New chelators for diagnostic and therapeutic pairs of radioactive metal isotopes

2. Aim of the PhD Project (max 50 words, as bullet points):
This project aims to:
Develop new chelators that can complex large radioactive metal ions that are used for for PET, SPECT and radiotherapy;
Identify the most promising chelator that can bind a diagnostic/therapeutic pair of radioactive metal ions with high stability;
Attach the most promising chelator to biological targets (antibodies, peptides) for radiolabelling;
Evaluate the in vitro and in vivo biology of radiometal-labelled bioconjugate derivatives of the most promising chelator.

Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT), allow quantitative whole-body molecular imaging of cancer. One class of PET and SPECT molecular radiopharmaceuticals incorporates a radioactive metal bound via a chelator attached to a peptide or protein, which targets cell-surface receptors of diseased cells. Systemic Peptide Receptor Radionuclide Therapy (PRRT) of cancer incorporates b-- or a-emitting radiometals into the same molecular architectures to deliver targeted therapeutic radiation. Gallium-68 (68Ga) PET agents and lutetium-177 (177Lu) b--emitting PRRTs have recently made a huge impact in prostate and neuroendocrine cancer in clinics where they are available. The 68Ga and 177Lu agents are used as a diagnostic/therapeutic pair of radiopharmaceuticals, and are often referred to as "theranostic" agents.
In this project, the student will prepare new hydrid chelators that combine aza-crown ethers (known to encapsulate lanthanide and actinide metal ions5), with hydroxypyridinones and hydroxypyridinthiones, and explore the coordination chemistry and radiolabelling of these new chelators with a range of metal ions with medically useful radioisotopes, including radioisotopes of Pb2+, Bi3+ and Ac3+ and Th4+ (with a view to assessing applicability with a-emitting isotopes) and imaging radioisotopes such as 89Zr4+, 111In3+ and 201Tl+/3+. The student will then select the most promising chelator, for bioconjugation to a peptide or antibody, as we have done with prior novel chelator derivatives.2,6 The student will radiolabel this bioconjugate with selected imaging and therapeutic radiometals, and undertake in vitro and in vivo experiments to evaluate the biological behaviour of these novel, targeted radiotracers.

Strains on the healthcare system in the UK create an acute need for finding more effective, efficient, safe, and accurate non-invasive imaging solutions for clinical decision-making, both in terms of diagnosis and prognosis, and to reduce unnecessary treatment procedures and associated costs. Medical imaging is currently undergoing a step-change facilitated through the advent of artificial intelligence (AI) techniques, in particular deep learning and statistical machine learning, the development of targeted molecular imaging probes and novel "push-button" imaging techniques. There is also the availability of low-cost imaging solutions, creating unique opportunities to improve sensitivity and specificity of treatment options leading to better patient outcome, improved clinical workflow and healthcare economics. However, a skills gap exists between these disciplines which this CDT is aiming to fill.

Consistent with our vision for the CDT in Smart Medical Imaging to train the next generation of medical imaging scientists, we will engage with the key beneficiaries of the CDT: (1) PhD students & their supervisors; (2) patient groups & their carers; (3) clinicians & healthcare providers; (4) healthcare industries; and (5) the general public. We have identified the following areas of impact resulting from the operation of the CDT.

- Academic Impact: The proposed multidisciplinary training and skills development are designed to lead to an appreciation of clinical translation of technology and generating pathways to impact in the healthcare system. Impact will be measured in terms of our students' generation of knowledge, such as their research outputs, conference presentations, awards, software, patents, as well as successful career destinations to a wide range of sectors; as well as newly stimulated academic collaborations, and the positive effect these will have on their supervisors, their career progression and added value to their research group, and the universities as a whole in attracting new academic talent at all career levels.

- Economic Impact: Our students will have high employability in a wide range of sectors thanks to their broad interdisciplinary training, transferable skills sets and exposure to industry, international labs, and the hospital environment. Healthcare providers (e.g. the NHS) will gain access to new technologies that are more precise and cost-efficient, reducing patient treatment and monitoring costs. Relevant healthcare industries (from major companies to SMEs) will benefit and ultimately profit from collaborative research with high emphasis on clinical translation and validation, and from a unique cohort of newly skilled and multidisciplinary researchers who value and understand the role of industry in developing and applying novel imaging technologies to the entire patient pathway.

- Societal Impact: Patients and their professional carers will be the ultimate beneficiaries of the new imaging technologies created by our students, and by the emerging cohort of graduated medical imaging scientists and engineers who will have a strong emphasis on patient healthcare. This will have significant societal impact in terms of health and quality of life. Clinicians will benefit from new technologies aimed at enabling more robust, accurate, and precise diagnoses, treatment and follow-up monitoring. The general public will benefit from learning about new, cutting-edge medical imaging technology, and new talent will be drawn into STEM(M) professions as a consequence, further filling the current skills gap between healthcare provision and engineering.

We have developed detailed pathways to impact activities, coordinated by a dedicated Impact & Engagement Manager, that include impact training provision, translational activities with clinicians and patient groups, industry cooperation and entrepreneurship training, international collaboration and networks, and engagement with the General Public.