Quantitative Analysis of 18F-PF-06684511, a Novel PET Radioligand for Selective β-Secretase 1 Imaging, in Nonhuman Primate Brain

• Published in: The Journal of nuclear medicine (1978) Vol. 60; no. 7; pp. 992 - 997
• Main Authors: Takano, Akihiro, Chen, Laigao, Nag, Sangram, Brodney, Michael A, Arakawa, Ryosuke, Chang, Cheng, Amini, Nahid, Doran, Shawn D, Dutra, Jason K, McCarthy, Timothy J, Nolan, Charles E, O'Neill, Brian T, Villalobos, Anabella, Zhang, Lei, Halldin, Christer
• Format: Journal Article
• Language: English
• Published: New York Society of Nuclear Medicine 01.07.2019
• Subjects: Alzheimer's disease; Binding; Brain; Fluorine isotopes; Inhibitors; Kinetics; Measurement methods; Medical imaging; Medicin och hälsovetenskap; Monkeys; Neurodegenerative diseases; Neuroimaging; Occupancy; Oral administration; Positron emission; Positron emission tomography; Quantitative analysis; Radiation; Radiation dosage; Radiochemical analysis; Radiolabelling; Regional analysis; Secretase; Tomography; β-Amyloid; β-Site APP-cleaving enzyme 1
• ISSN: 0161-5505; 1535-5667; 1535-5667
• DOI: 10.2967/jnumed.118.217372

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 18F-PF-06684511. In this effort, we aimed to quantitatively evaluate the regional brain distribution of 18F-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. Methods: 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 18F-PF-06684511 was estimated on the basis of the whole-body PET measurements in NHPs. Results: Radiolabeling was accomplished successfully with an incorporation radiochemical yield of 4%–12% (decay-corrected) from 18F ion. The radiochemical purity was greater than 99%. The whole-brain uptake of 18F-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 18F-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 18F-PF-06684511 was 0.043 mSv/MBq for humans. Conclusion: 18F-PF-06684511 is the first successful PET radioligand for BACE1 brain imaging that demonstrates favorable in vivo binding and brain kinetics in NHPs.