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

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Preclinical Evaluation of Novel Positron Emission Tomography (PET) Probes for Imaging Leucine-Rich Repeat Kinase 2 (LRRK2)
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-02-02 , DOI: 10.1021/acs.jmedchem.3c01687
Zhen Chen _{1,

2} , Jiahui Chen _{2,

3} , Wakana Mori ₄ , Yongjia Yi ₁ , Jian Rong _{2,

3} , Yinlong Li _{2,

3} , Erick R Calderon Leon ₅ , Tuo Shao ₂ , Zhendong Song ₃ , Tomoteru Yamasaki ₄ , Hideki Ishii ₄ , Yiding Zhang ₄ , Tomomi Kokufuta ₄ , Kuan Hu ₄ , Lin Xie ₄ , Lee Josephson ₂ , Richard Van ₅ , Yihan Shao ₅ , Stewart Factor ₆ , Ming-Rong Zhang ₄ , Steven H Liang _{2,

3}

Affiliation

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.

中文翻译：

用于富含亮氨酸的重复激酶 2 （LRRK2）成像的新型正电子发射断层扫描（PET）探针的临床前评价

帕金森病（PD）是最容易使人衰弱的神经退行性疾病之一，影响着全球数百万人，富含亮氨酸的重复激酶 2 （LRRK2）突变参与了 PD 的发病机制。开发有效的 LRRK2 正电子发射断层扫描（PET）示踪剂将允许 PD 患者 LRRK2 分布和表达的体内可视化。在这项工作中，我们介绍了两种有效且选择性的 LRRK2 放射性配体 [¹¹C]3 （[¹¹C]PF-06447475）和 [¹⁸F]4 （[¹⁸F]PF-06455943）的简单合成。两种放射性配体在啮齿动物放射自显影和 PET 成像研究中均表现出良好的脑摄取和特异性结合。更重要的是，[¹⁸F]4 在转基因 LRRK2-G2019S 突变体和脂多糖（LPS）注射小鼠模型中显示出显着更高的脑摄取。这项工作可作为未来设计强效 LRRK2 PET 示踪剂的路线图。

更新日期：2024-02-02

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