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Positron-emission-tomography (PET) imaging of tau pathology has facilitated development of anti-tau therapies. While members of the arylquinoline and pyridoindole families have been the most frequently used tau radioligands so far, analyses of their comparative performance  in vivo  are scantly documented. Here, we conducted a head-to-head PET comparison of the arylquinoline  18 FT807 and the pyridoindole  18 FTHK5117 PET in a mouse model of tau pathology. PET recordings were obtained in groups of ( N  = 5–7) P301S and wild-type (WT) mice at 6 and 9 months of age. Volume-of-interest based analysis (standard-uptake-value ratio, SUVR) was used to calculate effect sizes (Cohen’s  d ) for each tracer and age. Statistical parametric mapping (SPM) was used to assess regional similarity (dice coefficient) of tracer binding alterations for the two tracers. Immunohistochemistry staining of neurofibrillary tangles was performed for validation  ex vivo . Significantly elevated  18 F-T807 binding in the brainstem of P301S mice was already evident at 6 months (+14%,  p  < 0.01,  d  = 1.64), and increased further at 9 months (+23%,  p  < 0.001,  d  = 2.70).  18 F-THK5117 indicated weaker increases and effect sizes at 6 months (+5%,  p  < 0.05,  d  = 1.07) and 9 months (+10%,  p  < 0.001,  d  = 1.49). Regional similarity of binding of the two tracers was high (71%) at 9 months.  18 F-T807 was more sensitive than  18 F-THK5117 to tau pathology in this model, although both tracers present certain obstacles, which need to be considered in the design of longitudinal preclinical tau imaging studies.

Comparison of 18F-T807 and 18F-THK5117 PET in a Mouse Model of Tau Pathology