High-yield synthesis of a tau PET radioligand and its nonradioactive ligand using an alternative protection and deprotection strategy.

Recently developed tau imaging radiopharmaceuticals show specific uptake in tau protein-rich regions in human brains without off-target binding. These radiopharmaceuticals and their nonradioactive reference ligands are generally obtained in low (radio)chemical yields. In the present study, we investigated high-yield synthesis of ¹⁸ F-RO948 ([ ¹⁸ F]1) and its nonradioactive ligand (1). The ligand 1 was synthesized by a Suzuki-Miyaura coupling reaction between 9-(4-methoxybenzyl)-9H-pyrrolo[2,3-b:4,5-c']dipyridin-2-yl trifluoromethanesulfonate (3) and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4), followed by oxidative removal of the para-methoxybenzyl (PMB) group with ceric ammonium nitrate (CAN). This two-step reaction gave 1 in 55.8% yield. The precursor for [ ¹⁸ F]1 was synthesized from 3 and 2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (6). The resulting PMB-protected precursor 8 was obtained in 74.5% yield. [ ¹⁸ F]1 was synthesized by radiofluorination of 8 (radiochemical conversion (RCC): 95.7 ± 1.7%), followed by deprotection of the PMB group with CAN. This one-pot, two-step radiochemical synthesis followed by HPLC purification gave [ ¹⁸ F]1 in high decay-corrected radiochemical yield (54-60%). The RCC of [ ¹⁸ F]fluoride to [ ¹⁸ F]1 in our two-step synthesis method was similar to that in a one-step radiofluorination reaction of a tert-butoxycarbonyl (BOC)-protected precursor 10 that proceeds with concomitant thermal deprotection of the BOC group. Taken together, the results of this study suggest that this high-yield synthesis method is useful for the synthesis of ¹⁸ F-labeled (NH)heteroarene compounds.
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