Date of Degree

2-2018

Document Type

Dissertation

Degree Name

Ph.D.

Program

Chemistry

Advisor

Lynn Francesconi

Advisor

Thomas Reiner

Committee Members

Lynn Francesconi

Thomas Reiner

Brian Zeglis

David R Mootoo

Alexander Greer

Subject Categories

Chemistry | Neoplasms | Radiochemistry | Radiology

Keywords

PARP, PET, F18, molecular imaging, cancer

Abstract

The poly (adenosine-diphosphate (ADP) ribose) polymerase (PARP) family of enzymes has been of interest to researchers and clinicians for over fifty years, especially the first member of the family, PARP1. This enzyme has become a target for cancer therapeutics due the reliance of highly proliferating cells on PARP1 for genomic maintenance. In the coming age of individualized medicine, however, highly specific therapeutic agents like PARP inhibitors are in need of similarly highly specific companion diagnostic agents. These kind of agents have been made possible with the quickly progressing field of molecular imaging. Specifically, positron emission tomography (PET) has enabled the clinician to observe functional information about patients at a whole body level, and non-invasively. Our goal was to develop and validate an 18F-labeled PARP-targeted molecular imaging agent with the ultimate goal of translation to the clinical setting. To that end, we have developed [18F]PARPi and tested it in animal models of many different kinds of disease. Over and over again, we see that [18F]PARPi uptake clearly and specifically reveals information about PARP1 expression and therapeutic target engagement. This information could serve a crucial role in patient stratification and treatment monitoring where PARP targeted therapeutics are being considered. In addition, PARP targeted PET imaging provides a new diagnostic and prognostic tool for diseases that currently lack good options for this purpose. In summary, these investigations serve as preclinical validation of [18F]PARPi, and serve as the basis for future preclinical and clinical exploration of the possibilities of PARP PET imaging in conjunction with PARP targeted therapies.

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