De Novo Carbon-11 Chemistry: New and Explorative Radiolabelling Strategies for PET

Medical imaging technology is currently revolutionising our understanding of the human body, the human mind and the diseases that affect us. Imaging techniques are now routinely used for the diagnosis of illnesses and to assist in the discovery of new treatments and cures. Many of us are now familiar with the power of modern scanning technology, such as ultra-sound, MRI or CT, available within our hospitals for the diagnosing conditions ranging from broken bones to stroke. Positron Emission Tomography, or PET imaging for short, is certainly less familiar to the general public. Recent technological advances in computers, material sciences and radiochemistry have now enabled the routine use of PET imaging in many of the UK's major hospitals. PET is characteristically different from the other imaging techniques as it is primarily used to give a so-called 'functional' picture, as opposed to a purely anatomical image, of biological processes. The type of functional information gained from PET is extremely useful for better understanding biological processes involved in diseases such as cancer and neurodegenerative illnesses such as Alzheimer's. PET imaging requires the injection of a radioactive tracer into the body prior to scanning. The synthesis of these tracer molecules is particularly challenging because they need radioactive isotopes that have very short half-lives. PET tracers are typically prepared in the hours or even minutes prior to a scan. Chemistry therefore plays a hugely important role in the PET imaging process, both for the synthesis of existing tracers and the development of new ones. Currently, however, there is a limited range of chemical reactions that can be used to prepare tracers for PET. To develop new tracer molecules, which will ultimately lead to a greater understanding of disease processes and help to find treatments, new types of chemistry and technology need to be conceived. The aim of this research proposal is to develop completely new radiochemistry for the synthesis of new radiolabelled molecules that are currently inaccessible, and to use these new tracer molecules to probe the hall-marks of cancer. The new radiochemistry to be developed will be based on using a small reactive molecule, called carbon disulfide, that will be labelled with a radioactive carbon-11 atom. This so-called 'C-11 carbon disufide' will then be reacted to produce labelled molecules that will find applications in PET imaging.

PET imaging sits at the boundary between the physical sciences and medicine. It is leading to new discoveries in biology and medicine by exploiting radiolabelling tracers that specifically target molecular receptors and damaged tissues in vivo. This project, by developing fundamental chemistry and radiochemistry, will impact both within the physical sciences and find future applications in medicine, as such, there will be a number of beneficiaries of this research. For example, in terms of immediate beneficiaries, those working in the PET radioisotope production and PET radiolabelling fields will be to able to directly apply the labelling techniques and production methods resulting from this project. PET radiochemists will be able to exploit newly reported precursror molecules and labelling routes for the development of labelled molecules and tracers. In the longer term, others working directly in the field of PET imaging (biologists and clinicians), initially within the cancer imaging, will be able to apply the proposed CXCR4 imaging agents either as a diagnostic marker for cancer and metastasis, or for the development of therapeutics targeting this receptor. Indirectly, this research - both explorative radiolabelling aspect and the applied tracer production of [C-11]IT1t - will find much wider application. Such novel labelling methods have the potential to be applied to a range of tracer molecules that could find applications in other areas of PET imaging and medicine, for example in neurology, cardiology and pysciatry. Other potential beneficiaries include the pharmaceutical sector who may also be able to apply this research within drug discovery programmes. For example, this work will enable isotopic radiolabelling of molecules in atomic positions that were previously inaccessible with exiting technology and thus could be used to give information on the accumalation, distribution and metabolism of lead compounds under drug development. Additionally, the new tracers proposed under this project will be expected to have higher affinities and specificities for the CXCR4 receptor and may therefore lead to the development of better assays for assessing therapeutics. It is the expectation that in the longer term there will a clinical benefit arising from improvements in cancer imaging or therapeutic developments as a result of this research and will therefore impact on health and well being. In the UK, PET imaging is finding increasing applications for clinical diagnosis and as tool for research purposes. The new chemisties developed under this project will aid the future expected growth of PET and ensure the UK has a competitive edge in the discovery of new labelling technology, biomarkers and imaging agents. Thus it will directly contribute both to our society in terms of potential health benefits and to the economy as the resulting discoveries find commerical applications in the healthcare field. Such direct benefits to healthcare will happen only in the much longer term and may not be realised for 10-20 years after the project.
The staff and students that work on this project will gain a broad range of research skills and training in radiolabelling techniques, radio-analytical methods, tracer production, PET biology and imaging sciences. They will experience all aspects of the PET imaging process from intial radioistope production to the application of tracers for imaging. Working in both an academic environment at IC and in close collaboration with our inductrial partner, Imanova, will give staff the necessary research skills and understanding of the professional expectations within industry to seek employment in high level academic or industrial research sectors.