Positron emission tomography (PET) is a powerful and rapidly developing technology that plays key roles in medical imaging, as well as drug discovery and development. Despite the exceptional promise of PET imaging, the availability of PET agents is limited in many situations due to the lack of efficient and simple labeling methods to modify biologically active small molecules/drugs. Based on the highly innovative photoredox system described by the Nicewicz group (Science, 2015, 349, 1326-1330), this research will address the need for novel PET imaging agents by establishing broadly-useful methodologies for late-stage radiofluorination and radiocyanation of aromatic substrates. The proposed approaches could have transformative impacts on the imaging field by providing access to novel PET agents that are previously challenging or impossible to synthesize. There are three aims in this application.
Aim 1 seeks to develop a photocatalyst library with different electron density, sterics and photophysical characteristics for radiolabeling unactivated aromatic rings.
Aim 2 will develop C?H [18F]fluorination and C?H [11C]cyanation of arenes via organic photoredox Catalysis.
Aim 3 will establish novel nucleophilic aromatic substitution reactions of phenol derivatives to afford [18F]aromatics and [11C]?CN-aromatics. A key strength of this application is the extensive preliminary data for the proposed approaches. We have make the first breakthrough on direct arene C?H fluorination with 18F? (Science, 2019, in press) that not only allows direct conversion of drugs to PET agents, but also enables fast ligand screening as shown in working examples. For C?O to C?F direct conversion, we also demonstrated the approach is valid with excellent radiolabeling yields. The ?cold? cyanation reactions have been established and ready for radiolabeling testing. Taking all these factors together, the proposed research will lead to an entirely new method for incorporation of [18F]F and [11C]CN into aromatic compounds using late stage radiolabeling. The mild conditions coupled with easy access to the required precursors will allow for the unprecedented access to novel aromatic PET tracers of use in neurology, oncology, and various other research area, which will generate high impact in those fields.

Public Health Relevance

Positron emission tomography (PET) is a powerful and rapidly developing technology that plays key roles in medical imaging, as well as drug discovery and development. This application aims to establish a robust and mild method for efficient installation of radioisotopes (18F and 11C) into aromatic or heteroaromatic motif of bioactive molecules. The success of this approach will lead to a general method for preparing novel PET agents that are previously challenging or impossible to synthesize.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
1R01EB029451-01
Application #
9945737
Study Section
Imaging Probes and Contrast Agents Study Section (IPCA)
Program Officer
Atanasijevic, Tatjana
Project Start
2020-05-01
Project End
2024-01-31
Budget Start
2020-05-01
Budget End
2021-01-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599