Preclinical
Evaluation
of Novel Positron Emission
Tomography (PET) Probes for Imaging Leucine-Rich Repeat Kinase 2 (LRRK2)

Chen, Zhen; Chen, Jiahui; Mori, Wakana; Yi, Yongjia; Rong, Jian; Li, Yinlong; Leon, Erick R. Calderon; Shao, Tuo; Song, Zhendong; Yamasaki, Tomoteru; Ishii, Hideki; Zhang, Yiding; Kokufuta, Tomomi; Hu, Kuan; Xie, Lin; Josephson, Lee; Van, Richard; Shao, Yihan; Factor, Stewart; Zhang, Ming-Rong; Liang, Steven H.

doi:10.1021/acs.jmedchem.3c01687.s001

jm3c01687_si_001.pdf (1 MB)

Preclinical Evaluation of Novel Positron Emission Tomography (PET) Probes for Imaging Leucine-Rich Repeat Kinase 2 (LRRK2)

journal contribution

posted on 2024-02-02, 13:06 authored by Zhen Chen, Jiahui Chen, Wakana Mori, Yongjia Yi, Jian Rong, Yinlong Li, Erick R. Calderon Leon, Tuo Shao, Zhendong Song, Tomoteru Yamasaki, Hideki Ishii, Yiding Zhang, Tomomi Kokufuta, Kuan Hu, Lin Xie, Lee Josephson, Richard Van, Yihan Shao, Stewart Factor, Ming-Rong Zhang, Steven H. Liang

Parkinson’s disease (PD) is one of the most highly debilitating neurodegenerative disorders, which affects millions of people worldwide, and leucine-rich repeat kinase 2 (LRRK2) mutations have been involved in the pathogenesis of PD. Developing a potent LRRK2 positron emission tomography (PET) tracer would allow for in vivo visualization of LRRK2 distribution and expression in PD patients. In this work, we present the facile synthesis of two potent and selective LRRK2 radioligands [¹¹C]3 ([¹¹C]PF-06447475) and [¹⁸F]4 ([¹⁸F]PF-06455943). Both radioligands exhibited favorable brain uptake and specific bindings in rodent autoradiography and PET imaging studies. More importantly, [¹⁸F]4 demonstrated significantly higher brain uptake in the transgenic LRRK2-G2019S mutant and lipopolysaccharide (LPS)-injected mouse models. This work may serve as a roadmap for the future design of potent LRRK2 PET tracers.