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SYNTHESIS OF FLUORINATED AND IODINATED CARBOXYETHYLPYRROLE RECEPTOR LIGANDS

Zhang, Yu
http://rave.ohiolink.edu/etdc/view?acc_num=case1380551750

Abstract Details

2014, Doctor of Philosophy, Case Western Reserve University, Chemistry.
Cancer, a major health issue in the United States, is the second leading cause of death after disease of heart. The formation of new blood vessels, known as angiogenesis, which new capillaries sprout from the existing vessels, is believed to promote the tumor growth. Due to the dependence of tumor progression on angiogenesis, it has been an interesting field in the search of antiangiogenesis agents which stop the progression of tumor formation and also different types of receptors accounting for angiogenesis by the ever-evolving positron emission tomography (PET) technology. Phospholipids oxidation in biological systems contributes to diverse pathological processes and is also believed to introduce age-related diseases. Oxidative cleavage of phospholipids containing docosahexaenoic acid (DHA) yields the reactive electrophilic species such as 4-hydroxy-7-oxohept-enoates (HOHA) which would later on covalently bond to e-amino group of protein lysine residue and turn into the 2-(¿-carboxyethyl)pyrrole (CEP) protein adducts. The CEP adducts is found to be associated with age-related macular degeneration (AMD) by triggering the angiogenesis in the retina. Recent study also revealed the novel molecular pattern between CEP adducts and Toll-like receptor 2 (TLR2) which leads to the angiogenesis response. And it provides an alternative therapeutic target especially in cases cancers resistant to the conventional anti-VEGF therapy. Therefore it is necessary to synthesize the gamma radioactive isotope labeled CEP adducts and apply them for the targeting of TLR2 with PET imaging technique. A convenient synthesis of putative fluorine-18-labeled-CEP was achieved with satisfied yields and the fluorination condition was optimized as well because limited half-life of fluorine-18 (109.7min) required the reaction to be accomplished in a short time-frame. Meanwhile in order to overcome the limited stability of CEP adducts which prevents its long-term usage as standards in immunosorbent assays, their electron-deficient isostere, carboxyethylpyrazoles were synthesized. These synthesized pyrazole compounds showed their similar biological affinity with anti-CEP antibody and were also found to be able to introduce angiogenesis of endothelial cells. Therefore, it provides another approach to the PET imaging of TLR2 expression by incorporating radioactive iodine species.
Robert Salomon (Advisor)
Irene Lee (Committee Chair)
Gregory Tochtrop (Committee Member)
Rajesh Viswanathan (Committee Member)
Yanming Wang (Committee Member)
154 p.
Analytical Chemistry; Biochemistry; Organic Chemistry
Cancer Angiogenesis Phospholipids DHA CEP TLR2 PET VEGF AMD fluorine iodine imaging pyrrole pyrazole

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Citations

  • Zhang, Y. (2014). SYNTHESIS OF FLUORINATED AND IODINATED CARBOXYETHYLPYRROLE RECEPTOR LIGANDS [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1380551750

    APA Style (7th edition)

  • Zhang, Yu. SYNTHESIS OF FLUORINATED AND IODINATED CARBOXYETHYLPYRROLE RECEPTOR LIGANDS. 2014. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1380551750.

    MLA Style (8th edition)

  • Zhang, Yu. "SYNTHESIS OF FLUORINATED AND IODINATED CARBOXYETHYLPYRROLE RECEPTOR LIGANDS." Doctoral dissertation, Case Western Reserve University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1380551750

    Chicago Manual of Style (17th edition)

case1380551750
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© 2013, some rights reserved.Creative Commons License SYNTHESIS OF FLUORINATED AND IODINATED CARBOXYETHYLPYRROLE RECEPTOR LIGANDS by Yu Zhang is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.