Novel Approaches to 11C- and 18F-Trifluoromethylation for PET Tracer Development

Project Summary/Abstract Positron Emission Tomography (PET) is a powerful and non-invasive tool for biomedical research and diagnosis, allowing for the visualization of biochemical entities and metabolic processes in the body. The development of PET imaging rests heavily on the innovation of new PET tracers. One critical challenge in PET tracer synthesis is the lack of a universally applicable method for introducing radiolabeled trifluoromethyl groups, i.e. [11C]CF3 and [18F]CF3 groups, at aliphatic sites. Building on an existing collaboration between the Department of Chemistry at University of Cincinnati (Liu) and the PET Radiopharmaceutical Sciences of National Institute of Mental Health (Pike), this grant proposal unites their combined expertise to address this long-standing challenge. Within this proposal, we aim to demonstrate that alkyl–CF3 groups can be employed as primary labeling sites for PET tracer development. There are three aims in this application. Aim 1 seeks to develop a general strategy to transform alkyl halides to their corresponding alkyl– [11C]CF3 and alkyl–[18F]CF3 molecules. Aim 2 will develop a decarboxylative [11C]- and [18F]- trifluoromethylation of alkyl carboxylic acids. Aim 3 will establish a method that can install [11C]CF3 and [18F]CF3 groups in an enantioselective manner. We will apply these innovative radio- trifluoromethylation approaches to synthesize a range of PET tracers for important biological targets, including COX-1, MAO-B, and inflammation. These breakthroughs will pave the way for a paradigm shift in PET tracer development, enabling previously inaccessible avenues in this domain. Key strengths of this application include the extensive preliminary results for the proposed radiolabeling reactions and the mechanistically driven optimization of these new radio- trifluoromethylation reactions. Overall, our project will enable the synthesis of a diverse range of CF3-based PET tracers and potentially revolutionize the current paradigm of PET tracer development.