Quantitative Analysis of F-PF-06684511, a Novel PET Radioligand for Selective β-Secretase 1 Imaging, in Nonhuman Primate Brain.

β-secretase 1 (BACE1) is a key enzyme in the generation of β-amyloid, which is accumulated in the brain of Alzheimer disease patients. PF-06684511 was identified as a candidate PET ligand for imaging BACE1 in the brain and showed high specific binding in an initial assessment in a nonhuman primate (NHP) PET study using F-PF-06684511. In this effort, we aimed to quantitatively evaluate the regional brain distribution of F-PF-06684511 in NHPs under baseline and blocking conditions and to assess the target occupancy of BACE1 inhibitors. In addition, NHP whole-body PET measurements were performed to estimate the effective radiation dose. Initial brain PET measurements were performed at baseline and after oral administration of 5 mg/kg of LY2886721, a BACE1 inhibitor, in 2 cynomolgus monkeys. Kinetic analysis was performed with the radiometabolite-corrected plasma input function. In addition, a wide dose range of another BACE1 inhibitor, PF-06663195, was examined to investigate the relationship between the brain target occupancy and plasma concentration of the drug. Finally, the effective radiation dose of F-PF-06684511 was estimated on the basis of the whole-body PET measurements in NHPs. Radiolabeling was accomplished successfully with an incorporation radiochemical yield of 4%-12% (decay-corrected) from F ion. The radiochemical purity was greater than 99%. The whole-brain uptake of F-PF-06684511 peaked (∼220% SUV) at approximately 20 min and decreased thereafter (∼100% SUV at 180 min). A 2-tissue-compartment model described the time-activity curves well. Pretreatment with LY2886721 reduced the total distribution volume of F-PF-06684511 by 48%-80% depending on the brain region, confirming its in vivo specificity. BACE1 occupancy of PF-06663195, estimated using the Lassen occupancy plot, showed a dose-dependent increase. The effective dose of F-PF-06684511 was 0.043 mSv/MBq for humans. F-PF-06684511 is the first successful PET radioligand for BACE1 brain imaging that demonstrates favorable in vivo binding and brain kinetics in NHPs.