Development of [¹¹C]/[³H]THK-5351 - A potential novel carbon-11 tau imaging PET radioligand

Due to the rise in the number of patients with dementia the imperative for finding new diagnostic and treatment options becomes ever more pressing. While significant progress has been made in PET imaging of Aβ aggregates both in vitro and in vivo, options for imaging tau protein aggregates selectively are still limited. Based on the work previously published by researchers from the Tohoku University, Japan, that resulted in the development of [¹⁸F]THK-5351, we have undertaken an effort to develop a carbon-11 version of the identical structure - [¹¹C]THK-5351. In parallel, THK-5351 was also labeled with tritium ([³H]THK-5351) for use in in vitro autoradiography (ARG).

The carbon-11 labeling was performed starting with di-protected enantiomeric pure precursor - tert-butyl 5-(6-((2S)-3-fluoro-2-(tetrahydro-2H-pyran-2-yloxy)propoxy)quinolin-2-yl)pyridin-2-yl carbamate, which was reacted with [¹¹C]MeI, using DMF as the solvent and NaH as base, followed by deprotection with trifluoroacetic acid/water mixture, resulting in enantiomerically pure carbon-11 radioligand, [¹¹C]THK-5351 - (S)-1-fluoro-3-(2-(6-([¹¹C]methylamino)pyridin-3-yl)quinolin-6-yloxy)propan-2-ol. Tritium labeling and purification of [³H]THK-5351 were undertaken using similar approach, resulting in [³H]THK-5351 with RCP >99.8% and specific radioactivity of 1.3GBq/μmol.

[¹¹C]THK-5351 was produced in good yield (1900±355MBq), specific radioactivity (SRA) (361±119GBq/μmol at EOS+20min) and radiochemical purity (RCP) (>99.8%), with enantiomeric purity of 98.7%. [³H]THK-5351 was evaluated for ARG of tau binding in post-mortem human brain tissue using cortical sections from one AD patient and one control subject. [³H]THK-5351 binding density was higher in the AD patient compared to the control subject, the binding was displaced by unlabeled THK-5351 confirming specific [³H]THK-5351 binding.