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High‐yield synthesis of a tau PET radioligand and its nonradioactive ligand using an alternative protection and deprotection strategy
Author(s) -
Kim Hyunjung,
Choe Yearn Seong
Publication year - 2021
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/jlcr.3894
Subject(s) - chemistry , yield (engineering) , ligand (biochemistry) , trifluoromethanesulfonate , pyridine , chemical synthesis , ceric ammonium nitrate , radioligand , aryl , radiosynthesis , stereochemistry , combinatorial chemistry , medicinal chemistry , organic chemistry , in vivo , alkyl , binding site , in vitro , receptor , catalysis , microbiology and biotechnology , biochemistry , materials science , polymer , metallurgy , grafting , biology
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)‐9 H ‐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.