Positron Emission Tomography (PET) is a high precision imaging tool for early disease diagnosis and treatment efficacy monitoring. A continuous demand for new imaging agents and the absence of practical, robust, selective methods for their synthesis calls for expanding the existing radiochemistry technologies.
In Specific Aim I we propose a new prosthetic group approach toward 18F incorporation. Fluorine-18 is preferred for its favorable positron emission properties and longer half-life (t1/2 = 110 min), so imaging agents can be produced remotely and distributed to hospitals. A traditional radiofluorination of complex molecules by late-stage functional group interconversion is limited by challenging synthesis of each precursor. The alternative approaches relying on direct C?H activation methodologies are at their nascent stages. They exhibit low radiochemichal yields (RCY) and innate substrate control of the fluorination sites, which can be restrictive to target binding. Low selectivity, common to this approach, might result in inseparable isomer mixtures, thus preventing the clinical use of these PET imaging probes due to FDA regulations. The prosthetic group approach, despite requiring one extra step, offers perfect fluorine site-selectivity. Our proposed prosthetic method features robust fluorination at easily accessible terminal olefins followed by rapid C?C bond formation toward the synthesis of diverse radiofluorinated compounds. If successful, it would allow unprecedented access to the use of aromatic, heteroaromatic, and aliphatic groups bearing desirable functionalities for PET imaging.
In Specific Aim II we propose the application of visible light-induced palladium chemistry toward rapid hybrid 11C-methyl radical addition to produce radiomethylated imaging agents. Carbon-11 has a much shorter half-life than fluorine-18 (t1/2 = 20 min), so radiotracer synthesis is extremely challenging. The current methods for 11C-incorporation rely on methylation, with nucleophilic substitution of heteroatoms as the most common strategy. Coupling reactions are much less developed though stoichiometric approaches have been reported. It is expected that our hybrid radical approach could improve methods for rapid methylation toward 11C-labeled PET imaging agents.
In Specific Aim III we will apply the proposed methods under development toward the synthesis of a library of agents to target HIF2? and tau prions. The most important applications of PET imaging concern early diagnosis and treatment progression monitoring of cancer and neurodegenerative diseases. Based on the structural features of published inhibitors and radioligands, we selected two potential applications of our proposed methods: HIF2???a transcription factor selectively found in certain malignancies, whose expression is a negative prognosis; and tau protein, a hallmark of neurodegenerative diseases, such as Alzheimer?s Disease. The ?cold? chemistry will be carried out at The University of Texas at Dallas and the radiochemistry at the Advanced Imaging Research Center at The University of Texas Southwestern Medical Center, as part of the pre-doctoral training plan of the PI, which includes full- time research complemented by mentorship and professional development.
The proposed work aims at the development of practical, robust, selective approaches for 18F- and 11C- incorporation. These include new prosthetic group approach of halofluorination followed by visible-light-induced novel C?C bond formation, and strategies toward rapid methylation relying on hybrid radical addition technologies. If fully developed, the proposed research will be highly impactful in synthetic chemistry by the development of new rapid C?C bond forming reactions; PET imaging by substantially expanding the tools available for design and synthesis of new radiopharmaceutical tracers; and in clinical applications by adding to the existing knowledge on HIF2?- and tau prion-targeted radioligands for cancer and tauopathy early diagnosis and treatment monitoring.
