Positron emission tomography (PET) is a molecular imaging technique used in cancer research to visualize and assay enzyme activity, synthesis of DNA, cell proliferation, apoptosis, receptor occupancy and gene expression. Despite the synthesis of a wide variety of 18F labeled PET probes, their clinical translation is often hindered due to severe synthesis limitations, resulting from the 110-minute half-life of 18F. The only practical source of radioactive 18F is 18F-fluoride anion, which can only react with a molecule bearing partial positive charge. Currently, if tracer structures lack a positive charge at the labeling site they must be modified to create this charge, making synthesis complex and not suitable for routine production. This proposal aims to develop a new radiosynthesis platform to enable 18F-fluoride anion to react with neutral or partially negative molecules. If successful this will open new approaches for radiolabeling existing challenging radiotracers and will also dramatically expand the portfolio of PET probes and assays performed with them. Our preliminary studies demonstrate feasibility of catechol radiolabeling in an electrochemical cell. We obtained ~10% carrier-added radiochemical yield of model aromatic molecules after one hour of electrolysis. These experiments were performed using a conventional electrochemical cell integrated into an automated platform supporting safe handling of radioactive fluoride. These results have opened three parallel research avenues: optimization of the electrochemical fluorination reaction and achievement of higher specific activity than current electrophilic methods (~1000 x higher) (Aim 1), development of the microfluidic electrochemical cell (Aim 2), and investigation of the precursor structure and production of a clinically relevant example (Aim 3). Each of these aims individually has the potential to substantially improve PET probe production. Aim 1 provides a simpler radiofluorination technique and a new no-carrier added radiolabeling method for molecules previously not amenable to radiofluorination. Aim 2 takes advantage of recent developments and our capabilities in microfluidics and instrumentation to build a platform with efficient electrochemical radiofluorination. The automated platform technology will facilitate electrochemical nucleophilic radiofluorination synthesis and through its application in Aim 3 we will expand availability of clinical PET tracers based on nucleophilic fluorination, regardless of optimization or no-carrier added development. This will provide a widely accessible method to provide clinically relevant probes such. The new synthetic method will enable the radiolabeling of cancer PET probes with electron-rich moieties, presently not accessible due to difficulties in synthesis with conventional approaches. Moreover, simplification in synthesis will translate to improved availability of known and future PET probes that will enhance disease diagnosis and management. 18F-DOPA to patients