Publication Date
2015
Document Type
Thesis
Committee Members
William Feld (Committee Member), Daniel Ketcha (Advisor), Kenneth Turnbull (Committee Member)
Degree Name
Master of Science (MS)
Abstract
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.
Page Count
112
Department or Program
Department of Chemistry
Year Degree Awarded
2015
Copyright
Copyright 2015, all rights reserved. My ETD will be available under the "Fair Use" terms of copyright law. This may be required by third-party publishers you work with to publish your paper commercially.
