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

Abstract

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 18F‐RO948 ([18F]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 [18F]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. [18F]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 [18F]1 in high decay‐corrected radiochemical yield (54‐60%). The RCC of [18F]fluoride to [18F]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 18F‐labeled (NH)heteroarene compounds.

Synthesis and Evaluation of a 18F-Labeled Ligand for PET Imaging of Colony-Stimulating Factor 1 Receptor

“…At the end of synthesis, the reaction mixture was extracted with EtOAc, and the organic phase was dried and purified by HPLC. This radiochemical synthesis procedure may be improved by diluting the reaction mixture with water prior to HPLC purification to avoid the extraction step and by using solid-phase extraction cartridges for formulation of the product [ 35 ]. The total synthesis time was 80–85 min.…”

New Perspectives in Radiological and Radiopharmaceutical Hybrid Imaging in Progressive Supranuclear Palsy: A Systematic Review

“…Compared with [18F]flortaucipir, the tracer showed similar features capable of binding in the regions that are prone to tau deposition in AD, but with higher standardized uptake value (SUV) ranges [80]. Additionally, [18F]RO948, another relatively new tracer, has emerged as a promising radiopharmaceutical substance for detecting tau pathology in subcortical regions [81]. It demonstrated a distinct binding pattern in the globus pallidus and substantia nigra, making it valuable for differentiating PSP from other neurodegenerative disorders [82].…”