PF-06455943

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.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the common causes of inherited Parkinson's disease (PD) and emerged as a causative PD gene. Particularly, LRRK2-Gly2019Ser mutation was reported to alter the early phase of neuronal differentiation, increasing cell death. Selective inhibitors of LRRK2 kinase activity were considered as a promising therapeutic target for PD treatment. However, the development of effective brain-penetrant LRRK2 inhibitors remains challenging. Recently, we have developed a novel positron emission tomography (PET) radioligand for LRRK2 imaging and demonstrated preferable tracer properties in rodents. Herein, we evaluate [¹⁸F]PF-06455943 quantification methods in the nonhuman primate (NHP) brain using full kinetic modeling with radiometabolite-corrected arterial blood samples, and homologous blocking with two doses (0.1 and 0.3 mg/kg). Kinetic analysis results demonstrated that a two-tissue compartmental model and a Logan graphical analysis are appropriate for [¹⁸F]PF-06455943 PET quantification. In addition, we observed that total distribution volume (V_T) values can be reliably estimated with as short as a 30 min scan duration. Homologous blocking studies confirmed the specific binding of [¹⁸F]PF-06455943 and revealed that the nonradioactive mass of PF-06455943 achieved 45-55% of V_T displacement in the whole brain. This work supports the translation of [¹⁸F]PF-06455943 PET imaging for the human brain and target occupancy studies.