Late Stage 18F-Fluorination of -CHF2 and -OCHF2 Groups in CNS Drug-Like Molecules

Lead Research Organisation: University of Oxford
Department Name: Oxford Chemistry


Context: Positron emission tomography (PET) is a powerful imaging modality used for non-invasive molecular imaging which can provide valuable information on receptor occupancy and distribution of a compound within the body. It is particularly useful for central nervous system (CNS) drug discovery due to the otherwise inaccessibility of the brain (difficulty in passing the blood brain barrier). The most commonly used radionuclide in PET is 18F, due to the prevalence of fluorides in biologically active compounds and the small structural perturbation induced by fluorination. 18F has a reasonable half-life (t1/2= 110 min) providing flexibility in ligand syntheses and imaging protocol designs. Therefore, expanding the synthetic toolbox for 18F-labeling of complex drug-like molecules is an area of high interest to the PET community. We propose to develop methods to 18F label the difluoromethyl (-CHF2) and difluoromethoxy (-OCHF2) groups in CNS drug-like molecules.
We aim to access ArCHF18F and ArOCHF18F in high specific activity from three different precursors through C-H activation, decarboxylation and desulfinylation respectively. The methodology we aim to exploit, is closely related to the work of Groves and Baran who have previously reported on methods to generate benzylic radicals and CF2H radicals respectively to access ArCF2H.
Accessing ArCHF18F and ArOCHF18F through a radical mediated C-H activation is unreported. While a decarboxylation approach has been reported for ArCH218F and ArOCH218F it has not been reported for ArCHF18F and ArOCHF18F. The desulfinilation strategy is conceptually novel. In addition to labelling a variety of (hetero)aryl motifs using the methodology we develop, we aim to label a variety of CNS drug-like molecules which are of interest to pharmaceutical companies at large including our collaborators at Pfizer.
This project aligns with some of EPSRC's key research areas, including 'medical imaging' and 'Chemical Biology and Biological Chemistry.' This project falls within the EPSRC Healthcare Technologies and Physical Sciences research area


10 25 50

Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/N509711/1 01/10/2016 30/09/2021
1809880 Studentship EP/N509711/1 01/10/2016 30/09/2019 Jeroen Sap