Arene radiofluorination enabled by photoredox-mediated halide interconversion.

Wei Chen,Zibo Li,Vincent A Pistritto,Kang-Po Li,Tao Zhang,David A Nicewicz,Zhanhong Wu,Nicholas E S Tay,Hui Wang

doi:10.1038/s41557-021-00835-7

Wei Chen, Zibo Li + Show 7 more

Open Access

https://doi.org/10.1038/s41557-021-00835-7

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Abstract

Positron emission tomography (PET) is a powerful imaging technology that can visualize and measure metabolic processes in vivo and/or obtain unique information about drug candidates. The identification of new and improved molecular probes plays a critical role in PET, but its progress is somewhat limited due to the lack of efficient and simple labelling methods to modify biologically active small molecules and/or drugs. Current methods to radiofluorinate unactivated arenes are still relatively limited, especially in a simple and site-selective way. Here we disclose a method for constructing C-18F bonds through direct halide/18F conversion in electron-rich halo(hetero)arenes. [18F]F- is introduced into a broad spectrum of readily available aryl halide precursors in a site-selective manner under mild photoredox conditions. Notably, our direct 19F/18F exchange method enables rapid PET probe diversification through the preparation and evaluation of an [18F]-labelled O-methyl tyrosine library. This strategy also results in the high-yielding synthesis of the widely used PET agent L-[18F]FDOPA from a readily available L-FDOPA analogue.

Highlights

Positron emission tomography (PET) is one of the most sensitive non-invasive imaging techniques used in diagnosis and treatment monitoring of various human diseases, including oncological and neurological disorders[1,2]
This is routinely used for the synthesis of PET agents with high molar activity[11,12,13,14]; its application is limited to electron-deficientaromatic systems[15], restricting the classes of small molecules towards which radiofluorination is amenable
To evaluate whether acridinium photocatalysts could promote halide/18F exchange in electron-rich arenes, 1-chloro-4-methoxybenzene (1-Cl) was first tested with acridinium S1 in a multicomponent solvent system containing DCE/tBuOH/MeCN. [18F]TBAF and tetrabutylammonium bicarbonate (TBAB) were added to the solution which was irradiated with a 450 nm laser along with air bubbling for 30 min at 0 oC

Summary

Introduction

Positron emission tomography (PET) is one of the most sensitive non-invasive imaging techniques used in diagnosis and treatment monitoring of various human diseases, including oncological and neurological disorders[1,2]. Fluorine-18 is arguably the most widely used short-lived PET isotope (t1/2 ~110 min) due to its excellent imaging properties, wide availability and ideal half-life It is often introduced using 18F fluoride (18F–) its incorporation into organic scaffolds is nontrivial as fluoride is a recalcitrant nucleophile[7,8,9,10]. A common strategy used for constructing aryl C(sp2)–18F bonds is nucleophilic aromatic substitution (SNAr), which substitutes a (pseudo)halide with 18F- (Fig.1A) This is routinely used for the synthesis of PET agents with high molar activity[11,12,13,14]; its application is limited to electron-deficient (hetero)aromatic systems[15], restricting the classes of small molecules towards which radiofluorination is amenable. This strategy would enable direct translation of readily available fluorinated therapeutics into 18F-labeled radiopharmaceuticals though simple late-stage 19F to 18F conversion 34-36

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