title: Radiosynthesis, photoisomerization, biodistribution, and metabolite analysis of 11C-PBB3 as a clinically useful PET probe for imaging of tau pathology.
abstract: 2-((1E,3E)-4-(6-((11)C-methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol ((11)C-PBB3) is a clinically useful PET probe that we developed for in vivo imaging of tau pathology in the human brain. To ensure the availability of this probe among multiple PET facilities, in the present study we established protocols for the radiosynthesis and quality control of (11)C-PBB3 and for the characterization of its photoisomerization, biodistribution, and metabolism.
  
  
  METHODS
  (11)C-PBB3 was synthesized by reaction of the tert-butyldimethylsilyl desmethyl precursor ( 1: ) with (11)C-methyl iodide using potassium hydroxide as a base, followed by deprotection. Photoisomerization of (11)C-PBB3 under fluorescent light was determined. The biodistribution and metabolite analysis of (11)C-PBB3 was determined in mice using the dissection method.
  
  
  RESULTS
  (11)C-PBB3 was synthesized with 15.4% ± 2.8% radiochemical yield (decay-corrected, n = 50) based on the cyclotron-produced (11)C-CO2 and showed an averaged synthesis time of 35 min from the end of bombardment. The radiochemical purity and specific activity of (11)C-PBB3 were 98.0% ± 2.3% and 180.2 ± 44.3 GBq/μmol, respectively, at the end of synthesis (n = 50). (11)C-PBB3 showed rapid photoisomerization, and its radiochemical purity decreased to approximately 50% at 10 min after exposure to fluorescent light. After the fluorescent light was switched off, (11)C-PBB3 retained more than 95% radiochemical purity over 60 min. A suitable brain uptake (1.92% injected dose/g tissue) of radioactivity was observed at 1 min after the probe injection, which was followed by rapid washout from the brain tissue. More than 70% of total radioactivity in the mouse brain homogenate at 5 min after injection represented the unchanged (11)C-PBB3, despite its rapid metabolism in the plasma.
  
  
  CONCLUSIONS
  (11)C-PBB3 was produced with sufficient radioactivity and high quality, demonstrating its clinical utility. The present results of radiosynthesis, photoisomerization, biodistribution, and metabolite analysis could be helpful for the reliable production and application of (11)C-PBB3 in diverse PET facilities.
authors: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors: Hiroki
authors: H
authors: Hashimoto
authors: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors: Kazunori
authors: K
authors: Kawamura
authors: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan Tokyo Nuclear Services Co., Ltd., Tokyo, Japan; and.
authors: Nobuyuki
authors: N
authors: Igarashi
authors: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan Tokyo Nuclear Services Co., Ltd., Tokyo, Japan; and.
authors: Makoto
authors: M
authors: Takei
authors: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan Tokyo Nuclear Services Co., Ltd., Tokyo, Japan; and.
authors: Tomoya
authors: T
authors: Fujishiro
authors: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan Tokyo Nuclear Services Co., Ltd., Tokyo, Japan; and.
authors: Yoshiharu
authors: Y
authors: Aihara
authors: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan Tokyo Nuclear Services Co., Ltd., Tokyo, Japan; and.
authors: Satoshi
authors: S
authors: Shiomi
authors: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan Tokyo Nuclear Services Co., Ltd., Tokyo, Japan; and.
authors: Masatoshi
authors: M
authors: Muto
authors: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan SHI Accelerator Service Ltd., Tokyo, Japan.
authors: Takehito
authors: T
authors: Ito
authors: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan SHI Accelerator Service Ltd., Tokyo, Japan.
authors: Kenji
authors: K
authors: Furutsuka
authors: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors: Tomoteru
authors: T
authors: Yamasaki
authors: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors: Joji
authors: J
authors: Yui
authors: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors: Lin
authors: L
authors: Xie
authors: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors: Maiko
authors: M
authors: Ono
authors: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors: Akiko
authors: A
authors: Hatori
authors: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors: Kazuyoshi
authors: K
authors: Nemoto
authors: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors: Tetsuya
authors: T
authors: Suhara
authors: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors: Makoto
authors: M
authors: Higuchi
authors: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan zhang@nirs.go.jp.
authors: Ming-Rong
authors: MR
authors: Zhang
mesh_terms: D000544:Alzheimer Disease / Q000175:diagnosis*; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000378:metabolism; D000818:Animals; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002250:Carbon Radioisotopes; D006801:Humans; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D011786:Quality Control; D011854:Radiochemistry; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000378:metabolism; D014018:Tissue Distribution; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C000592806:2-(4-(6-(methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo(d)thiazol-6-ol; D000631:Aminopyridines; D052160:Benzothiazoles; D002250:Carbon Radioisotopes; C000619442:PBB3 compound; D019275:Radiopharmaceuticals; D016875:tau Proteins
keywords: 11C-PBB3; Alzheimer disease; PET; photoisomerization; tau pathology