Quantitative Analysis of 18 F-PF-06684511, a Novel PET Radioligand for Selective β-secretase 1 Imaging, in Non-human Primate Brain.

Beta-secretase 1 (BACE1) is a key enzyme in the generation of beta-amyloid, which is accumulated in the brain of Alzheimer's disease (AD) 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 non-human primate (NHP) PET study utilizing 18 F-PF-06684511. In this effort, we aimed to quantitatively evaluate the regional brain distribution of 18 F-PF-06684511 in NHPs under baseline and blocking conditions as well as assess the target occupancy of BACE1 inhibitors. In addition, NHP whole body PET measurements were performed to estimate the effective radiation dose. Methods: Initial brain PET measurements were performed at baseline and after oral administration of 5 mg/kg of LY2886721, a BACE1 inhibitor, in two 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 18 F-PF-06684511 was estimated based on the whole body PET measurements in NHPs. Results: Radiolabeling was accomplished successfully with an incorporation radiochemical yield of 4-12% (decay corrected) from fluorine-18 ion. The radiochemical purity was greater than 99%. The whole brain uptake of 18 F-PF-06684511 reached peak (approximately 220%SUV) at approximately 20 minutes and decreased thereafter (approximately 100%SUV at 180 minutes). Two-tissue compartment model described the time activity curves well. Pre-treatment with LY2886721 reduced the total distribution volume of 18 F-PF-06684511 by 48 - 80% depending on the brain region, confirming its in vivo specificity. BACE1 occupancy of PF-06663195, estimated using Lassen occupancy plot, showed a dose-dependent increase. The effective dose of 18 F-PF-06684511 was 0.043 mSv/MBq for humans. Conclusion: 18 F-PF-06684511 is the first successful PET radioligand for BACE1 brain imaging that demonstrates favorable in vivo binding and brain kinetics in NHPs.