P2‐392: Characterisation of [18F]‐THK523, a Novel in Vivo Tau Imaging Ligand

Neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal lobe degeneration (FTLD) are characterized by the pathological accumulation of tau. Tau accumulation is recognized histologically as intraneuronal neurofibrillary tangles (NFTs), neuropil threads and in the case of AD, as dystrophic neurites surrounding amyloid-β (Aβ) plaques. Unlike Aβ imaging, no tau imaging agent is available for clinical studies. In vivo imaging of tau pathology by positron emission tomography (PET) will allow new insights into tau deposition in the human brain, facilitating research into causes, diagnosis and treatment monitoring of AD and FTLD. In this study we characterized [18F]-THK523, developed at Tohoku University, Japan, as a novel tau imaging agent. In vitro [18F]-THK523 saturation studies were conducted using K18Δ280-tau fibrils; with non-specific binding established with THK523 (1μM). Human AD hippocampal serial sections were analysed by immunohistochemistry and fluorescence microscopy and [18F]-THK523 microPET studies were undertaken in tau transgenic (rTg4510) mice (n = 8) and wildtype littermates (n = 8). In vitro binding assays indicated that there are two [18F]-THK523 high affinity binding sites on K18Δ280-tau fibrils (KD1'KD2 = 1.67, 21.74nM; Bmax1, Bmax2 = 2.20, 4.46pmol [18F]-THK523/nmol fibrils). Furthermore, THK523 bound to NFTs, with negligible binding to Aβ plaques in AD brain sections. MicroPET studies demonstrated that brain radioactivity peaked at 5 min post injection (2.4% injected dose) and the binding appeared to be reversible with slower washout from rTg4510 mice than from wildtype mice. At 30 min after injection, significantly higher brain retention of [18F]-THK523 (48%; p < 0.007) was observed in rTg4510 mice compared to wildtype littermates, while there were no significant differences on the other organs examined. This study has demonstrated that [18F]-THK523 satisfies a number of criteria making it a viable tau neuroimaging agent for human PET studies.