Evaluation of [ 18 F]PF-06455943 as a Potential LRRK2 PET Imaging Agent in the Brain of Nonhuman Primates.
Chi-Hyeon YooZhen ChenNisha RaniJiahui ChenJian RongLaigao ChenLei ZhangSteven H LiangHsiao-Ying WeyPublished in: ACS chemical neuroscience (2023)
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 [ 18 F]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 [ 18 F]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 [ 18 F]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 [ 18 F]PF-06455943 PET imaging for the human brain and target occupancy studies.
Keyphrases
- pet imaging
- positron emission tomography
- computed tomography
- resting state
- white matter
- cell death
- cerebral ischemia
- pet ct
- dna damage
- protein kinase
- magnetic resonance imaging
- genome wide
- copy number
- multiple sclerosis
- high resolution
- mass spectrometry
- cell proliferation
- transcription factor
- tyrosine kinase
- contrast enhanced
- subarachnoid hemorrhage
- oxidative stress
- combination therapy
- data analysis
- case control
- smoking cessation
- fluorescence imaging