Development of Radiofluorination Methods and Prosthetic Groups Suitable for Quick Iterative Constructions of PET Tracer Analogs in Rapid Radiopharmaceutical Development and SAR Study

Project Summary The screening of biologically active substrates’ analogs and derivatives represents an eƯective and straightforward strategy in new drug discoveries, as such strategy provides Structure Activity Relationship (SAR) study data that can be useful in identifying the most promising drug structures. The screening could also be incorporated into High Throughput Experiments (HTE) to facilitate rapid research process, and sometimes could generate unexpected findings from screening to inspire new drug designs. Radiofluorinated Positron Emission Tomography (PET) tracers are an important type of radiopharmaceuticals that are used in PET imaging, which could provide valuable diagnostic data in the early stages of disease progressions. Even though the benefits of screening large numbers of drug candidates’ analogs apply to the development of both nonradioactive pharmaceuticals as well as radiopharmaceuticals, the challenges in radiosynthesis can sometimes present obstacles in utilizing such strategy in novel PET tracer development. This is especially a concern in 18F-labeled radiopharmaceutical development, as the poor nucleophilicity of the [18F]fluoride ion exacerbates these radiosynthetic challenges. To promote the utilization of quick candidates screening strategy in 18F-labeled PET tracer development, the fluorine-18 nuclide must be incorporated at late-stages of the synthesis in a manner that is fast (to avoid decay loss) and selective (to allow for the construction of PET tracer analogs with diƯerent functional groups for SAR studies). This can be done either via 1) radiofluorination methods that are functional group compatible, or via 2) the utilization of robust and selective 18F-labeled prosthetic groups. Progress in both categories have been reported by many groups in recent years. My proposal focuses on the further developments of both new labeling methods and prosthetic groups, and to construct large numbers of 18F-labeled PET tracer analogs in a quick and iterative manner via these new methods/prosthetic groups for biodistribution evaluation in order to support radiopharmaceutical development via quick screening strategy. To be specific, I propose to develop late-stage direct radiofluorination method to synthesize [18F]fluorohydrin substrates via organophotoredox-mediated reactions. I also propose to develop new prosthetic groups such as radiolabeled isocyanate prosthetic groups and new strained alkynes for Strain- Promoted Azide Akyne Cyclizations (SPAAC). These proposed method/synthon developments will promote quick and iterative constructions of new PET tracer analogs for biodistribution evaluations, facilitate SAR studies, and have the potential to promote rapid development process of radiopharmaceuticals.