Ortho‐Stabilized ¹⁸F‐Azido Click Agents and their Application in PET Imaging with Single‐Stranded DNA Aptamers

Abstract

Azido 18F-arenes are important and versatile building blocks for radiolabeling of biomolecules via Huisgen cycloaddition (‘click chemistry’) in positron emission tomography (PET). However, routine access of such clickable agents is challenged by inefficient multi-step and esoteric radiochemical approaches. Herein we describe a high-yielding direct radiofluorination for azido 18F-arenes by developing an oxygen ortho-stabilized iodonium derivative (OID). This OID strategy addresses an unmet need for a reliable azido 18F-arene clickable agent in bioconjugation reactions. A ssDNA aptamer is radiolabeled and visualized in a xenograft mouse model of human colon cancer by PET, which demonstrates a convenient and highly efficient way of labeling biomolecules and tracking them by OID approach.

Hypervalent aryliodine compounds as precursors for radiofluorination

“…[ 18 F]3‐Fluorobenzaldehyde has been prepared in variable yield (7%‐52%) yield (Table , entry 3) . [ 18 F]3‐Fluorobenzyl azide (entry 4) and [ 18 F]4‐fluorobenzyl azide (entries 5‐7) have been prepared in good nonisolated yields. Isolated yields for the 4‐fluoro isomers ranged from low to moderate (entries 5‐7).…”

“…In ortho‐oxygen‐stabilized iodonium derivatives, secondary bonding from the oxygen of a pendant ortho aliphatic substituent to the iodonium center provides extra thermal stability, which may account for the high radiofluorination yields. These labeling synthons were successfully applied to labeling single‐stranded DNA aptamers (Figure ) …”

In Vitro and in Vivo Evaluation of 11C-Labeled Azetidinecarboxylates for Imaging Monoacylglycerol Lipase by PET Imaging Studies

“…70–73, 75 The aryl iodide 12 could be oxidized in chloroform. 70 Without further purification, the resulted intermediate could couple the spirocyclic auxiliaries (SPIAd) 71 directly to afford the desired ylide precursor 17 .…”

Click Chemistry and Radiochemistry: The First 10 Years

“…Much, although not all, of this work has focused on 18 F. 35–38 Indeed, a variety of radiosynthetic methods have been employed to create azide- and alkyne-bearing 18 F-labeled prosthetic groups (Figure 2A). 37,39,40 These tools and the CuAAC reaction have been harnessed with great success in the radiolabeling of a wide variety of vectors, including phosphonium ions, 41 peptides, 42–50 oligonucleotides, 39,47 and proteins. 27,47 This application of the CuAAC reaction is not without its flaws, however.…”