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

被引：62

作者：

Xiang, Jie ^{[1
,2
]}

Tao, Youqi ^{[3
,4
]}

Xia, Yiyuan ^{[1
,5
,6
]}

Luo, Shilin ^{[1
,7
]}

Zhao, Qinyue ^{[3
]}

Li, Bowei ^{[8
]}

Zhang, Xiaoqian ^{[9
]}

Sun, Yunpeng ^{[10
]}

Xia, Wencheng ^{[10
]}

Zhang, Mingming ^{[10
]}

Kang, Seong Su ^{[1
]}

Ahn, Eun-Hee ^{[1
]}

Liu, Xia ^{[1
]}

Xie, Fang ^{[11
,12
]}

Guan, Yihui ^{[11
,12
]}

Yang, Jenny J. ^{[13
]}

Bu, Lihong ^{[14
]}

Wu, Shengxi ^{[2
]}

Wang, Xiaochuan ^{[5
]}

Cao, Xuebing

Liu, Cong ^{[10
,15
]}

Zhang, Zhentao ^{[16
]}

Li, Dan ^{[3
,4
]}

Ye, Keqiang ^{[1
,17
]}

机构：

[1] Emory Univ, Dept Pathol & Lab Med, Sch Med, Atlanta, GA 30322 USA

[2] Fourth Mil Med Univ, Dept Neurobiol, Xian, Peoples R China

[3] Shanghai Jiao Tong Univ, Bio X Inst, Key Lab Genet Dev & Neuropsychiat Disorders, Minist Educ, Shanghai, Peoples R China

[4] Shanghai Jiao Tong Univ, Zhangjiang Inst Adv Study, Shanghai 200240, Peoples R China

[5] Huazhong Univ Sci & Technol, Tongji Med Coll, Dept Pathophysiol, Wuhan, Peoples R China

[6] JiangHan Univ, Inst Biomed Sci, Sch Med, 8 Sanjiaohu Rd, Wuhan 430056, Peoples R China

[7] Cent South Univ, Xiangya Hosp 2, Dept Pharm, Changsha, Peoples R China

[8] Univ Chinese Acad Sci, Shenzhen Inst Adv Technol, Shenzhen 518055, Guangdong, Peoples R China

[9] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Neurol, Wuhan 430022, Peoples R China

[10] Chinese Acad Sci, Shanghai Inst Organ Chem, Interdisciplinary Res Ctr Biol & Chem, Shanghai 201210, Peoples R China

[11] Fudan Univ, Huashan Hosp, Dept Nucl Med, Shanghai, Peoples R China

[12] Fudan Univ, Huashan Hosp, PET Ctr, Shanghai, Peoples R China

[13] Georgia State Univ, Dept Chem, Atlanta, GA 30303 USA

[14] Wuhan Univ, PET CT MRI Ctr, Renmin Hosp, Wuhan 430060, Peoples R China

[15] Chinese Acad Sci, Shanghai Inst Organ Chem, State Key Lab Chem Biol, Shanghai 200032, Peoples R China

[16] Wuhan Univ, Renmin Hosp, Dept Neurol, Wuhan 430060, Peoples R China

[17] Chinese Acad Sci, Shenzhen Inst Adv Technol, Fac Life & Hlth Sci, Shenzhen 518055, Guangdong, Peoples R China

来源：

CELL | 2023年 / 186卷 / 16期

关键词：

PAIRED HELICAL FILAMENTS; IN-VIVO EVALUATION; ALPHA-SYNUCLEIN; ALZHEIMERS-DISEASE; MOUSE MODEL; PROTEIN; ACCUMULATION; PATHOLOGY; INTERFACE; BINDING;

D O I：

10.1016/j.cell.2023.06.004

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Synucleinopathies are characterized by the accumulation of a-synuclein (a-Syn) aggregates in the brain. Positron emission tomography (PET) imaging of synucleinopathies requires radiopharmaceuticals that selec-tively bind a-Syn deposits. We report the identification of a brain permeable and rapid washout PET tracer [18F]-F0502B, which shows high binding affinity for a-Syn, but not for Ab or Tau fibrils, and preferential bind-ing to a-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 a-Syn deposits in the brains of mouse and non-human primate PD models. We further determined the atomic structure of the a-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 im-aging aggregated a-Syn in synucleinopathies.

引用

页码：3350 / +

页数：38

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