Novel chelators for Scandium-44 in PET imaging of prostate cancer

博士项目的目的：开发能够在室温和中性pH下放射性标记钪-44的新型螯合剂，以提高钪-44复合物对生物竞争对手的动力学稳定性开发用于前列腺癌模型中靶向钪-44的双功能螯合剂项目描述/背景：该项目旨在开发下一代钪-44螯合剂，其可以在生理条件下快速放射性标记，以便轻松转换为临床/放射性药物学中使用的当前技术。开发新的螯合剂，可以络合钪-44是必不可少的，以促进翻译和扩大这些PET放射性核素的应用范围。在温和条件下，在中性pH和低温下进行放射性标记是重要的，因为它将简化从放射性核素生产到患者的过程，通过去除目前在医院放射性药物或PET中心用于生产成像示踪剂的多个合成步骤。钪-44：44 Sc是一种正电子发射同位素，具有巨大的潜力，尚未用于临床PET。由于半衰期为3.9小时，44 Sc可用于研究比镓-68更长时间的生物过程，并且可以从生产现场进一步运输。除此之外，钪的另一种同位素47 Sc发射β-（半衰期3.3天），可用作治疗癌症的治疗剂。这两种放射性核素的组合将成为一种强大的治疗诊断工具：可以使用PET试剂精确地跟踪治疗剂的分布。因此，钪是一种用途广泛的放射性金属，在未来可能会被广泛使用。目前，钪的配体设计方面的研究还很缺乏，而新型螯合剂的开发对于钪-44的临床应用至关重要。本项目将开发一系列具有不同配位模式的钪-44螯合剂，寻找在中性pH和动力学稳定性下的理想放射性标记体系，我们将在前列腺癌模型中验证这些钪-44示踪剂的靶向作用，并将其与临床上的镓-68示踪剂进行比较。

Aim of the PhD Project:Develop new chelators capable of radiolabelling Scandium-44 at room temperature and neutral pHValidate the kinetic stability of the Scandium-44 complexes against biological competitorsDevelop a bifunctional chelator for targeting Scandium-44 in a prostate cancer modelProject description/background:This project sets out to develop the next generation of chelators for scandium-44, which can be rapidly radiolabeled under physiological conditions for facile translation into current technology used within the clinic/radiopharmacy. The development of new chelators that can complex scandium-44 is essential to facilitate translation and widen the scope of applications for these PET radionuclides. Radiolabeling under mild conditions, at neutral pH and low temperatures is important as it will simplify the procedure from radionuclide production to patient by removing multiple synthetic steps currently used in a hospital radiopharmacy or PET centre to produce a tracer for imaging. This will also allow for the use of targeting moieties, such as proteins, that are sensitive to harsh radiolabeling conditions.Scandium-44: 44Sc is a positron emitting isotope which has great potential that is not yet used in clinical PET. With a half-life of 3.9 hours, 44Sc can be used to study longer time course biological processes than Gallium-68, and it can be transported further from the manufacturing site. In addition to this, another isotope of scandium, 47Sc, emits beta- (half-life 3.3 days), and can be used as a therapeutic agent for treatment of cancers. The combination of these two radionuclides would make a powerful theranostic tool: the distribution of the therapeutic agent could be followed exactly using the PET agent. Scandium is thus a versatile radiometal that could be widely used in the future. There is a lack of research into the ligand design for scandium and producing a novel chelator is vital for 44Sc translation into the clinic.In this project we will develop a series of chelators, that show various coordination modes for binding scandium-44, find the ideal system for radiolabeling at neutral pH and kinetic stability, while being able to functionalise with proteins for imaging cancer.We will validate the targeting of these scandium-44 tracers in a prostate cancer model and compare them to the gallium-68 counterparts that are in the clinic.