Evaluation of [18F]PF-06455943 as a Potential LRRK2 PET Imaging Agent in the Brain of Nonhuman Primates

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 (VT) 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 VT displacement in the whole brain. This work supports the translation of [18F]PF-06455943 PET imaging for the human brain and target occupancy studies.

Automated summary

This study evaluated the methods of PET quantification for [18F]PF-06455943, a radioligand for LRRK2 imaging. The results showed that a two-tissue compartmental model and a Logan graphical analysis were appropriate for PET quantification. Additionally, it was found that total distribution volume (VT) values could 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 VT displacement in the whole brain. This work supports the translation of [18F]PF-06455943 PET imaging for the human brain and target occupancy studies.