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

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.

Automated summary

In this study, a promising PET radioligand compound 8 was designed and developed through PET-specific structure-activity relationship optimization. The comprehensive pharmacology and ADME/neuroPK characterization confirmed the high brain penetration of [18F]8 in nonhuman primates, and its specific binding was validated through autoradiography in postmortem NHP brain tissues and PET imaging studies in vivo.