Sulfur [¹⁸F]Fluoride Exchange Click Chemistry Enabled Ultrafast Late-Stage Radiosynthesis

Abstract

The lack of efficient [ 18 F]fluorination processes and target-specific organofluorine chemotypes remains the major challenge of fluorine-18 positron emission tomography (PET). We report here an ultrafast isotopic exchange method for the radiosynthesis of novel PET agent aryl [ 18 F]fluorosulfate enabled by the emerging sulfur fluoride exchange (SuFEx) click chemistry. The method has been applied to the fully automated 18 Fradiolabeling of 25 structurally and functionally diverse aryl fluorosulfates with excellent radiochemical yield (83−100%, median 98%) and high molar activity (280 GBq μmol −1 ) at room temperature in 30 s. The purification of radiotracers requires no time-consuming HPLC but rather a simple cartridge filtration. We further demonstrate the imaging application of a rationally designed poly(ADP-ribose) polymerase 1 (PARP1)-targeting aryl [ 18 F]fluorosulfate by probing subcutaneous tumors in vivo.

18F-Fluorination: Challenge and Opportunity for Organic Chemists

“… 68 , 69 Recently, the Sharpless group has developed a fast radiosynthesis process to prepare aryl [ 18 F]fluorosulfates via sulfur(VI) fluoride exchange (SuFEx) between phenyl fluorosulfate and [ 18 F]fluoride and demonstrated the first PET imaging application of S– 18 F-based probes ( Scheme 12 ). 70 …”

Reaction of [18F]Fluoride at Heteroatoms and Metals for Imaging of Peptides and Proteins by Positron Emission Tomography

“…In addition to arylsulfonylchlorides, arylfluorosulfates ( 87 ) have also been radiolabeled with fluorine-18. Remarkably, they can be rapidly radiolabeled through 19 F/ 18 F isotopic exchange using the traditional azeotropically dried [ 18 F]KF/Kryptofix 222 in acetonitrile in as little as 30 s at room temperature ( Figure 14 ) ( Zheng et al, 2021 ). Furthermore, they show excellent stability in vivo .…”

Click Chemistry in Natural Product Modification

“…Professor Sharpless in 2014 (Dong et al, 2014;Barrow et al, 2019), have already gained wide application in the synthesis of drug screening libraries (Kitamura et al, 2020;Smedley et al, 2020), late-stage modification of drugs and natural products (Li S. et al, 2017;Liu et al, 2018), DNA-encoded library synthesis (Liu et al, 2019;Xu H. et al, 2019;Zhang et al, 2021), and the synthesis of 18 F radio tracers (Zheng et al, 2021).…”

“…Today several elegant click chemistries have been well developed, such as strain-promoted azide-alkyne cycloaddition (SPAAC), inverse electron-demanded Diels-Alder (IEED-DA), and Sulfur (VI) Fluoride Exchange (SuFEx) chemistry. These chemistries have played a key in chemical biology and drug discovery, particularly the emerging SuFEx chemistry, another ideal click reaction proposed by Professor Sharpless in 2014 ( Dong et al, 2014 ; Barrow et al, 2019 ), have already gained wide application in the synthesis of drug screening libraries ( Kitamura et al, 2020 ; Smedley et al, 2020 ), late-stage modification of drugs and natural products ( Li S. et al, 2017 ; Liu et al, 2018 ), DNA-encoded library synthesis ( Liu et al, 2019 ; Xu H. et al, 2019 ; Zhang et al, 2021 ), and the synthesis of 18 F radio tracers ( Zheng et al, 2021 ).…”