18F-Difluoromethylation: The Missing Link in Radiochemistry for Positron Emission Tomography

"The importance of the physical sciences to advance life sciences has never been greater" and novel chemistry is continuously needed to program, understand and control function. This proposal fits within this context through innovation in the field of radiochemistry for applications in molecular imaging.

Positron-emission tomography (PET) is a unique modality for functional and quantitative molecular imaging of living tissues and organs. PET scans can interrogate biological processes in vivo, facilitate drug discovery and experimental medicine, enable early-stage clinical trials, and guide clinical practice (e.g. cancer and neurological disorders diagnosis, staging, and response to treatment). Combined with other diagnostic tests such as computed tomography (CT) or magnetic resonance imaging (MRI), this technology can facilitate for example the diagnosis of cancer, evaluate epilepsy, Alzheimer's disease and coronary artery disease.

Since PET is a type of nuclear medicine procedure relying on the emission of gamma rays, a tiny amount of a radioactive substance, called a radiopharmaceutical (radioactive tracer) is required to perform these studies. This radioactive substance must be prepared in a specialised laboratory that performs radiochemistry with a cyclotron-produced positron emitting radioisotope such as 18F, which is often used. Since the half-life of 18F is short (just under two hours), the chemistry involved is challenging. Many groups around the world have worked relentlessly to develop novel radiochemical transformations to form a carbon-18F or a carbon-[18F]CF3 bond because these are metabolically robust, and both the F and CF3 groups are frequently encountered in pharmaceutical drugs. Medicinal chemists have however recently discovered that the difluoromethyl group (CF2H) group has specific properties that can be hugely beneficial to improve the efficacy of pharmaceuticals, a discovery that has fuelled the demand for inventive radiochemistry to construct not only carbon-[18F]CF2H bonds but also oxygen-[18F]CF2H, sulfur-[18F]CF2H and nitrogen-[18F]CF2H bonds as well as other molecules with a CF2 motif, for example difluorinated cyclopropanes. A unified strategy to solve these problems would be ideal especially if it makes use of starting materials that are readily accessible. This is exactly what we intend to achieve with this project.

We propose to develop novel 18F-difluoromethylation reagents that we have carefully selected for their ability to release a highly reactive 18F-labelled difluorocarbene species that can react with a range of readily available precursors for 18F-difluoromethylation. These reagents will lead to the invention of novel radiochemical transformations that are most needed for PET applications, specifically various heteroatom-hydrogen insertions as well as cross-coupling reactions mediated by transition metals. These novel radiosyntheses will be performed on a range of automated platforms that are widely used in the UK and in the world. This aspect of the project is very important to ensure rapid translation of the novel radiochemistry proposed from a research laboratory to the clinic for immediate use to improve patient healthcare, and eventually manufacturing of new diagnostics or radioligands. In order to demonstrate within the timeframe of this project the value of the CF2H group in radiotracer development, we also propose to exemplify that 18F-radiotracers known to underperform because of metabolic radiodefluorination can be rescued by introducing an [18F]CF2H substituent; this is an exciting prospect for all scientists interested in PET imaging.