Arene radiofluorination enabled by photoredox-mediated halide interconversion

Abstract

Positron emission tomography (PET) is a powerful imaging technology that could visualize and measure metabolic processes in vivo and/or obtain unique information about drug candidates at early stages. Identi cation of new and improved molecular probes plays a critical role in PET, but its progress is limited in many situations due to the lack of e cient and simple labeling methods to modify biologically active small molecules and/or drugs. Although various approaches have been reported, current methods to radio uorinate unactivated arenes are still limited. Here we document the discovery of a robust method for constructing C-18F bonds through direct halide/18F conversion in electron-rich halo(hetero)arene substrates. Based on readily available halide precursors and mild photoredox conditions, [18F]F-is e ciently introduced into a broad spectrum of organic molecules, including pharmaceutical compounds in a site-selective manner. Notably, the direct 19F/18F conversion method is demonstrated to be a simple and robust protocol for PET probe screening/preparation: this methodology not only identi es a new cancer imaging agent L-61-18F-COOH after a rapid screening of a tyrosine isomer library; but also allows the simple and high-yielding synthesis of the widely used PET agent L-[18F]FDOPA. Taken together, photoredox-mediated halide/18F interconversion strategies represent an innovative chemical tool to prepare new and clinically signi cant PET agents that are synthetically inaccessible or cumbersome to achieve by traditional methods.

Recent Advances in Synthetic Methodologies to Form C-18F Bonds

“…In addition to direct arene C-H radiofluorination, nucleophilic aromatic substitution was investigated subsequently. They have also applied this catalyst to the aromatic halides and their derivatives, with leaving groups such as F, Cl, Br, I, OTf, NO 2 ( Chen et al, 2021 ) and OR (R = para -chlorophenyl) ( Tay et al, 2020 ) ( Figure 4 , Reaction 2). This method did not perform well when X was the iodine substituent, and the RCYs of reactions varied from non-detected to 79.7%.…”

Fluorine-18: Radiochemistry and Target-Specific PET Molecular Probes Design

“…Vismodegib analog, a basal cell carcinoma treatment drug ( Dlugosz et al, 2012 ), and PH089, an MK-2 inhibitor ( Anderson et al, 2007 ), smoothly underwent radiofluorination. Li, Nicewicz, and co-workers demonstrated a method for constructing aryl C- 18 F bonds through direct halogen-fluorine exchange on electron-rich arene halides under mild photoredox conditions ( Chen et al, 2021 ) ( Figure 3C2 ). 18 F-labeled 2-phenoxyaniline analogs as translocator protein (TSPO)-specific PET tracers for neuroinflammation imaging have been investigated ( Werry et al, 2019 ).…”

Highly selective α-aryloxyalkyl C–H functionalisation of aryl alkyl ethers

“…31 Direct oxidation of arenes to their radical cations has been achieved with 10, leading principally to two types of reactions: 32 (i) C-H functionalisation reactions of arenes as shown in the preparation of 12 (Scheme 3a) 26,[33][34][35][36][37] and (ii) substitution of an alkoxy or halo substituent on the aryl ring of the radical cations of arenes by nucleophiles as exemplied by the formation of 15 (Scheme 3b). 27,[38][39][40][41][42] In both these cases, the aryl ether e.g. anisole 1a is oxidised to its radical cation 16 by the excited state, MesAcr + *, and the ring of the arene radical cation is then attacked by a nucleophile.…”