Positron emission tomography (PET) is currently the premiere molecular imaging technique for the detection and staging of cancer in vivo. Owing to the desirable nuclear properties of the short- lived positron emitter 18F, and the remarkable targeting potential of many peptides, proteins and nucleic acid- based compounds, the efficient radiolabelling of these sensitive biomolecules with 18F remains a fundamental objective in nuclear diagnostic medicine. Antisense imaging remains a promising tool for the identification and treatment of genetic diseases, particularly cancer. Herein, we expand the utility of the 2-[18F]fluoropyridine- bearing labelling agent [18F]FPy5yne to include nucleic acid- based probes for PET imaging. We describe the conjugation of [18F]FPy5yne by way of a copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction to a 5'-azide-modified antisense oligodeoxyribonucleotide, which was first prepared from a 5'-aminohexyl-modified DNA 20mer. This work also describes protocols suitable for the coupling of [18F]FPy5yne and mini-PEGylated analog PEG-[18F]FPyKYNE to azide- modified peptide receptor ligands derived from bombesin and neuropeptide Y. These 18F- labelled targeting vectors were assayed by collaborators for the detection of prostate, breast and brain cancer in mouse models by way of PET imaging and ex vivo autoradiography. Finally, a new approach for the 18F- labelling of biological molecules is introduced and investigated. Sulfonyl [18F]fluorides can be prepared under aqueous conditions and at room temperature, yet they have not yet been assayed as a potential means to 18F- label biomarkers. A general route was developed for the synthesis of bifunctional arylsulfonyl [18F]fluorides from their sulfonyl chloride precursors in 1:1 mixtures of MeCN, THF, or t-BuOH and Cs[18F]F/Cs2CO3 over 15 minutes at room temperature. In most cases, pyridine could be used to selectively degrade the precursor without significantly affecting observed yields. As proof-of-principle, 3-formylmesitylenesulfonyl [18F]fluoride was synthesized in excellent preparative yields and used to radiolabel an oxyamino-modified bombesin(6-14) analog. The 18F bioconjugate showed signs of both defluorination and modification in mouse serum.
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Thesis advisor: Storr, Tim
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