18F-THK5351: A Novel PET Radiotracer for Imaging Neurofibrillary Pathology in Alzheimer Disease

Imaging of neurofibrillary pathology in the brain helps in diagnosing dementia, tracking disease progression, and evaluating the therapeutic efficacy of antidementia drugs. The radiotracers used in this imaging must be highly sensitive and specific for tau protein fibrils in the human brain. We developed a novel tau PET tracer, ¹⁸F-THK5351, through compound optimization of arylquinoline derivatives. Methods: The in vitro binding properties, pharmacokinetics, and safety of ¹⁸F-THK5351 were investigated, and a clinical study on Alzheimer disease (AD) patients was performed. Results:¹⁸F-THK5351 demonstrated higher binding affinity for hippocampal homogenates from AD brains and faster dissociation from white-matter tissue than did ¹⁸F-THK5117. The THK5351 binding amount correlated with the amount of tau deposits in human brain samples. Autoradiography of brain sections revealed that THK5351 bound to neurofibrillary tangles selectively and with a higher signal-to-background ratio than did THK5117. THK5351 exhibited favorable pharmacokinetics and no defluorination in mice. In first-in-human PET studies in AD patients, ¹⁸F-THK5351 demonstrated faster kinetics, higher contrast, and lower retention in subcortical white matter than¹⁸F-THK5117. Conclusion:¹⁸F-THK5351 is a useful PET tracer for the early detection of neurofibrillary pathology in AD patients.