microPET Imaging of Tau Pathology with [18F]-THK5117 in two Transgenic Mouse Models

Abnormal accumulation of tau aggregates in brain is one of the hallmarks of Alzheimer's disease neuropathology. We visualized tau deposition in vivo with the previously developed 2-arylquinoline derivative ¹⁸F-THK5117 using small animal positron-emission-tomography (µPET) in conjunction with autoradiography and immunohistochemistry gold standard assessment in two transgenic mouse models expressing hyperphosphorylated tau. µPET recordings were obtained in groups of P301S (N = 11) and biGT mice (N = 16) of different ages, with age-matched wild-type (WT) serving as controls. After i.v. administration of 16±2 MBq ¹⁸F-THK5117, a dynamic 90 min emission recording was initiated for P301S mice and during 20-50 min p.i. for biGT mice, followed by a 15 min transmission scan (Siemens Inveon DPET). After co-registration to the MRI atlas and scaling to the cerebellum, we performed volume-of-interest based analysis (standard-uptake-value-ratio, SUVR) and statistical parametric mapping (SPM). µPET results were compared with autoradiography ex vivo and in vitro, and further validated with AT8 staining for neurofibrillary tangles. SUVRs calculated from static recordings during the interval of 20–50 min after tracer injection correlated highly with estimates of BPND based on the entire dynamic emission recordings (R=0.85). SUVR increases were detected in brainstem of aged P301S mice (+11%; p<0.001), and in entorhinal/amygdaloidal areas (+15%; p<0.001) of biGT mice when compared to WT, whereas aged WT mice did not show increased tracer uptake. Immunohistochemical tau loads correlated with µPET-SUVR for both P301S (R=0.8; p<0.001) and biGT (R=0.7; p<0.001) mice, and distribution patterns of AT8 positive neurons matched voxel-wise SPM analysis. Saturable binding of the tracer was verified by autoradiographic blocking studies. In the first dedicated µPET study in two different transgenic tauopathy mouse models using the novel tau tracer ¹⁸F-THK5117, the temporal and spatial progression could be visualized in good correlation with gold standard assessments of tau accumulation. Serial µPET method could afford the means for preclinical testing of novel therapeutic approaches by accommodating inter-animal variability at baseline, while detection thresholds in young animals have to be considered.

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