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. Identification 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 efficient and simple labeling methods to modify biologically active small molecules and/or drugs. Although various approaches have been reported, current methods to radiofluorinate 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 efficiently 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 identifies 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 significant PET agents that are synthetically inaccessible or cumbersome to achieve by traditional methods.

Chemoselective Decarboxylative Protonation Enabled by Cooperative Earth‐Abundant Element Catalysis

“…Nicewicz and co-workers have demonstrated the wide applications of acridinium photoredox catalysts in cation-radical acceleratednucleophilic aromatic substitutions (CRA-S N Ar) via single electron oxidation of electron-rich arenes. [14] Similar aromatic radical cation intermediates were also used to form high energy alkoxy radical species integrating proton-coupled electron transfer (PCET) for CÀ C bond cleavage. [24] While powerful for these alternative reactions, such competing outerspheric electron transfer processes render the generation of the key carboxylic radical needed for decarboxylation inefficient in the presence of electron-rich arenes (Figure 3).…”

Synthesis and Evaluation of 18F-Labeled Boramino Acids as Potential New Positron Emission Tomography Agents for Cancer Management

“…The labeling protocol was modified from the literature . In a 2 mL Eppendorf tube, compound 4a (500 nmol) was mixed with 50 μL of target water (containing about 25 to 30 mCi 18 F fluoride, which was prepared by 18 O (p,n) 18 F using cyclotron).…”

“…1 H NMR (400 MHz, acetone-d 6 ) δ 7.21 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 8.1 Hz, 2H), 6.74−6.17 (m, 3H), 3.77 (s, 3H), 2.58 (dd, J = 47.0, 32.6 Hz, 2H). 13 16 In a 2 mL Eppendorf tube, compound 4a (500 nmol) was mixed with 50 μL of target water (containing about 25 to 30 mCi 18 F fluoride, which was prepared by 18 O (p,n) 18 F using cyclotron). Then, the reaction was heated at 85 °C for 15 min, quenched with 1 mL of deionized water (containing 0.1% TFA), and separated by semi-preparative HPLC.…”

“…Previously, simple fluorine exchange methods have been successfully applied to make 18 F-silicon agents and 18 F-boron agents . Liu et al developed boramino acids, such as fluoroboronotyrosine (FBY), as new theranostic agents for both boron delivery and cancer diagnosis. , In our previous work, we demonstrated that the position of substitution groups in amino acids could greatly impact their tumor uptake, retention, and contrast . In particular, introducing methoxyl and fluorine to the aromatic ring of Phe could lead to new PET agents that show prominent tumor uptakes.…”

“…14,15 In our previous work, we demonstrated that the position of substitution groups in amino acids could greatly impact their tumor uptake, retention, and contrast. 16 In particular, introducing methoxyl and fluorine to the aromatic ring of Phe could lead to new PET agents that show prominent tumor uptakes. Based on these reports, here we synthesize and evaluate a series of boramino acids based on the Phe core structure, aiming to study the impact of substitution groups on tumor uptake and retention.…”