Synthesis and biological evaluation of F-18 labeled tetrahydroisoquinoline derivatives targeting orexin 1 receptor |
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| Institution: | 1. Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan;2. Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan;1. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia;2. Department of Chemistry, College of Science and Humanities, Prince Sattam bin Abdulaziz University, PO Box 83, Al Kharj 11942, Saudi Arabia;3. Chemistry of Natural Products Group, Centre of Excellence for Advanced Sciences, National Research Centre, 33 El-Bohouth St. (Former El-Tahrir St.) Dokki, Cairo 12622, Egypt;1. Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden;2. N.P. Bechtereva Institute of Human Brain Russian Academy of Sciences, St.-Petersburg, Russia;3. Department of Chemistry – Radiochemistry, University of Helsinki, Finland;4. Petersburg Nuclear Physics Institute named after B.P. Konstantinov, NRC “Kurchatov Institute”, Gatchina, Russia;5. Peter the Great St.-Petersburg Polytechnic University, St.-Petersburg, Russia;6. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore;1. Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China;2. Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, 04318 Leipzig, Germany;3. Nuclear Medicine Department, Chinese PLA General Hospital, Beijing 100853, China;4. PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA;1. Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraβe 19, D-91052 Erlangen, Germany;2. Department of Nuclear Medicine, Ulmenweg 18, D-91054 Erlangen, Germany |
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| Abstract: | Orexin 1 receptor (OX1R) is thought to be involved in various body functions, including arousal maintenance and emotional control, but the full details of its function remain unknown. OX1R imaging with positron emission tomography (PET) would be useful in elucidating the orexin system including OX1R, but no PET probes targeting OX1R have been reported. We, therefore, designed and synthesized tetrahydroisoquinoline (THIQ) derivatives as novel PET probes targeting OX1R, and evaluated their utility. In an in vitro competitive binding assay, THIQ-1 and THIQ-2 showed significantly higher binding to OX1R (IC50 = 30 and 31 nM, respectively) than OX2R (IC50 = 160 and 332 nM, respectively). These features were also observed in a cell binding assay using 18F]THIQ-1 and 18F]THIQ-2, demonstrating their OX1R-specific binding property in vitro. In a biodistribution study using normal mice, the brain uptake of 18F]THIQ-1 was higher than that of 18F]THIQ-2, but further improvement is required for in vivo imaging with PET. Taken together, 18F]THIQ-1 and 18F]THIQ-2 have the potential to become useful imaging probes for PET targeting the OX1R, but require additional structural changes to improve their brain uptake. |
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| Keywords: | Orexin 1 receptor PET Tetrahydroisoquinoline |
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