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18F-Labeling of Aromatic Amines for Molecular Imaging
By developing protection schemes for drug-like amines, I have expanded the scope of diaryliodonium salt labeling chemistry. Diaryliodonium salts are well-known intermediates for the preparation of labeled compounds, particularly 18F-fluorinated arene imaging agents for positron emission tomography (PET). PET imaging is an established non-invasive imaging technique used for the diagnosis and staging of diseases such as cancer and Alzheimer's. Despite the utility of PET and the importance of 18F-fluoride in the preparation of PET radiotracers, chemists still struggle to incorporate fluorine-18 into electron-rich arenes efficiently. There are several challenges to the introduction of [18F]fluorine for the preparation of PET tracers: time (< 2 h), scale (~1 ng fluorine-18), and high isotopic purity requirements. In practice, these considerations require that the source of fluorine-18 is 18F-fluoride, and that only nucleophilic reactions can be considered. In the DiMagno laboratories, we have developed an efficient, nucleophilic method to incorporate 18F-fluoride into a wide array of aromatic compounds. The scope of substrates that can be radiolabeled using diaryliodonium salts is broad, but has several limitations. Reducing functional groups such as free N-H groups and tertiary sp3-hybridized amines are incompatible with the strongly oxidizing iodine(III) center. Additionally, diaryliodonium salt stability and regiochemical control suffer when particularly electron-rich aryl groups, such as anilines, are substituents on iodine(III). These synthetic hurdles can be overcome by use of a protecting group strategy. Installing electron-withdrawing protective groups on the aniline nitrogen opens a straightforward route to functionalizing and radiolabeling aminoaryl substituents in relatively complex molecules. I have also developed a novel protecting group using tetra-alkyl quaternary ammonium salts that allows functionalization of arenes containing sp3-hybridized amines via diaryliodonium salts. Using these protection schemes, I have successfully radiofluorinated several compounds of interest that were previously inaccessible using diaryliodonium salts.
Linstad, Ethan J, "18F-Labeling of Aromatic Amines for Molecular Imaging" (2018). ETD collection for University of Nebraska-Lincoln. AAI10790690.