Synthesis, preclinical evaluation and pilot clinical study of a P2Y12 receptor targeting radiotracer [18F]QTFT for imaging brain disorders by visualizing anti-inflammatory microglia

Bolin Yao; Yanyan Kong; Jianing Li; Fulin Xu; Yan Deng; Yuncan Chen; Yixiu Chen; Jian Chen; Minhua Xu; Xiao Zhu; Liang Chen; Fang Xie; Xin Zhang; Cong Wang; Cong Li

doi:10.1016/j.apsb.2025.01.009

Acta Pharmaceutica Sinica B (Feb 2025)

Synthesis, preclinical evaluation and pilot clinical study of a P2Y12 receptor targeting radiotracer [18F]QTFT for imaging brain disorders by visualizing anti-inflammatory microglia

Bolin Yao,
Yanyan Kong,
Jianing Li,
Fulin Xu,
Yan Deng,
Yuncan Chen,
Yixiu Chen,
Jian Chen,
Minhua Xu,
Xiao Zhu,
Liang Chen,
Fang Xie,
Xin Zhang,
Cong Wang,
Cong Li

Affiliations

Bolin Yao: School of Pharmacy, MOE Key Laboratory of Smart Drug Delivery, MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases, Zhongshan Hospital, Fudan University, Shanghai 201203, China
Yanyan Kong: PET Center, Department of Nuclear Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
Jianing Li: School of Pharmacy, MOE Key Laboratory of Smart Drug Delivery, MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases, Zhongshan Hospital, Fudan University, Shanghai 201203, China
Fulin Xu: Department of Neurosurgery, Minhang Hospital, Fudan University, Shanghai 201199, China
Yan Deng: School of Pharmacy, MOE Key Laboratory of Smart Drug Delivery, MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases, Zhongshan Hospital, Fudan University, Shanghai 201203, China
Yuncan Chen: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China
Yixiu Chen: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China
Jian Chen: School of Pharmacy, MOE Key Laboratory of Smart Drug Delivery, MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases, Zhongshan Hospital, Fudan University, Shanghai 201203, China
Minhua Xu: Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai 201203, China
Xiao Zhu: Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai 201203, China
Liang Chen: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China
Fang Xie: PET Center, Department of Nuclear Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
Xin Zhang: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China; Corresponding authors.
Cong Wang: School of Pharmacy, MOE Key Laboratory of Smart Drug Delivery, MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases, Zhongshan Hospital, Fudan University, Shanghai 201203, China; Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China; The Key Laboratory of Biomedical Imaging Science and System, Chinese Academy of Sciences, State Key Laboratory of Biomedical Imaging Science and System, Shenzhen 518055, China; Corresponding authors.
Cong Li: School of Pharmacy, MOE Key Laboratory of Smart Drug Delivery, MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases, Zhongshan Hospital, Fudan University, Shanghai 201203, China; The Key Laboratory of Biomedical Imaging Science and System, Chinese Academy of Sciences, State Key Laboratory of Biomedical Imaging Science and System, Shenzhen 518055, China; Corresponding authors.

DOI: https://doi.org/10.1016/j.apsb.2025.01.009
Journal volume & issue: Vol. 15, no. 2
pp. 1056 – 1069

Abstract

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As the brain's resident immune cells, microglia perform crucial functions such as phagocytosis, neuronal network maintenance, and injury restoration by adopting various phenotypes. Dynamic imaging of these phenotypes is essential for accessing brain diseases and therapeutic responses. Although numerous probes are available for imaging pro-inflammatory microglia, no PET tracers have been developed specifically to visualize anti-inflammatory microglia. In this study, we present an 18F-labeled PET tracer (QTFT) that targets the P2Y12, a receptor highly expressed on anti-inflammatory microglia. [18F]QTFT exhibited high binding affinity to the P2Y12 (14.43 nmol/L) and superior blood–brain barrier permeability compared to other candidates. Micro-PET imaging in IL-4-induced neuroinflammation models showed higher [18F]QTFT uptake in lesions compared to the contralateral normal brain tissues. Importantly, this specific uptake could be blocked by QTFT or a P2Y12 antagonist. Furthermore, [18F]QTFT visualized brain lesions in mouse models of epilepsy, glioma, and aging by targeting the aberrantly expressed P2Y12 in anti-inflammatory microglia. In a pilot clinical study, [18F]QTFT successfully located epileptic foci, showing enhanced radioactive signals in a patient with epilepsy. Collectively, these studies suggest that [18F]QTFT could serve as a valuable diagnostic tool for imaging various brain disorders by targeting P2Y12 overexpressed in anti-inflammatory microglia.

Published in Acta Pharmaceutica Sinica B

ISSN: 2211-3835 (Print); 2211-3843 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.sciencedirect.com/journal/acta-pharmaceutica-sinica-b

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