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

• DOI: 10.2967/jnumed.115.164848
• Publication Date: 2015-11-06T03:08:40Z
• Authors: Ryuichi Harada; Nobuyuki Okamura; Shozo Furumoto; Katsutoshi Furukawa; Aiko Ishiki; Naoki Tomita; Tetsuro Tago; Kotaro Hiraoka; Shoichi Watanuki; Miho Shidahara; Masayasu Miyake; Yoichi Ishikawa; Rin Matsuda; Akie Inami; Takeo Yoshikawa; Yoshihito Funaki; Ren Iwata; Manabu Tashiro; Kazuhiko Yanai; Hiroyuki Arai; Yukitsuka Kudo
• Keywords: Mice, Inbred ICR; Aminopyridines; Brain; Neurofibrillary Tangles; tau Proteins; Radiation Dosage; Hippocampus; Magnetic Resonance Imaging; White Matter; 3. Good health; Mice; 03 medical and health sciences; 0302 clinical medicine; Alzheimer Disease; Positron-Emission Tomography; Quinolines; Animals; Autoradiography; Tissue Distribution; Radiopharmaceuticals; Biotransformation

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, (18)F-THK5351, through compound optimization of arylquinoline derivatives.The in vitro binding properties, pharmacokinetics, and safety of (18)F-THK5351 were investigated, and a clinical study on Alzheimer disease (AD) patients was performed.(18)F-THK5351 demonstrated higher binding affinity for hippocampal homogenates from AD brains and faster dissociation from white-matter tissue than did (18)F-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, (18)F-THK5351 demonstrated faster kinetics, higher contrast, and lower retention in subcortical white matter than(18)F-THK5117.(18)F-THK5351 is a useful PET tracer for the early detection of neurofibrillary pathology in AD patients.