Construction of 18F-perfluorinated motifs by mechanistic leverage with fluorine

The range of applications of fluorinated compounds is incredibly diverse, particularly when one considers the cyclotron-produced radioisotope fluorine-18, a radionuclide which decays by positron emission. Fluorine-18 has physical properties that are well-suited to the radiolabelling of small organic molecules for Positron Emission Tomography (PET) imaging, a medical imaging technique that is routinely used in academia and industrial laboratories to help answer key biomedical questions in the diagnosis of numerous diseases, as well as key applications in the drug development process.

In fact PET imaging is unique in its ability to provide quantitative information on biological processes using radiolabelled compounds. This information is used in key decision making stages in the drug development pipeline by providing data on drug-target engagement, or determining the pharmacokinetic profiles. With the progression of "personalized medicine" to individually tailor diagnosis and treatment, PET imaging will play an increasingly important role in the future healthcare treatments. However, a crucial requirement of this medical imaging technique is the ability to synthesize the desired radioactive molecules necessary for imaging. In this regard, the synthesis of 18F-perfluorinated motifs is a major unmet challenge in the field of 18F-radiochemistry due the lack of suitable synthetic methods for their construction. This consequently limits the continued development of 18F-PET for diagnostic imaging and drug development.

The main focus of this research is address a critical gap in 18F-radiochemical methodology, by providing methods to access the 18F-perfluorinated motifs typically found in pharmaceuticals and radiotracers. In doing so we will be able to expand the range and diversity of small molecules that can be radiolabelled with fluorine-18, and consequently further 18F-PET imaging as a healthcare technology. Key to this proposal is to fundamentally understand the chemical reactivity of the fluorinated precursors and their suitability for radiochemistry. It is well recognized that fluorinated compounds have remarkable properties and reactivity in comparison to their non-fluorinated counterparts, and studies have shown that fluorinated electrophiles are typically unreactive towards [18F]fluoride in bimolecular nucleophilic substitution reactions (SN2), the most common method to introduce [18F]fluoride.

We propose to make use of the unique reactivity of fluorine atoms as leverage to help promote an alternative reaction pathway that is synergistic with the inherent reactivity of both the fluorinated precursor and [18F]fluoride. This will expand the 18F-radiochemical space such that researchers developing radiotracers for biomarkers or pharmaceuticals can consider entirely new functional groups and molecules to aid in their synthetic strategies. More generally we anticipate that the knowledge gleaned from this work on the reactivity of fluorinated building blocks will likely influence the construction of complex organofluorine compounds in research fields such as agrochemicals and materials science, where selective synthetic methods remain in high demand.

Outside of academia the direct beneficiaries of the proposed research those working in pharmaceutical and medicinal chemistry companies who use PET as an enabling technology for drug development. By providing expertise and robust radiochemical methods, companies will be able to use 18F-PET more routinely to gain a better insight to biological process to aid in the optimization of drug candidates. This will lead to more long-term societal impacts by improving healthcare for patients through new treatments and the development of better diagnostics and may inform on future clinical practice. The greater uptake of 18F-PET chemistry will lead to greater collaboration between industry and academia and attract more investment for future research, which will support more generally the UK-PET chemistry.

New methodologies for the synthesis of fluorinated compounds are highly valued in the pharmaceutical, agrochemical and material industries where fluorinated compounds are highly represented in commercially available products essential to modern society. These companies will be able to utilise the knowledge on the reactivity of fluorinated building blocks to address new and existing challenges in synthetic organofluorine chemistry.

Where appropriate any technological developments from this research will be handled by Cardiff University's Research and Innovation Services have a Technology Transfer Team, whose aim is to help academics commercialise research by further development of the technology and the protection of intellectual property. The generation of spin out companies or new products would be of clear economic benefit to the UK.

From an educational perspective this proposal will provide the PDRA with expert training in a highly multidiscipline environment, gaining skills in organic synthesis, fluorine chemistry and 18F-radiochemistry. This diverse training would be highly advantageous to the PDRA in an increasingly competitive job market, whose skill set would be highly valued by many industrial sectors.