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

Abstract

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 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 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 18 F-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 18 F ion. The radiochemical purity was greater than 99%. The whole-brain uptake of 18 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 18 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 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.

PET imaging of beta-secretase 1 in the human brain: radiation dosimetry, quantification, and test-retest examination of [18F]PF-06684511

“…The results from the test-retest study showed that the distribution pattern of [ 18 F]PF-06684511 was similar to the one observed in NHPs, with wide distribution throughout the brain and relatively higher uptake in subcortical regions and relatively lower uptake in the cerebellum [5]. This pattern of distribution is similar to the one previously reported in postmortem human brain tissue [16].…”

“…The results of the dosimetry study showed that the calculated ED of [ 18 [11][12][13]. Contrary to the results obtained in NHPs, there was no evidence of uptake in the gastric lumen, suggesting that the relatively high radiation effective dose (43 μSv/MBq) in the previous NHP study was likely related to experimental conditions or species differences between NHPs and humans [5].…”

“…[ 18 F]PF-06684511 was synthesized as reported previously [4,5]. In brief, an aqueous [ 18 F]fluoride was produced via the 18 O(p,n) 18 F nuclear reaction using a GE Medical Systems PETtrace cyclotron in a silver fluoride-18 water target.…”

“…The PET radioligand [ 18 F]PF-06684511 has been developed for in vivo imaging and quantification of BACE1 [4]. Recently, we showed that [ 18 F]PF-06684511 displays suitable kinetic properties in the brain of non-human primates (NHPs) and also reported a dose-dependent blocking effect on [ 18 F]PF-06684511 brain uptake by BACE1 inhibitors [5]. These data suggested that [ 18 F]PF-06684511 is a promising PET radioligand for brain imaging of BACE1.…”

“…These data suggested that [ 18 F]PF-06684511 is a promising PET radioligand for brain imaging of BACE1. In addition to brain imaging, we also evaluated the whole-body distribution and dosimetry of [ 18 F]PF-06684511 in NHPs [ 5 ]. Remarkably, we found that the effective dose (ED) in humans estimated from NHP data was 43 μSv/MBq, a value that is relatively high compared with the ED of other 18 F radioligands [ 6 ].…”