Imaging Leucine-Rich Repeat Kinase 2 In Vivo with <sup>18</sup>F-Labeled Positron Emission Tomography Ligand
Zhen Chen, Jiahui Chen, Laigao Chen, Chi‐Hyeon Yoo, Jian Rong, Hualong Fu, Tuo Shao, Karen J. Coffman, Stefanus J. Steyn, April T. Davenport, James B. Daunais, Ahmed Haider, Lee Collier, Lee Josephson, Hsiao‐Ying Wey, Lei Zhang, Steven H. Liang
Abstract
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.