Next generation molecular imaging and therapy with radionuclides

For the last half-century doctors have routinely used radioactive drugs - radiopharmaceuticals - to detect and diagnose disease in patients and to treat cancer. This speciality is known as nuclear medicine. Modern imaging with radiopharmaceuticals is known as molecular imaging, and treating cancer with them is known as radionuclide therapy. Currently there are economic and geographical barriers, both in the UK and overseas, for patients accessing these scans and treatments. Our programme will develop technologies to perform both molecular imaging and radionuclide therapy more cost-effectively, benefitting more patients and greatly enhancing quality of information, depth of understanding of the disease, and therapeutic benefit. We will use new chemistry to make synthesis of the radiopharmaceuticals faster, more cost-effective and usable in more locations, and hence more accessible for patients. It will improve healthcare by producing and clinically translating new radioactive probes for positron emission tomography (PET), single photon emission computed tomography (SPECT) and radionuclide therapy, to harness the potential of emerging new scanners and therapeutic radionuclides, and provide a diagnostic foundation for emerging advanced therapies.
Advanced medicines such as cell-based and immune therapies, targeted drug delivery and radionuclide therapy pose new imaging challenges such as personalised profiling to optimise benefit to patients and minimise risk, and tracking the fate of drug/radionuclide carriers and therapeutic cells in the body. New alpha-emitting radionuclides for cancer therapy are impressing in early trials. New understanding of cancer heterogeneity shows that imaging a single molecular process in a tumour cannot predict treatment outcome. New generation scanners such as combined PET-MR are finding clinical utility, creating niche applications for combined modality tracers; new gamma camera designs and world-wide investment in production of technetium-99m, the staple raw material for gamma camera imaging, demand a new generation of technetium-99m tracers; and "total body PET" will emerge soon, enhancing the potential of long-lived radionuclides for cell and nanomedicine tracking. Demand for new tracers is thus greater than ever, but their short half-life (minutes/hours) means that many of them must be synthesised at the time and place of use. Except for outdated technetium-99m probes, current on-site syntheses are complex and costly, limiting availability, patient access and market size, particularly for modern biomolecule-based probes. Therefore, to grasp opportunities to improve healthcare afforded by the aforementioned advances in therapies and scanners, they must be matched by new chemistry for tracer synthesis.
This Programme will dramatically enhance patient access to molecular imaging and radionuclide therapy in both developed and low/middle-income countries, by developing and biologically evaluating faster, simpler, more efficient, kit-based biomolecule labelling with radioactive isotopes for imaging and therapy, streamlining production and reducing need for costly and complex automated synthesisers.
In addition, it will maximise future impacts of total body PET, SPECT, PET-MR by evaluating and developing the potential of multiplexed PET to harness the full potential of total body PET: combined imaging of multiple molecular targets, not just one, using fast chemistry for several very short half-live tracers in tandem in a single session to offer a new level of personalised medicine.
The programme will also enable the tracking of nanomedicines and cells within the body using long half-life radionuclides - an area where total body PET and PET-MR will be transformative). Finally, we will secure additional funding of selected probes into clinical use in heart disease, cancer, inflammation and neurodegenerative disease.

The beneficiaries will be hospitals in the UK (NHS) and abroad, and their patients with various diseases including those with major socioeconomic impact - cancer, cardiovascular disease, neurodegenerative disease and other brain disorders, transplantation, metabolic disease (e.g. diabetes), inflammatory disease and infectious disease. Molecular imaging plays a role in both research in these diseases and the management of patients, while radionuclide therapy is important in cancer and arthritis. These impacts will be achieved both through development of new tracers for aspects of disease not hitherto imageable, or even not yet perceived as important; and by making tracers more widely available for diseases that can currently be imaged. This is because short-lived tracers must be synthesised on-site in the hospital; the complexity of current synthesis and labelling requires costly and complex technology and expertise that is not universally available. This Programme emphasises fast, simple synthesis, reducing dependence on costly equipment (e.g. automated synthesisers, local cyclotron), making scanning available to more hospitals and hence more patients. This applies also to therapeutic radiopharmaceuticals, particularly in LMICs where large distances make delivery of ready-made radiopharmaceuticals impractical or uneconomic. The gains in diagnostic potential will improve decision making for individual patients, and hence their quality of life and survival. They will also improve patient stratification in clinical trials and use of drugs - personalised medicine. This benefits health services by identifying patients who will or will not benefit from treatments that may be costly or impair quality of life, allowing treatments to be targeted more effectively to the right patients.

The new chemistry will benefit companies, and hence the economy and jobs, both in pharma and medical and engineering. Pharma will benefit both by direct involvement in the development and supply chain for radiopharmaceuticals (e.g. GE Healthcare, Theragnostics), and by use of molecular imaging in clinical evaluation and use of new drugs (e.g. GSK and other industrial collaborators in the drug delivery field) to stratify patients in trials and measure clinical outcomes. Engineering companies (GE Healthcare, Siemens, Philips etc.) will benefit by expansion of the market for new advanced scanners (PET-CT, PET-MR, SPECT-CT and new SPECT designs such as D-SPECT, solid-state SPECT) to hospitals far from major PET centres, and the opportunity to develop new scanning technology to complement the new tracers.

Radionuclide therapy is well-established in cancer and arthritis. Recent years have seen tantalising advances in this field using alpha-emitting radionuclides. This Programme will provide new chemistry and radiobiological insight to help apply alpha-emitters in treating cancer patients, providing benefit both to patients, pharma and companies producing the radionuclides (see letters of support for examples).

The Programme will impact on workforce training. Multidisciplinary radiochemistry and medical engineering skills, particularly for working with short half-life radionuclides, are in short supply. This is being addressed by the current EPSRC Centre for Doctoral Training (CDTs) in imaging at King's and Imperial. The Programme will provide outlets to employ and further train PhDs emerging from CDTs, as well as a setting for training a new generation of PhD students attached to the Programme. This field is also attractive for encouraging students in schools and universities into science and technology because of its interdisciplinarity (accessible from physics, chemistry, biology, engineering, medicine and mathematics backgrounds) and its clear impact on health. The Programme has activities to achieve this impact at school and undergraduate level (including supporting undergraduate research projects), and for the general public.