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Mallin FINAL THESIS-8.18.pdf (2.43 MB)

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Proxy-PET Building Blocks as a Design Element for Library Synthesis

Mallin, Lainey Jo
http://rave.ohiolink.edu/etdc/view?acc_num=wright1439982190

Abstract Details

2015, Master of Science (MS), Wright State University, Chemistry.
In exploring radioligands for positron emission tomography (PET) imaging, it is not unusual to synthesize a library of compounds around some targeting scaffold, screen for optimal binding to a relevant diagnostic cellular target, remove some portion of optimized molecule so as to append the requisite reporter group, and then re-evaluate. To this end, the use of “click labeling” in radiochemistry is proving an increasingly attractive means of conjugating a 18F-reporter group, wherein the targeting scaffold bearing a terminal alkyne is allowed to react with a 2-[18F]-fluoroethylazide to forge a linkage as a 1,2,3-triazole substituent. Since the triazole linked prosthetic group is a necessary portion of the eventual PET imaging agent, it was envisioned that building blocks possessing a “cold” version of the triazole linked fluoroethyl group might be incorporated early in the synthetic plan as a crucial library design element. The analog so designed and exhibiting optimal binding would, in a radioactive form, represent the eventual PET imaging agent. To that end, we have prepared such building blocks from the copper(I) catalyzed click reaction between sodium azide, 2-fluoroethyl tosylate (or benzyl bromide) and propargylic alcohol. Conversion of the alcohol building block to the corresponding aldehyde could be effected using MnO2, which was appended to a scaffold of interest using an aldol condensation. Conversion to the bromomethyl derivative was achieved with PBr3 in the case of the benzyl surrogate but not the fluoroethyl derivative. The usefulness of such building blocks has been demonstrated in the case of synthesizing and evaluating small libraries around the oxindole and isatin privileged scaffolds. Subsequent manipulations led to the ultimate target structure, being a benzylidene oxindole bearing a N-triazole linked moiety. For instance, whereas the bromomethyl triazole can be utilized for N-alkylations of the aforementioned scaffolds towards targets of importance in Alzheimer’s disease (such as tau proteins, caspase-3, cdk5, and AChE), the aldehyde can be employed in aldol reactions. The introduction of such proxy-PET moieties at an early stage of the library synthesis has an added benefit of avoiding the presence of copper species in the last step before biological testing.
Daniel Ketcha, Ph.D. (Advisor)
William Feld, Ph.D. (Committee Member)
Kenneth Turnbull, Ph.D. (Committee Member)
112 p.
Chemistry
Alzheimers Disease; Click Chemistry; triazole; PET imaging

Recommended Citations

Citations

  • Mallin, L. J. (2015). Proxy-PET Building Blocks as a Design Element for Library Synthesis [Master's thesis, Wright State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=wright1439982190

    APA Style (7th edition)

  • Mallin, Lainey. Proxy-PET Building Blocks as a Design Element for Library Synthesis. 2015. Wright State University, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=wright1439982190.

    MLA Style (8th edition)

  • Mallin, Lainey. "Proxy-PET Building Blocks as a Design Element for Library Synthesis." Master's thesis, Wright State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=wright1439982190

    Chicago Manual of Style (17th edition)

wright1439982190
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This open access ETD is published by Wright State University and OhioLINK.