Synthesis and Evaluation of 11C-Labeled Triazolones as Probes for Imaging Fatty Acid Synthase Expression by Positron Emission Tomography

Cancer cells require lipids to fulfill energetic, proliferative, and signaling requirements. Even though these cells can take up exogenous fatty acids, the majority exhibit a dependency on de novo fatty acid synthesis. Fatty acid synthase (FASN) is the rate-limiting enzyme in this process. Expression and activity of FASN is elevated in multiple cancers, where it correlates with disease progression and poor prognosis. These observations have sparked interest in developing methods of detecting FASN expression in vivo. One promising approach is the imaging of radiolabeled molecular probes targeting FASN by positron emission tomography (PET). However, although [11C]acetate uptake by prostate cancer cells correlates with FASN expression, no FASN-specific PET probes currently exist. Our aim was to synthesize and evaluate a series of small molecule triazolones based on GSK2194069, an FASN inhibitor with IC50 = 7.7 ± 4.1 nM, for PET imaging of FASN expression. These triazolones were labeled with carbon-11 in good yield and excellent radiochemical purity, and binding to FASN-positive LNCaP cells was significantly higher than FASN-negative PC3 cells. Despite these promising characteristics, however, these molecules exhibited poor in vivo pharmacokinetics and were predominantly retained in lymph nodes and the hepatobiliary system. Future studies will seek to identify structural modifications that improve tumor targeting while maintaining the excretion profile of these first-generation 11C-methyltriazolones

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\u27s. 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 (\u3c 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

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\u27s. 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 (\u3c 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