Radiosynthesis, photoisomerization, biodistribution, and metabolite analysis of ¹¹C-PBB3 as a clinically useful PET probe for imaging of tau pathology

2-((1E,3E)-4-(6-(¹¹C-methylamino)pyridin-3-yl)buta-1,3-dienyl) benzo[d]thiazol-6-ol (¹¹C-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 ¹¹C-PBB3 and for the characterization of its photoisomerization, biodistribution, and metabolism. Methods: ¹¹C-PBB3 was synthesized by reaction of the tert-butyldimethylsilyl desmethyl precursor (1) with ¹¹C-methyl iodide using potassium hydroxide as a base, followed by deprotection. Photoisomerization of ¹¹C-PBB3 under fluorescent light was determined. The biodistribution and metabolite analysis of ¹¹C-PBB3 was determined in mice using the dissection method. Results: ¹¹C-PBB3 was synthesized with 15.4% ± 2.8% radiochemical yield (decay-corrected, n = 50) based on the cyclotron-produced ¹¹C-CO₂and showed an averaged synthesis time of 35 min from the end of bombardment. The radiochemical purity and specific activity of ¹¹C-PBB3 were 98.0% ± 2.3% and 180.2 ± 44.3 GBq/μmol, respectively, at the end of synthesis (n = 50). ¹¹C-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, ¹¹C-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 ¹¹C-PBB3, despite its rapid metabolism in the plasma. Conclusion: ¹¹C-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 ¹¹C-PBB3 in diverse PET facilities.