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.**