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Organic Chemistry Methods Towards the Development of Molecular Imaging Tracers


This dissertation describes how modern organic chemistry can be used to improve and advance the field of molecular imaging, particularly in the realm of positron emission tomography (PET) imaging. Organic chemistry is an interdisciplinary art that is featured in many scientific disciplines to advance problem-solving capabilities. Herein, I report how chemical methods developed in our laboratory have expanded the scope of available labeling technologies for molecular imaging applications. Additionally, we designed a bifunctional chemical linker to produce a dual-modality (optical/PET) imaging tracer and investigated its physicochemical properties in vivo.

Chapter One reviews the procedures developed in organic chemistry that have been of particular importance to PET and fluorescence imaging. The topics covered in detail are fluorine-18 chemical methodologies, bioorthogonal chemistry, and multi-functional chemical linkers used in antibody imaging systems.

Chapter Two describes the development of a regiospecific copper-mediated oxidative fluorination methodology that is compatible with aryl stannanes. This methodology tolerates nucleophilic functionalities, uses a recyclable fluorine source and proceeds under mild conditions (60 oC, 3.2h). In addition to nucleophilic groups, the procedure allows for the fluorination of heteroaryl rings and bioactive molecules, such as estrone.

Chapter Three demonstrates the creation of an ambiphilic cyclopentadiene that can be used as a bioorthogonal reagent. The diene undergoes fast reaction rates with multiple dienophiles already being used in bioorthogonal applications. Practical applications of this new bioorthogonal ligation are highlighted via fluorescence labeling of a commercial neuropeptide.

Chapter Four discloses the synthesis of a series of multi-modal imaging linkers used in the molecular imaging of prostate specific cell antigen (PSCA) expressing tumors. These linkers were conjugated to engineered antibody fragments that target PSCA and allow for dual PET and optical imaging. The PET imaging portion allows for whole body PET scans to obtain tumor localization and metastasis information while the optical portion facilitates intra-operative removal of tumor tissue through fluorescence-guided surgery.

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