Preclinical Evaluation of Novel Positron Emission Tomography (PET) Probes for Imaging Leucine-Rich Repeat Kinase 2 (LRRK2).
Zhen ChenJiahui ChenWakana MoriYongjia YiJian RongYinlong LiErick R Calderon LeonTuo ShaoZhendong SongTomoteru YamasakiHideki IshiiYiding ZhangTomomi KokufutaKuan HuLin XieLee JosephsonRichard VanYihan ShaoStewart FactorMing-Rong ZhangSteven H LiangPublished in: Journal of medicinal chemistry (2024)
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 [ 11 C] 3 ([ 11 C]PF-06447475) and [ 18 F] 4 ([ 18 F]PF-06455943). Both radioligands exhibited favorable brain uptake and specific bindings in rodent autoradiography and PET imaging studies. More importantly, [ 18 F] 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.
Keyphrases
- positron emission tomography
- pet imaging
- computed tomography
- pet ct
- anti inflammatory
- end stage renal disease
- poor prognosis
- ejection fraction
- resting state
- mouse model
- chronic kidney disease
- toll like receptor
- white matter
- stem cells
- prognostic factors
- immune response
- protein kinase
- living cells
- multiple sclerosis
- current status
- bone marrow
- patient reported
- photodynamic therapy