发现一种高选择性糖原合酶激酶-3 抑制剂（PF-04802367），可调节大脑中的 Tau 磷酸化：用于 PET 神经影像学的翻译。
Discovery of a Highly Selective Glycogen Synthase Kinase-3 Inhibitor (PF-04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging.
机构信息
Gordon Center for Medical Imaging & Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA, 02114, USA.
Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT, 06340, USA.
出版信息
Angew Chem Int Ed Engl. 2016 Aug 8;55(33):9601-5. doi: 10.1002/anie.201603797. Epub 2016 Jun 29.
Abstract
Glycogen synthase kinase-3 (GSK-3) regulates multiple cellular processes in diabetes, oncology, and neurology. N-(3-(1H-1,2,4-triazol-1-yl)propyl)-5-(3-chloro-4-methoxyphenyl)oxazole-4-carboxamide (PF-04802367 or PF-367) has been identified as a highly potent inhibitor, which is among the most selective antagonists of GSK-3 to date. Its efficacy was demonstrated in modulation of tau phosphorylation in vitro and in vivo. Whereas the kinetics of PF-367 binding in brain tissues are too fast for an effective therapeutic agent, the pharmacokinetic profile of PF-367 is ideal for discovery of radiopharmaceuticals for GSK-3 in the central nervous system. A (11) C-isotopologue of PF-367 was synthesized and preliminary PET imaging studies in non-human primates confirmed that we have overcome the two major obstacles for imaging GSK-3, namely, reasonable brain permeability and displaceable binding.
摘要
糖原合酶激酶-3（GSK-3）在糖尿病、肿瘤学和神经学中调节多种细胞过程。N-(3-(1H-1,2,4-三唑-1-基)丙基)-5-(3-氯-4-甲氧基苯基)恶唑-4-甲酰胺（PF-04802367 或 PF-367）已被确定为一种高效抑制剂，是迄今为止最具选择性的 GSK-3 拮抗剂之一。其在体外和体内调节 tau 磷酸化方面的功效已得到证明。虽然 PF-367 在脑组织中的结合动力学太快，无法成为有效的治疗药物，但 PF-367 的药代动力学特征非常适合发现中枢神经系统中的 GSK-3 放射性药物。PF-367 的 (11)C-同位素类似物已被合成，非人类灵长类动物的初步 PET 成像研究证实，我们已经克服了成像 GSK-3 的两个主要障碍，即合理的脑通透性和可置换性结合。
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本文引用的文献
1
Glycogen Synthase Kinase-3 (GSK-3)-Targeted Therapy and Imaging.
Theranostics. 2016 Feb 17;6(4):571-93. doi: 10.7150/thno.14334. eCollection 2016.
2
Discovery of Isonicotinamides as Highly Selective, Brain Penetrable, and Orally Active Glycogen Synthase Kinase-3 Inhibitors.
J Med Chem. 2016 Feb 11;59(3):1041-51. doi: 10.1021/acs.jmedchem.5b01550. Epub 2016 Jan 22.
3
Tau in physiology and pathology.
Nat Rev Neurosci. 2016 Jan;17(1):5-21. doi: 10.1038/nrn.2015.1. Epub 2015 Dec 3.
4
Radiosynthesis and preliminary PET evaluation of glycogen synthase kinase 3β (GSK-3β) inhibitors containing [(11)C]methylsulfanyl, [(11)C]methylsulfinyl or [(11)C]methylsulfonyl groups.
Bioorg Med Chem Lett. 2015 Aug 15;25(16):3230-3. doi: 10.1016/j.bmcl.2015.05.085. Epub 2015 Jun 3.
5
Synthesis and Initial in Vivo Studies with [(11)C]SB-216763: The First Radiolabeled Brain Penetrative Inhibitor of GSK-3.
ACS Med Chem Lett. 2015 Mar 10;6(5):548-52. doi: 10.1021/acsmedchemlett.5b00044. eCollection 2015 May 14.
6
GSK-3 modulates cellular responses to a broad spectrum of kinase inhibitors.
Nat Chem Biol. 2015 Jan;11(1):58-63. doi: 10.1038/nchembio.1690. Epub 2014 Nov 17.
7
Synthesis and evaluation of [(11)C]PyrATP-1, a novel radiotracer for PET imaging of glycogen synthase kinase-3β (GSK-3β).
Nucl Med Biol. 2014 Jul;41(6):507-12. doi: 10.1016/j.nucmedbio.2014.03.025. Epub 2014 Apr 2.
8
Alternative approaches for PET radiotracer development in Alzheimer's disease: imaging beyond plaque.
J Labelled Comp Radiopharm. 2014 Apr;57(4):323-31. doi: 10.1002/jlcr.3158. Epub 2013 Dec 11.
9
Lessons learnt from glycogen synthase kinase 3 inhibitors development for Alzheimer's disease.
Curr Top Med Chem. 2013;13(15):1808-19. doi: 10.2174/15680266113139990138.
10
Moving beyond rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties.
ACS Chem Neurosci. 2010 Jun 16;1(6):435-49. doi: 10.1021/cn100008c. Epub 2010 Mar 25.
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