Project Summary/Abstract Fluorine is an essential constituent of many commercial molecules, including (radio)pharmaceuticals, agrochemicals, and functional materials. Fluorine-19 ( stable isotope) is routinely introduced into pharmaceuticals to modulate pharmacological properties. Many positron emission tomography (PET) imaging agents are labeled with fluorine-18 (radioactive isotope) for studying and monitoring disease, evaluating drug-target engagements, and enriching clinical trials of therapeutics. Critically, PET is continually used to improve disease detection, treatment, and prevention, which is fundamentally consistent with the mission of NIBIB. Despite progress in developing fluorine-18 imaging agents for these applications, more robust, efficient, and reproducible radiosyntheses are required to support and expedite tracer discovery and meet the urgent demand for radiopharmaceuticals from the healthcare and pharmaceutical industries. Therefore, the primary focus of this proposal is to overcome challenges associated with radiofluorination by inventing radiolabeling methods that support the design of PET imaging agents. Specifically, the central claim is that fluorine-18 labeled organic molecules can be rapidly accessed by designing zinc-mediated and metal-free amide C-H radiofluorination radiolabeling reactions. Zinc is an abundant, inexpensive, and non-toxic element that facilitates a-amido C-H radiofluorination reactions, albeit inefficiently, with a limited scope. Over the K99 phase, the candidate collected rigorous preliminary data demonstrating that amide C-H radiofluorination reactions are possible, and this award will study, refine, optimize, and showcase this protocol for PET biomedical imaging applications. Specifically, the ROO proposal is divided into three aims: Aim 1 is to develop a fully optimized amide C-H radiofluorination protocol that delivers stereochemically enriched fluorine-18 labeled amides containing a broad range of valuable fluoroalkyl functional groups. Aim 2 is to demonstrate the feasibility of new amide C-H radiofluorination reactions with bioactive PET imaging scaffolds on a commercial radiosynthesis module for clinical production Aim 3 is to prepare and assess the stability of multiple representative therapeutics containing fluorine-18 labeled amides. Ultimately, the enhancement of PET imaging technology, as described in this proposal, is expected to fundamentally alter the current (radio)synthetic fluorination paradigm and expedite radiofluorination, providing unrealized and rapid access to fluorine-18 labeled pharmaceuticals that support the improvement of patient outcomes and a reduction in healthcare costs for the American people in the long term. Broadly, this project will provide new opportunities to merge radiochemistry and organic/organometallic chemistry, supporting the development of a world-leading radiosynthetic methods program at the University of Pennsylvania.