Silicon-18F and Metal Chelator Radio-Chemistries for Theranostic Applications

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This NSERC proposal's goal is to enrich the current portfolio of fluorine-18 (18F) labeling chemistries by introducing new strategies for radiotracer development for theranostic and diagnostic applications. We propose a number of novel techniques for imaging agent discovery, coalescing around the programmatic theme of radiochemical technology development. The common goal of all program parts is finding new theranostic platforms in nuclear medicine and labeling chemistries to enhance the current portfolio of imaging technologies using Positron Emission Tomography (PET). In program part 1, we will develop building blocks (BBs) for introducing simplified dual labeling protocols, combining the possibility to label a tumor targeting compound (e.g. peptides or antibodies (ABs)) with either the diagnostic nuclide 18F or with a therapeutic nuclide (e.g. 177Lu). This strategy omits the necessity to clinically validate two different compounds, one for diagnostic imaging and a second for endo-radiotherapy and concomitantly reduce the regulatory effort for clinical translation. These BBs consist of a Silicon-Fluoride-Acceptor (SiFA: a silicon-based BB for 18F introduction) integrated into a chelator structure for radiometal binding. This dual labeling BB can be easily attached to any kind of peptide or protein structure to serve as a labeling tag. In program part 2, we will develop a novel 18F-radiolabeling method based on the formation of silsesquioxan 18F- cages providing 18F-labeled peptide octamer radiotracers for oncologic diagnostic applications. Through accumulated strength of multiple affinities and cooperative binding of individual peptide/receptor binding interactions, we will introduce novel compounds with improved tumor binding and tissue retention. The 18F- ion acts as a structural template selectively facilitating the chemical formation of the silsesquioxan through fluoride silicon affinity interaction. This "fluoride-caging" or "F-click to cage" chemistry yields 18F-labeled compounds of exceptionally high molar activities. In program part 3, we will develop theranostic polymeric nanoparticles (PNPs) with the SiFA functionality for easy 18F-radiolabeling to take advantage of radiolabeled nanoparticles in cancer imaging and therapy. To use our PNPs as a theranostic platform for simultaneous PET imaging and therapeutic radionuclide delivery, we started to chemically locate the SiFA moiety inside the PNPs and plan to modify the PNP surface with radiometal chelators (e.g. DOTA). Different sizes of PNPs will be synthesized and decorated with different chelators as well as an internal SiFA unit exploiting the Enhanced Permeability and Retention Effect for tumor targeting.