PET imaging of tau pathology in a transgenic mouse model using [18F]THK-5117

Objectives Abnormal accumulation of tau aggregates in brain is one of the hallmarks of Alzheimer’s disease (AD). To visualize the tau deposition by PET, a previously developed 2-arylquinoline derivative [18F]THK-5117 showed excellent brain kinetics in the normal mouse brain and high binding affinities for synthetic tau fibrils as well as for postmortem brain homogenates from AD patients. In this study, we intended to evaluate the radioligand in an established tau mouse model using microPET in combination with autoradiography and histopathology.

Methods A total of 18 microPET scans were performed using five P301S (5mo: N=2 / 11mo: N=3) mice (TG) and seven C57Bl/6 (WT) age-matched littermates. After i.v. application of 18 ± 3 MBq [18F]THK-5117 a dynamic 90 min emission recording was initiated followed by a 15 min transmission scan using the Siemens Inveon DPET. A static rescan (25-50 min) within a week was performed in order to investigate test-retest variability. After coregistration to an MRI atlas and cerebellar scaling, a VOI-based analysis was performed. At termination of the PET study, autoradiography as well as histopathological analyses were conducted in one hemisphere each.

Results Based on time-activity curves of the full dynamic data range 25-50 min emerged to be robust for the calculation of standardized uptake value ratios (SUVR). Test-retest analyses revealed excellent agreement (r=0.8). Significant group differences were detected in aged TG mice (1.27 ± 0.03) compared to young TG (1.02 ± 0.05; p<0.01) and WT animals (0.98 ± 0.04; p<0.001) when using a brainstem VOI. Corresponding findings could be detected in autoradiographic analyses.

Conclusions [18F]THK-5117 is a promising PET tracer for imaging of tau pathology in AD. Age-related effects could be successfully imaged in vivo, enabling PET-monitored treatment studies in the future.