New chelators for diagnostic and therapeutic pairs of radioactive metal isotopes

2. 博士项目目标（最多50字，以项目符号形式）：该项目旨在：开发新的螯合剂，可以复合用于PET， SPECT和放疗的大型放射性金属离子；确定最有前途的螯合剂，可以结合高稳定性的诊断/治疗放射性金属离子对；将最有希望的螯合剂附着在生物靶标（抗体、肽）上进行放射性标记；评价最有前途的螯合剂的放射性金属标记的生物偶联衍生物的体外和体内生物学。正电子发射断层扫描（PET）和单光子发射计算机断层扫描（SPECT），可以对癌症进行定量的全身分子成像。一类PET和SPECT分子放射性药物通过附着在肽或蛋白质上的螯合剂结合放射性金属，靶向病变细胞的细胞表面受体。癌症的全身性肽受体放射性核素治疗（PRRT）将b-或a-发射放射性金属纳入相同的分子结构中，以提供靶向治疗放射。镓-68 (68Ga) PET制剂和发射镥-177 (177Lu) b的prrt最近在前列腺癌和神经内分泌癌的临床应用中产生了巨大的影响。68Ga和177Lu试剂被用作诊断/治疗对放射性药物，通常被称为“治疗”试剂。在本项目中，学生将制备新的氢化物螯合剂，将叠氮冠醚（已知可包封镧系和锕系金属离子5）与羟基吡啶酮和羟基吡啶硫酮结合，并探索这些新的螯合剂与一系列金属离子的配位化学和放射性标记，这些金属离子具有医学上有用的放射性同位素，包括Pb2+的放射性同位素。Bi3+、Ac3+和Th4+（为了评估a发射同位素的适用性）和成像放射性同位素，如89Zr4+、111In3+和201Tl+/3+。然后，学生将选择最有前途的螯合剂，用于肽或抗体的生物偶联，就像我们对先前的新型螯合剂衍生物所做的那样学生将用选定的成像和治疗放射性金属对这种生物偶联物进行放射性标记，并进行体外和体内实验，以评估这些新型靶向放射性示踪剂的生物学行为。

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.