen Hang, Lester-Zeiner Dianna, Shi Jianxia, Miller Silke, Glaus Charlie, Hu Essa, Chen Ning, Able Jessica, Biorn Christopher, Wong Jamie, Ma Ji, Michelsen Klaus, Hill Della Puppa Geraldine, Kazules Tim, Dou Hui Hannah, Talreja Santosh, Zhao Xiaoning, Chen Ada, Rumfelt Shannon, Kunz Roxanne K, Ye Hu, Thiel Oliver R, Williamson Toni, Davis Carl, Porter Amy, Immke David, Allen Jennifer R, Treanor James
机构信息
Department of Neuroscience (H.C., D.L.-Z., J.A., C.B., H.H.D., S.T., A.P.), Department of Pharmacokinetics and Drug Metabolism (J.S., J.W., J.M.), and Department of Molecular Structures and Characterization (X.Z., A.C.), Amgen Inc., South San Francisco, California; Department of Neuroscience (S.M., G.H.D.P., D.I., J.T.), Department of Pharmacokinetics and Drug Metabolism (C.D.), Research Imaging Sciences (C.G., T.K., H.Y.), Department of Small Molecule Chemistry (E.H., N.C., S.R., R.K.K., J.R.A.), and Department of Process Development (O.R.T.), Amgen Inc., Thousand Oaks, California; and Department of Molecular Structures and Characterization (K.M.) and Department of Discovery Toxicology (T.W.), Amgen Inc., Cambridge, Massachusetts (K.M.)
Department of Neuroscience (H.C., D.L.-Z., J.A., C.B., H.H.D., S.T., A.P.), Department of Pharmacokinetics and Drug Metabolism (J.S., J.W., J.M.), and Department of Molecular Structures and Characterization (X.Z., A.C.), Amgen Inc., South San Francisco, California; Department of Neuroscience (S.M., G.H.D.P., D.I., J.T.), Department of Pharmacokinetics and Drug Metabolism (C.D.), Research Imaging Sciences (C.G., T.K., H.Y.), Department of Small Molecule Chemistry (E.H., N.C., S.R., R.K.K., J.R.A.), and Department of Process Development (O.R.T.), Amgen Inc., Thousand Oaks, California; and Department of Molecular Structures and Characterization (K.M.) and Department of Discovery Toxicology (T.W.), Amgen Inc., Cambridge, Massachusetts (K.M.).
出版信息
J Pharmacol Exp Ther. 2015 Feb;352(2):327-37. doi: 10.1124/jpet.114.220517. Epub 2014 Dec 11.
Phosphodiesterase 10A (PDE10A) inhibitors have therapeutic potential for the treatment of psychiatric and neurologic disorders, such as schizophrenia and Huntington's disease. One of the key requirements for successful central nervous system drug development is to demonstrate target coverage of therapeutic candidates in brain for lead optimization in the drug discovery phase and for assisting dose selection in clinical development. Therefore, we identified AMG 580 [1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one], a novel, selective small-molecule antagonist with subnanomolar affinity for rat, primate, and human PDE10A. We showed that AMG 580 is suitable as a tracer for lead optimization to determine target coverage by novel PDE10A inhibitors using triple-stage quadrupole liquid chromatography-tandem mass spectrometry technology. [(3)H]AMG 580 bound with high affinity in a specific and saturable manner to both striatal homogenates and brain slices from rats, baboons, and human in vitro. Moreover, [(18)F]AMG 580 demonstrated prominent uptake by positron emission tomography in rats, suggesting that radiolabeled AMG 580 may be suitable for further development as a noninvasive radiotracer for target coverage measurements in clinical studies. These results indicate that AMG 580 is a potential imaging biomarker for mapping PDE10A distribution and ensuring target coverage by therapeutic PDE10A inhibitors in clinical studies.
磷酸二酯酶10A（PDE10A）抑制剂在治疗精神疾病和神经疾病方面具有治疗潜力，如精神分裂症和亨廷顿舞蹈症。成功开发中枢神经系统药物的关键要求之一是在药物发现阶段证明治疗候选药物在大脑中的靶点覆盖情况，以便进行先导化合物优化，并在临床开发中辅助剂量选择。因此，我们鉴定出了AMG 580 [1-(4-(3-(4-(1H-苯并[d]咪唑-2-羰基)苯氧基)吡嗪-2-基)哌啶-1-基)-2-氟丙烷-1-酮]，这是一种新型的选择性小分子拮抗剂，对大鼠、灵长类动物和人类的PDE10A具有亚纳摩尔亲和力。我们表明，AMG 580适合作为一种用于先导化合物优化的示踪剂，通过使用三级四极杆液相色谱-串联质谱技术来确定新型PDE10A抑制剂的靶点覆盖情况。[(3)H]AMG 580在体外与大鼠、狒狒和人类的纹状体匀浆及脑片以特异性和饱和性的方式高亲和力结合。此外，[(18)F]AMG 580在大鼠体内通过正电子发射断层扫描显示出显著摄取，这表明放射性标记的AMG 580可能适合进一步开发成为一种用于临床研究中靶点覆盖测量的非侵入性放射性示踪剂。这些结果表明，AMG 580是一种潜在的成像生物标志物，可用于在临床研究中绘制PDE10A分布图并确保治疗性PDE10A抑制剂的靶点覆盖。
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