PROJECT SUMMARY Positron emission tomography (PET) is a highly sensitive molecular imaging technique used for studying biological systems in vivo, as well as for clinical diagnostic purposes. The ubiquitous presence of carbon in most organic molecules makes carbon-11 an attractive and important positron-emitting radionuclide for labeling molecules of biological interest. Because 11C has the same chemical properties as 12C, 11C is especially useful for rapid exploration of molecules with well-characterized biological and pharmacological properties (i.e., metabolism, receptor binding affinity, enzyme substrate affinity, etc.). In addition, the short half- life of 11C (20.4 min) facilitates the possibility of multiple studies on the same subject in a single day due to the low radiation dose and absence of overlapping activity between scans. This opens up the possibility for longitudinal studies and studies involving an intervention, making it particularly desirable for basic and clinical research investigations. The lack of methods to introduce and incorperate11C into organic molecules conveniently and quickly limits the utility of this radioisotope. So far, the main criteria for successful synthesis of 11C-lableled PET tracers is a rapid, robust and practical radiolabeling method that yields the desired tracer with high radiochemical purity, chemical purity, and/or high molar activity. This is especially a challenge when [11C]CO2 is used as radiosynthon for synthesis of desired PET tracers. In this proposal, we will develop methods to address this issue. Our three Specific Aims are: 1). develop a fluoride-mediated desilylation (FMDS) 11C-labeling methodology to directly incorporate [11C]CO2 into skeleton of molecules with diversified structures. It is expected that this novel approach will provide facile and rapid access to 11C-labeled compounds with carbon-11 attached at various hybridized carbons (sp, sp 2 and sp3) with broad functional group tolerance; 2). Further extend FMDS 11C-labeling methodology to other accessible 11C-electrophiles (such as [11C]CH3I/[11C]CH3OTf). Our goal is to develop a new 11C-methylation method, which can serve as a complementary approach for synthesis of various 11C-labeled PET tracers; 3). Utilize FMDS 11C-labeling to solve some long-standing problems in radiotracer chemistry research by developing facile and practical labeling methods for radiotracers of high clinical interest where regular production is very difficult using currently reported methods, such as [11C]pyruvic acid, [11C]succinic acid, [11C]PHNO, [11C]vorozole. This newly developed FMDS 11C-labeling methodology may lead a brand new direction in radiotracer chemistry and open multiple avenues for developing novel and practical radiolabeling methodologies.