Department of Psychiatry, Columbia University Medical Center , New York, New York 10032, United States.
Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute , New York, New York 10032, United States.
ACS Chem Neurosci. 2017 Aug 16;8(8):1697-1703. doi: 10.1021/acschemneuro.6b00376. Epub 2017 May 17.
Dysfunction of glycogen synthase kinase 3 (GSK-3) is implicated in the etiology of Alzheimer's disease, Parkinson's disease, diabetes, pain, and cancer. A radiotracer for functional positron emission tomography (PET) imaging could be used to study the kinase in brain disorders and to facilitate the development of small molecule inhibitors of GSK-3 for treatment. At present, there is no target-specific or validated PET tracer available for the in vivo monitoring of GSK-3. We radiolabeled the small molecule inhibitor [C]1-(7-methoxy- quinolin-4-yl)-3-(6-(trifluoromethyl)pyridin-2-yl)urea ([C]A1070722) with high affinity to GSK-3 (K = 0.6 nM) in excellent radiochemical yield. PET imaging experiments in anesthetized vervet/African green monkey exhibited that [C]A1070722 penetrated the blood-brain barrier (BBB) and accumulated in brain regions, with highest radioactivity binding in frontal cortex followed by parietal cortex and anterior cingulate, and with the lowest bindings found in caudate, putamen, and thalamus, similarly to the known distribution of GSK-3 in human brain. Our studies suggest that [C]A1070722 can be a potential PET radiotracer for the in vivo quantification of GSK-3 in brain.
糖原合酶激酶 3（GSK-3）功能障碍与阿尔茨海默病、帕金森病、糖尿病、疼痛和癌症的病因有关。功能性正电子发射断层扫描（PET）成像的示踪剂可用于研究大脑疾病中的激酶，并促进小分子 GSK-3 抑制剂的开发用于治疗。目前，尚无用于体内监测 GSK-3 的特异性或经过验证的靶标 PET 示踪剂。我们用高亲和力（K = 0.6 nM）小分子抑制剂 [C]1-（7-甲氧基-喹啉-4-基）-3-（6-（三氟甲基）吡啶-2-基）脲（[C]A1070722）对其进行放射性标记，用于 GSK-3。在麻醉的长尾猴/非洲绿猴中进行的 PET 成像实验表明，[C]A1070722穿透血脑屏障（BBB）并在大脑区域积聚，额叶皮质的放射性活性最高，其次是顶叶皮质和前扣带，尾状核、壳核和丘脑的放射性活性最低，与 GSK-3 在人脑的已知分布相似。我们的研究表明，[C]A1070722可以作为一种潜在的 PET 示踪剂，用于体内定量检测大脑中的 GSK-3。
