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Novel radiotracers for the molecular imaging of cyclooxygenase-2 (COX-2) using positron emission tomography (PET) Open Access


Other title
cyclooxygenase-2 (COX-2)
positron emission tomography (PET)
Type of item
Degree grantor
University of Alberta
Author or creator
Tietz, Ole
Supervisor and department
Wuest, Frank (Oncology)
Examining committee member and department
Mercer, John (Oncology)
Velazquez, Carlos (Pharmacy and Pharmaceutical Sciences)
Baracos, Vickie (Oncology)
Schaffer, Paul (TRIUMF)
Department of Oncology
Experimental Oncology
Date accepted
Graduation date
Doctor of Philosophy
Degree level
Cancer remains one of the most prevalent causes of death in the western world. Effective treatment of this disease relies on the ability to diagnose patients early and assess response to treatment accurately. This can be achieved by monitoring the expression of biomarkers relevant to the type and staging of the cancer. Inflammation has recently been recognized as a hallmark of cancer, as a result the diagnostic and therapeutic molecular targets within inflammatory pathways are of great interest in oncology. Cyclooxygenase-2 (COX-2) is the inducible isoform of the cyclooxygenase enzyme family. COX-2 is involved in tumour development and progression, and frequent overexpression of COX-2 in a variety of human cancers has made COX-2 an important drug target for cancer treatment. Non-invasive imaging of COX-2 expression in cancer would be useful for assessing COX-2 mediated effects on chemoprevention and radiosensitization using COX-2 inhibitors as an emerging class of anti-cancer drugs, especially for colorectal cancer. The aim of this study is the design, synthesis and characterization of novel molecular probes (radiotracers) and the preclinical assessment of those probes in cells and animals to evaluate their ability to functionally image COX-2 in vivo using positron emission tomography. Herein, we describe the synthesis of various novel COX-2 inhibitors based on a pyrimidine central scaffold and the radiosynthesis of three novel 18F-labeled COX-2 radiotracers. Radiosynthesis was accomplished by direct and indirect radiolabeling methods, based on a 4-[18F]fluorobenzylamine ([18F]FBA) building block and radiofluorination of iodyl precursors respectively. Radiotracers N-(4-[18F]Fluorobenzyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidin-2-amine ([18F]1a), 4-{2-[(4-[18F]Fluorobenzyl)amino]-6-(trifluoromethyl)pyrimidin-4-yl}benzenesulfonamide ([18F]2a) and 2-[(4-[18F]Fluorobenzyl)oxy]-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine ([18F]3a) were evaluated in a colorectal cancer model using HCA-7 cells in vitro and HCA-7 xenograft tumors in NIH-III mice as in vivo model. Lead radiotracer [18F]1a showed the most promising in vitro and in vivo properties and underwent the most extensive pre-clinical evaluation. In vitro cell uptake studies of [18F]1a showed that the uptake of radiotracer into COX-2 positive HCA-7 cells is significantly higher than in COX-2 negative HCT-116 cells. Furthermore, the uptake of [18F]1a in HCA-7 cells could be reduced by pre-treating cells with high doses of known COX-2 inhibitors, indicating that the uptake of [18F]1a in HCA-7 cells is due to COX-2 specific binding. Experiments in HCA-7 tumor bearing NIH-III mice showed that the uptake of [18F]1a in the tumor is significantly higher than the uptake in reference tissue (muscle). Furthermore, the uptake in the tumor could be reduced by pre-treatment of animals with known COX-2 inhibitors, indicating that uptake of [18F]1a in HCA-7 xenografts is due to COX-2 specific binding. These pre-clinical studies indicate that the uptake of [18F]1a in COX-2 positive tissues is at least partially due to specific interaction with COX-2. Radiotracers [18F]1a, [18F]2a and [18F]3a underwent further pharmacokinetic evaluation in various tissues of interest, such as blood pool, lung, tumor, muscle, brain, liver and kidney. While the pharmacokinetic properties of [18F]2a are not favorable for the development of a radiopharmaceutical, [18F]3a shows promising properties as a neuroimaging agent and might be investigated further as an imaging agent for neuroinflammation. Finally, efforts were made to develop a radiotracer based on 125I-labeling. An iodine containing COX-2 inhibitor was synthesized on the basis of the pyrimidine scaffold and radiolabeled using novel oxidant fluorous chloroamine-T (F-CAT), recently developed by the Valliant group at McMaster.
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
Citation for previous publication
Tietz, O; Marshall, A; Wuest, M; Wang, M; Wuest, F. “Radiotracers for Molecular Imaging of Cyclooxygenase-2 (COX-2) Enzyme.” Curr. Med. Chem., 2013, 20(35), 4350.Tietz, O; Sharma, S; Kaur, J; Way, J; Marshall, A; Wuest, M; Wuest, F. “Synthesis of three 18F-labelled Cyclooxygenase-2 (COX-2) Inhibitors based on a Pyrimidine Scaffold.” Org. Biomol. Chem., 2013, 11(46), 8052.

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