Novel radiolabeling methods for molecular imaging probes

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Molecular imaging (MI) enables in vivo visualization of biologic processes such as metabolic pathways, enzyme activity and receptor occupancy. MI probes require a radiotracer to localize and quantify a molecule designed to probe specific biological processes or attach to certain cells or biomarkers. Radiotracers produce signals that can be detected by a gamma camera (single photon emission computed tomography, or SPECT) or a positron emission tomography (PET) scanner. The most widely available SPECT and PET radiotracers are technetium-99m and fluorine-18. These isotopes are attractive for their excellent nuclear properties, relatively low cost, ease of production and wide availability. Unfortunately, current methods of radiolabeling with 99mTc and 18F preclude labeling many bioactive molecules of interest. Their short half-lives (6 h and 2 h, respectively) dictate that labeling be done late in the synthetic sequence, with minimal post-labeling deprotection / purification. There is an unmet need for basic science to expand the synthetic toolbox and develop new labeling strategies to increase the number and availability of MI probes. In the long-term, I aim to build a research program that bridges the fields of synthetic organic, organometallic, and radiochemistry, cancer biology and MI. The first step is to solve the urgent basic science challenges in synthesizing SPECT and PET probes. In the short-term, we will design and develop electrochemical fluorination methods, 99mTc sandwich chemistry, bioorthogonal chemistry and automated reactors to facilitate radiofluorination and 99mTc labeling of bioactive molecules at the late stage of radiosynthetic sequences. Anodic oxidation under controlled potential conditions represents a strategy to overcome the reactivity challenge of late-stage radiolabeling of aromatic moieties and electron rich reaction centers with 18F. Small ligands such as phenyl groups 99mTc-labeled in a sandwich-type structure would allow labeling where the large chelating agents employed in 99mTc radiopharmaceuticals cannot be used. Bioorthogonal coupling reactions enable antibody imaging with these short-lived radioisotopes, while automated platforms will simplify access to imaging agents for use in a radiochemical laboratory. The interdisciplinary nature of the research program will create new opportunities for students and collaborations between experts in the field of synthetic, organometallic, electro- and radiochemistry, as well as microfluidics. The fluorination and 99mTc labeling methods proposed here would have a substantial and measurable impact in the fields of synthetic chemistry, medicinal chemistry, and MI development, beyond the creation of new fundamental knowledge. The research outlined in this proposal will fundamentally impact and improve access to MI agents, such as those used for imaging infection, inflammation and cancer metabolism, urgently required for medicinal diagnostics and drug development.