Characterization of 18F-PM-PBB3 (18F-APN-1607) Uptake in the rTg4510 Mouse Model of Tauopathy

Abstract

Misfolding, aggregation, and cerebral accumulation of tau deposits are hallmark features of Alzheimer’s disease. Positron emission tomography study of tau can facilitate the development of anti-tau treatment. Here, we investigated a novel tau tracer 18F-PM-PBB3 (18F-APN-1607) in a mouse model of tauopathy. Dynamic PET scans were collected in groups of rTg4510 transgenic mice at 2–11 months of age. Associations between distribution volume ratios (DVR) and standardized uptake value ratios (SUVR) with cerebellum reference were used to determine the optimal scanning time and uptake pattern for each age. Immunohistochemistry staining of neurofibrillary tangles and autoradiography study was performed for ex vivo validation. An SUVR 40–70 min was most consistently correlated with DVR and was used in further analyses. Significant increased 18F-PM-PBB3 uptake in the brain cortex was found in six-month-old mice (+28.9%, p < 0.05), and increased further in the nine-month-old group (+38.8%, p < 0.01). The trend of increased SUVR value remained evident in the hippocampus and striatum regions except for cortex where uptake becomes slightly reduced in 11-month-old animals (+37.3%, p < 0.05). Radioactivity distributions from autoradiography correlate well to the presence of human tau (HT7 antibody) and hyperphosphorylated tau (antibody AT8) from the immunohistochemistry study of the adjacent brain sections. These findings supported that the 40–70 min 18F-PM-PBB3 PET scan with SUVR measurement can detect significantly increased tau deposits in a living rTg4510 transgenic mouse models as early as six-months-old. The result exhibited promising dynamic imaging capability of this novel tau tracer, and the above image characteristics should be considered in the design of longitudinal preclinical tau image studies.

An App knock-in rat model for Alzheimer’s disease exhibiting Aβ and tau pathologies, neuronal death and cognitive impairments

“…We also used APN-1607 (also known as PM-PBB3), a PET tracer known to fluorescently label various aggregates tau species but not monomeric tau. 54,55 We found significant fluorescence labeling in the CA1 region of 22month-old App NL-G-F rat brain, similar to that in 3× Tg-AD mice (positive control) (Fig. 2j).…”

18F-THK5351 PET imaging in patients with progressive supranuclear palsy: associations with core domains and diagnostic certainty

“…However, interpretation of PET results obtained with first-generation tau tracers can be made difficult by off-target tracer binding to neuromelanin and/or hemorrhagic lesions, as well as by the use of MAOI 23 , 38 . Although 18 F-THK5351 PET and MR images were carefully matched, our results should be interpreted cautiously and require confirmation in future independent studies using second-generation tau ligands—including MK-6240, 18 F-JNJ64349311, and 18 F-APN1607 39 , 40 .…”

Positron Emission Tomography in Animal Models of Tauopathies

“…Thus, the second-generation [ 18 F]PM-PBB3 with improved binding properties was developed to overcome the limitations. Similar observations were reported by Tagai et al (2020) and Weng et al (2020) using [ 18 F]PM-PBB3 in rTg4510 mouse models with increased tracer retention in the cortical and hippocampal regions. Among the other second-generation tau tracers, [ 18 F]JNJ-64349311 ( Declercq et al, 2017 ) and [ 18 F]PI-6240 ( Kroth et al, 2019 ) have so far been reported in wild-type mice for brain uptake and biodistribution assessment.…”