Development of an α-synuclein positron emission tomography tracer for imaging synucleinopathies

Jie Xiang; Youqi Tao; Yiyuan Xia; Shilin Luo; Qinyue Zhao; Bowei Li; Xiaoqian Zhang; Yunpeng Sun; Wencheng Xia; Mingming Zhang; Seong Su Kang; Eun-Hee Ahn; Xia Liu; Fang Xie; Yihui Guan; Jenny J Yang; Lihong Bu; Shengxi Wu; Xiaochuan Wang; Xuebing Cao; Cong Liu; Zhentao Zhang; Dan Li; Keqiang Ye

doi:10.1016/j.cell.2023.06.004

Development of an α-synuclein positron emission tomography tracer for imaging synucleinopathies

Cell. 2023 Aug 3;186(16):3350-3367.e19. doi: 10.1016/j.cell.2023.06.004. Epub 2023 Jul 7.

Authors

Jie Xiang¹, Youqi Tao², Yiyuan Xia³, Shilin Luo⁴, Qinyue Zhao², Bowei Li⁵, Xiaoqian Zhang⁶, Yunpeng Sun⁷, Wencheng Xia⁷, Mingming Zhang⁷, Seong Su Kang⁸, Eun-Hee Ahn⁸, Xia Liu⁸, Fang Xie⁹, Yihui Guan⁹, Jenny J Yang¹⁰, Lihong Bu¹¹, Shengxi Wu¹², Xiaochuan Wang¹³, Xuebing Cao⁶, Cong Liu¹⁴, Zhentao Zhang¹⁵, Dan Li¹⁶, Keqiang Ye¹⁷

Affiliations

¹ Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Neurobiology, Fourth Military Medical University, Xi'an, China.
² Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China; Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai 200240, China.
³ Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Institute of Biomedical Sciences, School of Medicine, JiangHan University, #8, Sanjiaohu Rd., Wuhan 430056, China.
⁴ Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China.
⁵ Shenzhen Institute of Advanced Technology, University of Chinese Academy of Science, Shenzhen, Guangdong 518055, China.
⁶ Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430022, China.
⁷ Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China.
⁸ Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
⁹ Department of Nuclear Medicine & PET Center, Huashan Hospital, Fudan University, Shanghai, China.
¹⁰ Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA.
¹¹ PET-CT/MRI Center, Renmin Hospital of Wuhan University, Wuhan 430060, China.
¹² Department of Neurobiology, Fourth Military Medical University, Xi'an, China.
¹³ Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
¹⁴ Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
¹⁵ Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China. Electronic address: zhentaozhang@whu.edu.cn.
¹⁶ Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China; Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address: lidan2017@sjtu.edu.cn.
¹⁷ Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA; Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China. Electronic address: kq.ye@siat.ac.cn.

Abstract

Synucleinopathies are characterized by the accumulation of α-synuclein (α-Syn) aggregates in the brain. Positron emission tomography (PET) imaging of synucleinopathies requires radiopharmaceuticals that selectively bind α-Syn deposits. We report the identification of a brain permeable and rapid washout PET tracer [¹⁸F]-F0502B, which shows high binding affinity for α-Syn, but not for Aβ or Tau fibrils, and preferential binding to α-Syn aggregates in the brain sections. Employing several cycles of counter screenings with in vitro fibrils, intraneuronal aggregates, and neurodegenerative disease brain sections from several mice models and human subjects, [¹⁸F]-F0502B images α-Syn deposits in the brains of mouse and non-human primate PD models. We further determined the atomic structure of the α-Syn fibril-F0502B complex by cryo-EM and revealed parallel diagonal stacking of F0502B on the fibril surface through an intense noncovalent bonding network via inter-ligand interactions. Therefore, [¹⁸F]-F0502B is a promising lead compound for imaging aggregated α-Syn in synucleinopathies.

Keywords: Lewy body; PET tracer; cryoelectron microscopy; protein aggregation; synucleinopathies.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Brain / diagnostic imaging
Brain / metabolism
Humans
Neurodegenerative Diseases* / metabolism
Positron-Emission Tomography
Synucleinopathies* / diagnostic imaging
Synucleinopathies* / metabolism
alpha-Synuclein / metabolism

Substances

alpha-Synuclein

Grants and funding

RF1 AG051538/AG/NIA NIH HHS/United States