Abstract Positron emission tomography (PET) is a powerful and rapidly developing technology that plays key roles in medical imaging, as well as drug discovery and development. Despite the exceptional promise of PET imaging, the availability of PET agents is limited in many situations due to the lack of efficient and simple labeling methods to modify biologically active small molecules/drugs. Based on the highly innovative photoredox system described by the Nicewicz group (Science, 2015, 349, 1326-1330), this research will address the need for novel PET imaging agents by establishing broadly-useful methodologies for late-stage radiofluorination and radiocyanation of aromatic substrates. The proposed approaches could have transformative impacts on the imaging field by providing access to novel PET agents that are previously challenging or impossible to synthesize. There are three aims in this application. Aim 1 seeks to develop a photocatalyst library with different electron density, sterics and photophysical characteristics for radiolabeling unactivated aromatic rings. Aim 2 will develop C–H [18F]fluorination and C–H [11C]cyanation of arenes via organic photoredox Catalysis. Aim 3 will establish novel nucleophilic aromatic substitution reactions of phenol derivatives to afford [18F]aromatics and [11C]–CN-aromatics. A key strength of this application is the extensive preliminary data for the proposed approaches. We have make the first breakthrough on direct arene C–H fluorination with 18F– (Science, 2019, in press) that not only allows direct conversion of drugs to PET agents, but also enables fast ligand screening as shown in working examples. For C–O to C–F direct conversion, we also demonstrated the approach is valid with excellent radiolabeling yields. The “cold” cyanation reactions have been established and ready for radiolabeling testing. Taking all these factors together, the proposed research will lead to an entirely new method for incorporation of [18F]F and [11C]CN into aromatic compounds using late stage radiolabeling. The mild conditions coupled with easy access to the required precursors will allow for the unprecedented access to novel aromatic PET tracers of use in neurology, oncology, and various other research area, which will generate high impact in those fields.