Grant: Project Grant

Targeted radioligand therapy (RLT) is a very promising yet expensive procedure which uses toxic radioisotopes that are linked to a targeting agent that binds to and directs the radiation specifically to cancer. Every cancer patient who is a candidate for RLT must receive a PET (positron emission tomography) scan to see if the tumor will respond to treatment. PET scans also use ligands that are labeled with different isotopes, typically 68Ga or 18F with 18F being the preferred isotope of choice owing to its higher resolution, lower radiotoxicity, and commercial availability. Theranostics are agents that let us "treat what we can see and see what we can treat". Theranostics should bind the target in the same way with the same affinity to maximize the chance that what is seen by imaging will be followed up with treatment. Ideally therefore, the theranostic used for imaging should be: a) identical to the one used for therapy and b) should be labeled with 18F to afford the best resolution. Before 2019, this concept was never known in practice. Yet we published the first-ever proof of concept where a single molecule can be labeled with 18F for diagnostic PET and then labeled with 177Lu for therapy. This is made possible by a breakthrough method we invented for one-step, aqueous radiofluorination of complex theranostics. This approach has several salient advantages: 1) we can access 18F-fluoride, with all of its advantages, 2) we can use any number of radiotherapeutic metals e.g. 177Lu, 212Pb and 225Ac, and 3) we can use specific chelators that cannot be imaged with 68Ga. The outcomes of this proposal will be new knowledge in the development of dual-isotope theranostic while being chemically identical across both diagnostic and therapeutic modalities. At the same time, this work will shift imaging practice towards simplicity in 18F-labeling. Long-term, this will inform the development of 18F-labeled companion diagnostics for radiometal chelating peptides.