Synthesis of 18F-PET-sensitive Agents for Targeted Visualization of Brain Tumors translation missing: zh.hyrax.visibility.files_restricted.text

Syed, Mahmood (Summer 2019)

Permanent URL: https://etd.library.emory.edu/concern/etds/ms35t9847?locale=zh
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Abstract

High-grade gliomas (HGGs; grades III and IV by the World Health Organization) carry a dismal prognosis. In 2017 in the US alone, roughly 16,700 deaths resulted from a total of 23,800 cases of such gliomas. Current imaging techniques lack the selectivity necessary to properly visualize and detect the development of these malignant tumors. To address this gap in selective HGG visualization, we proposed a method of glioma detection using novel positron emission tomography (PET)-radiotracers with an alternative mechanism of action. By exploiting the phenomena of extensive binding of the fluorescent heme analog protoporphyrin IX (PpIX) to the peripheral benzodiazepine receptor (PBR) protein in several tumorous cell lines (including gliomas), we aimed to synthesize 18F-radiolabeled 5-aminolevulinc acid (5-ALA) derivatives, where 5-ALA is a precursor to the biosynthesis of PpIX. These fluorinated species will potentially be detectable under PET scans, and aid in pre-operative assessment of gliomas. Precursors to the 2- and 3-18F-5ALA were successfully made, but preliminary 18F-labelling was unsuccessful for either isomer. Other methods of accessing 2- and 3-fluoro isomers were explored, but ultimately were unsuccessful due to competing E1/E2 reactions and inability to translate conditions to a radiochemical context. However, 5-ALA fluoro esters were successfully synthesized, with a 18F-5-ALA-propyl ester being synthesized in 8% radiochemical yield. Unfortunately, initial tumor cell studies indicated no uptake of the 18F-labeled ester. Currently, a catalytic fluorination method is being implemented for the 2-18F-isomer along with further investigation into an amide-based fluorination strategy; for the 3-isomer, other leaving group activators (brosylate, nosylate, etc.) are being tested along with a Mn(salen) benzylic fluorination.

Table of Contents

Introduction……………………………………………………………………………..10

           Results and Discussion………………………………………………………..12

           Conclusion and Future Work…………………………………………………28

References………………………………………………………………………………..30

           Supporting Information………………………………………………………33

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