New chelators for diagnostic and therapeutic pairs of radioactive metal isotopes

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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.