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用于正电子发射断层扫描成像帕金森病中聚集的α-突触核蛋白的-(6-甲氧基吡啶-3-基)喹啉-2-胺衍生物的发现

Discovery of -(6-Methoxypyridin-3-yl)quinoline-2-amine Derivatives for Imaging Aggregated α-Synuclein in Parkinson's Disease with Positron Emission Tomography.

作者信息

Zhao Haiyang, Huang Tianyu, Dhavale Dhruva D, O'Shea Jennifer Y, Lengyel-Zhand Zsofia, Guarino Dinahlee Saturnino, Gu Jiwei, Yue Xuyi, Nai Ying-Hwey, Jiang Hao, Lougee Marshall G, Pagar Vinayak V, Kim Hee Jong, Garcia Benjamin A, Petersson E James, Mathis Chester A, Kotzbauer Paul T, Perlmutter Joel S, Mach Robert H, Tu Zhude

机构信息

Department of Radiology, Washington University School of Medicine, St Louis, MO 63110, USA.

Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA.

出版信息

Cells. 2025 Jul 18;14(14):1108. doi: 10.3390/cells14141108.

DOI:10.3390/cells14141108
PMID:40710362
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12293736/
Abstract

The fibrillary aggregation of α-synuclein is a hallmark of Parkinson's disease (PD) and a potential target for diagnostics and therapeutics. Although substantial effort has been devoted to the development of positron emission tomography (PET) probes for detecting α-synuclein aggregates, no clinically suitable tracer has been reported. The design and synthesis of 43 new -(6-methoxypyridin-3-yl)quinolin-2-amine derivatives and an evaluation of their α-synuclein binding affinity is reported here. Compounds , , and exhibited high affinity for α-synuclein and were selected for C, F, I, or H radiolabeling. A photoaffinity variant, , structurally related to and , demonstrated preferential binding to the C-terminal region of α-synuclein fibrils. PET brain imaging studies using [C], [F], and [C] in non-human primates indicated that these three α-synuclein PET tracers penetrated the blood-brain barrier. Both [C] and [F] showed more favorable brain washout pharmacokinetics than [C]. In vitro binding assays showed that [I] is a very potent α-synuclein radioligand, with K values of 5 nM for both PD brain tissues and LBD-amplified fibrils; it is also selective for PD tissues versus AD or control tissues. These results strongly suggest that the PET probes based on the -(6-methoxypyridin-3-yl)quinoline-2-amine scaffold have potential utility in detecting α-synuclein aggregates in vivo.

摘要

α-突触核蛋白的纤维状聚集是帕金森病（PD）的一个标志，也是诊断和治疗的潜在靶点。尽管人们在开发用于检测α-突触核蛋白聚集物的正电子发射断层扫描（PET）探针方面付出了巨大努力，但尚未有临床适用的示踪剂报道。本文报道了43种新型-(6-甲氧基吡啶-3-基)喹啉-2-胺衍生物的设计与合成及其对α-突触核蛋白结合亲和力的评估。化合物、和对α-突触核蛋白表现出高亲和力，并被选用于碳、氟、碘或氢的放射性标记。一种与和结构相关的光亲和变体对α-突触核蛋白原纤维的C末端区域表现出优先结合。在非人类灵长类动物中使用[C]、[F]和[C]进行的PET脑成像研究表明，这三种α-突触核蛋白PET示踪剂能够穿透血脑屏障。[C]和[F]的脑清除药代动力学均比[C]更有利。体外结合试验表明，[I]是一种非常有效的α-突触核蛋白放射性配体，对PD脑组织和LBD扩增的原纤维的K值均为5 nM；它对PD组织相对于AD或对照组织也具有选择性。这些结果强烈表明，基于-(6-甲氧基吡啶-3-基)喹啉-2-胺支架的PET探针在体内检测α-突触核蛋白聚集物方面具有潜在用途。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d71/12293736/94b66e4cecdb/cells-14-01108-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d71/12293736/129728cbf956/cells-14-01108-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d71/12293736/8df2293167da/cells-14-01108-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d71/12293736/9edc9e16e00f/cells-14-01108-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d71/12293736/f82bd7375274/cells-14-01108-sch002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d71/12293736/e819cecee009/cells-14-01108-sch003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d71/12293736/452463793cf2/cells-14-01108-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d71/12293736/508b2b975d45/cells-14-01108-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d71/12293736/4e279bef0e60/cells-14-01108-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d71/12293736/adb182f73238/cells-14-01108-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d71/12293736/6417eaf2445c/cells-14-01108-sch004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d71/12293736/34835a77810b/cells-14-01108-sch005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d71/12293736/94b66e4cecdb/cells-14-01108-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d71/12293736/129728cbf956/cells-14-01108-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d71/12293736/8df2293167da/cells-14-01108-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d71/12293736/9edc9e16e00f/cells-14-01108-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d71/12293736/f82bd7375274/cells-14-01108-sch002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d71/12293736/e819cecee009/cells-14-01108-sch003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d71/12293736/452463793cf2/cells-14-01108-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d71/12293736/508b2b975d45/cells-14-01108-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d71/12293736/4e279bef0e60/cells-14-01108-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d71/12293736/adb182f73238/cells-14-01108-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d71/12293736/6417eaf2445c/cells-14-01108-sch004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d71/12293736/34835a77810b/cells-14-01108-sch005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d71/12293736/94b66e4cecdb/cells-14-01108-g007.jpg

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