Abstract
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Objectives Definitive diagnosis of Alzheimer’s disease (AD) and non-AD tauopathies still relies on post-mortem examination. These diseases are often difficult to differentiate clinically due to overlapping phenotypes, especially at early stages. In vivo imaging with PET will allow new insights into tau deposition, facilitating research into causes, diagnosis and treatment of taupathies. We have characterized 18F-THK523 (THK523), a novel tau imaging ligand developed at Tohoku University in Sendai, Japan, assessing its selectivity and specificity for tau pathology both in vitro and in vivo.
Methods Preclincal evaluation included in vitro binding studies with recombinant tau and Aβ fibrils, autoradiographic (ARD) and histofluorescence (HF) analysis of human AD hippocampal brain sections, and in vivo microPET studies in tau an APP/PS1 transgenic mice. To date, 9 human participants underwent both THK523 and PiB PET studies.
Results THK523 binds with higher affinity to recombinant tau compared with Aβ fibrils. ARG and HF analysis of human hippocampal sections demonstrated THK523 co-localized with immunoreactive tau pathology, but failed to highlight Aβ plaques. MicroPET studies revealed higher brain retention of THK523 in tau transgenic mice compared with their wild-type littermates or APP/PS1 mice. Initial human PET studies comparing THK523 and PiB have shown that THK523 does not bind to Aβ in AD. Despite a higher THK523 cortical retention in AD, there were no distinctive visual features in the THK523 PET scans between AD, healthy controls and Semantic Dementia patients.
Conclusions Preliminary PET human studies suggest that despite fulfilling preclinical ligand criteria for tau, the signal to noise ratio from THK523 is not sufficient to distinguish clinical groups by visual inspection. Further studies are needed to confirm these initial findings.
Research Support Supported in part by ADDF Research Grant (20101208 AFTD) and by the New Energy and Industrial Technology Development Organization of Japan