Ryuichi Harada1, Nobuyuki Okamura2, Shozo Furumoto3, Katsutoshi Furukawa4, Aiko Ishiki4, Naoki Tomita4, Tetsuro Tago3, Kotaro Hiraoka5, Shoichi Watanuki5, Miho Shidahara6, Masayasu Miyake5, Yoichi Ishikawa3, Rin Matsuda5, Akie Inami5, Takeo Yoshikawa7, Yoshihito Funaki3, Ren Iwata3, Manabu Tashiro5, Kazuhiko Yanai7, Hiroyuki Arai4, Yukitsuka Kudo8. 1. Division of Neuro-imaging, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan. 2. Division of Neuro-imaging, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan Division of Cyclotron Nuclear Medicine, Cyclotron and Radioisotope Center, Tohoku University, Sendai, Japan nookamura@med.tohoku.ac.jp. 3. Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope Center, Tohoku University, Sendai, Japan. 4. Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan; and. 5. Division of Cyclotron Nuclear Medicine, Cyclotron and Radioisotope Center, Tohoku University, Sendai, Japan. 6. Division of Cyclotron Nuclear Medicine, Cyclotron and Radioisotope Center, Tohoku University, Sendai, Japan Division of Medical Physics, Tohoku University School of Medicine, Sendai, Japan. 7. Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan. 8. Division of Neuro-imaging, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope Center, Tohoku University, Sendai, Japan.
Abstract
UNLABELLED: 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. METHODS: 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. RESULTS: (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. CONCLUSION: (18)F-THK5351 is a useful PET tracer for the early detection of neurofibrillary pathology in AD patients.
UNLABELLED: 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. METHODS: 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. RESULTS: (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 ADpatients, (18)F-THK5351 demonstrated faster kinetics, higher contrast, and lower retention in subcortical white matter than(18)F-THK5117. CONCLUSION: (18)F-THK5351 is a useful PET tracer for the early detection of neurofibrillary pathology in ADpatients.
Authors: Dustin W Wooten; Nicolas J Guehl; Eline E Verwer; Timothy M Shoup; Daniel L Yokell; Nevena Zubcevik; Neil Vasdev; Ross D Zafonte; Keith A Johnson; Georges El Fakhri; Marc D Normandin Journal: J Nucl Med Date: 2016-09-22 Impact factor: 10.057