Imaging Leucine-Rich Repeat Kinase 2 In Vivo with 18F‑Labeled Positron Emission Tomography Ligand

• Published in: Journal of medicinal chemistry Vol. 66; no. 3; pp. 1712 - 1724
• Main Authors: Chen, Zhen, Chen, Jiahui, Chen, Laigao, Yoo, Chi-Hyeon, Rong, Jian, Fu, Hualong, Shao, Tuo, Coffman, Karen, Steyn, Stefanus J., Davenport, April T., Daunais, James B., Haider, Ahmed, Collier, Lee, Josephson, Lee, Wey, Hsiao-Ying, Zhang, Lei, Liang, Steven H.
• Format: Journal Article
• Language: English
• Published: American Chemical Society 09-02-2023
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.2c00551

Leucine-rich repeat kinase 2 (LRRK2) has been demonstrated to be closely involved in the pathogenesis of Parkinson’s disease (PD), and pharmacological blockade of LRRK2 represents a new opportunity for therapeutical treatment of PD and other related neurodegenerative conditions. The development of an LRRK2-specific positron emission tomography (PET) ligand would enable a target occupancy study in vivo and greatly facilitate LRRK2 drug discovery and clinical translation as well as provide a molecular imaging tool for studying physiopathological changes in neurodegenerative diseases. In this work, we present the design and development of compound 8 (PF-06455943) as a promising PET radioligand through a PET-specific structure–activity relationship optimization, followed by comprehensive pharmacology and ADME/neuroPK characterization. Following an efficient 18F-labeling method, we have confirmed high brain penetration of [18F]8 in nonhuman primates (NHPs) and validated its specific binding in vitro by autoradiography in postmortem NHP brain tissues and in vivo by PET imaging studies.