Late-Stage Fluorination with 18F^{18}F

Positron 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.Chemistry and Chemical Biolog

Application of Palladium-Mediated 18F-Fluorination to PET Radiotracer Development: Overcoming Hurdles to Translation

New 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.Chemistry and Chemical Biolog

A Fluoride-Derived Electrophilic Late-Stage Fluorination Reagent for PET Imaging

The 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.Chemistry and Chemical Biolog

Reactivity-Dependent PCR: Direct, Solution-Phase In Vitro Selection for Bond Formation

(Figure Presented) In 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

A biomolecule-compatible visible-light-induced azide reduction from a DNA-encoded reaction-discovery system

Using a system that accelerates the serendipitous discovery of new reactions by evaluating hundreds of DNA-encoded substrate combinations in a single experiment, we explored a broad range of reaction conditions for new bond-forming reactions. We discovered reactivity that led to a biomolecule-compatible, Ru(II)-catalysed azide-reduction reaction induced by visible light. In contrast to current azide-reduction methods, this reaction is highly chemoselective and is compatible with alcohols, phenols, acids, alkenes, alkynes, aldehydes, alkyl halides, alkyl mesylates and disulfides. The remarkable functional group compatibility and mild conditions of the reaction enabled the azide reduction of nucleic acid and oligosaccharide substrates, with no detectable occurrence of side reactions. The reaction was also performed in the presence of a protein enzyme without the loss of enzymatic activity, in contrast to two commonly used azide-reduction methods. The visible-light dependence of this reaction provides a means of photouncaging functional groups, such as amines and carboxylates, on biological macromolecules without using ultraviolet irradiation.Chemistry and Chemical Biolog

Reactivity-Dependent PCR: Direct, Solution-Phase <i>in Vitro</i> Selection for Bond Formation

Reactivity-Dependent PCR: Direct, Solution-Phase <i>in Vitro</i> Selection for Bond Formatio

Development of a Chiral DMAP Catalyst for the Dynamic Kinetic Resolution of Azole Hemiaminals

A new catalyst for the dynamic kinetic resolution of azole hemiaminals has been developed using late-stage structural modifications of the <i>tert</i>-leucinol-derived chiral subunit of DMAP species

Development of a Chiral DMAP Catalyst for the Dynamic Kinetic Resolution of Azole Hemiaminals

A new catalyst for the dynamic kinetic resolution of azole hemiaminals has been developed using late-stage structural modifications of the <i>tert</i>-leucinol-derived chiral subunit of DMAP species