Person: Kamlet, Adam Seth
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Kamlet
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Adam Seth
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Kamlet, Adam Seth
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Publication Application of Palladium-Mediated 18F-Fluorination to PET Radiotracer Development: Overcoming Hurdles to Translation(Public Library of Science, 2013) Kamlet, Adam Seth; Neumann, Constanze N.; Lee, Eunsung; Carlin, Stephen M.; Moseley, Christian K.; Stephenson, Nickeisha A; Hooker, Jacob; Ritter, TobiasNew chemistry methods for the synthesis of radiolabeled small molecules have the potential to impact clinical positron emission tomography (PET) imaging, if they can be successfully translated. However, progression of modern reactions from the stage of synthetic chemistry development to the preparation of radiotracer doses ready for use in human PET imaging is challenging and rare. Here we describe the process of and the successful translation of a modern palladium-mediated fluorination reaction to non-human primate (NHP) baboon PET imaging–an important milestone on the path to human PET imaging. The method, which transforms [18F]fluoride into an electrophilic fluorination reagent, provides access to aryl–18F bonds that would be challenging to synthesize via conventional radiochemistry methods.Publication A Fluoride-Derived Electrophilic Late-Stage Fluorination Reagent for PET Imaging(American Association for the Advancement of Science, 2011) Lee, Eunsung; Kamlet, Adam Seth; Powers, David C.; Neumann, Constanze N.; Boursalian, Gregory; Furuya, Takeru; Choi, Daniel C.; Hooker, Jacob; Ritter, TobiasThe unnatural isotope fluorine-18 \((^{18}F)\) is used as a positron emitter in molecular imaging. Currently, many potentially useful \(^{18}F\)-labeled probe molecules are inaccessible for imaging because no fluorination chemistry is available to make them. The 110-minute half-life of \(^{18}F\) requires rapid syntheses for which \([^{18}F]\)fluoride is the preferred source of fluorine because of its practical access and suitable isotope enrichment. However, conventional \([^{18}F]\)fluoride chemistry has been limited to nucleophilic fluorination reactions. We report the development of a palladium-based electrophilic fluorination reagent derived from fluoride and its application to the synthesis of aromatic \(^{18}F\)-labeled molecules via late-stage fluorination. Late-stage fluorination enables the synthesis of conventionally unavailable positron emission tomography (PET) tracers for anticipated applications in pharmaceutical development as well as preclinical and clinical PET imaging.Publication Late-Stage Fluorination with \(^{18}F\)(2013-03-19) Kamlet, Adam Seth; Ritter, Tobias; Liu, David Ruchien; Jacobsen, Eric; Betley, TedPositron emission tomography (PET) is a powerful, non-invasive in vivo imaging technique used for diagnostics and drug development. The synthesis of \(^{18}F\)-PET tracers is challenging due to the short half-life of the unnatural isotope that necessitates late-stage fluorination, and the limited reactivity of nucleophilic fluoride, the preferred and widely accessible form of \(^{18}F\). This thesis describes the development of an electrophilic fluorination reagent derived from fluoride. The reagent can be employed in a late-stage fluorination reaction of palladium aryl complexes to give access to small molecule aryl fluorides. The reagent can be made from \([^{18}F]\)fluoride and used to synthesize radiolabeled small molecules for PET imaging experiments. Two small molecules known to interact with the serotonergic system were synthesized, radiolabeled, and imaged in rats and non-human primates and evaluated for use as PET tracers.Publication Reactivity-Dependent PCR: Direct, Solution-Phase in Vitro Selection for Bond Formation(American Chemical Society, 2009) Gorin, David Joel; Kamlet, Adam Seth; Liu, DavidIn vitro selection is a key component of efforts to discover functional nucleic acids and small molecules from libraries of DNA, RNA, and DNA-encoded small molecules. Such selections have been widely used to evolve RNA and DNA catalysts and, more recently, to discover new reactions from DNA-encoded libraries of potential substrates. While effective, current strategies for selections of bond-forming and bond-cleaving reactivity are generally indirect, require the synthesis of biotin-linked substrates, and involve multiple solution-phase and solid-phase manipulations. In this work we report the successful development and validation of reactivity-dependent PCR (RDPCR), a new method that more directly links bond formation or bond cleavage with the amplification of desired sequences and that obviates the need for solid-phase capture, washing, and elution steps. We show that RDPCR can be used to select for bond formation in the context of reaction discovery and for bond cleavage in the context of protease activity profiling.