To separate and bind: Chelators for extraction and stable coordination of radioactive metal ions

该项目旨在开发新的螯合剂，能够：(i)选择性地协调遗留核废料中存在的医学上有用的放射性金属离子；㈡稳定地协调这些医学上有用的同位素，使其能够应用于分子放射性药物；（iii）功能化，可附着于树脂上用于固相萃取，或附着于生物活性基团（如多肽）上用于疾病靶向。该项目将以螯合设计和合成一系列放射性核素为特色，这些放射性核素以前很少开发配体化学，位于元素周期表的低端，例如Ra-223， Pb-212， Ac-225和Th-227，存在于遗留的核废料中。这些放射性同位素提供了一系列成像、诊断和治疗特性，目前由于缺乏合适的螯合剂和放射性同位素本身缺乏可用性而未得到充分利用。这些金属中的许多已经以简单的卤化物，硝酸盐或氢氧化物的形式被利用，但在文献中已知的稳定的螯合物的真正缺乏。在这个项目中，学生将制备一系列大环“冠”配体，这些配体具有一系列在环系统内或作为垂坠基团的供体杂原子，这可以定制放射性金属的“硬-软”性质，并应用于NNL的固相萃取实验。将选择最有前途的螯合剂进行肽或抗体的生物偶联，并进行一系列放射性标记，体外和体内实验，以评估这些新的靶向放射性示踪剂的生物功效。

This project aims to develop new chelators that can: (i) selectively coordinate medically useful radioactive metal ions that are present in legacy nuclear waste; (ii) stably coordinate these medically useful isotopes to enable application in molecular radiopharmaceuticals; (iii) be functionalised for attachment to either resins for solid-phase extraction purposes, or biologically active groups (e.g. peptides) for disease targeting.This project will feature the chelate design and synthesis of a range of radionuclides for which previously very little ligand chemistry has been developed, and are situated towards the lower end of the periodic table e.g. Ra-223, Pb-212, Ac-225 and Th-227 and present in legacy nuclear waste. These radioisotopes offer a range of imaging, diagnostic and therapeutic properties which have currently been underutilised by the lack of suitable chelators, and the lack of availability of the radioisotopes themselves. Many of these metals have been utilised in their simple halide, nitrate or hydroxide compound state, but there is a real dearth of stable chelate complexes known in the literature. In this project, the student will prepare a range of macrocyclic 'crown' ligands featuring a range of donor heteroatoms either within the ring system or as pendant groups, which can enable a tailoring of the 'hard-soft' nature of the radiometals - and application in solid phase extraction experiments at NNL. The most promising chelators will be chosen to take forward for bioconjugation to a peptide or antibody, and subjected to a range of radiolabelling, in vitro and in vivo experiments to evaluate the biological efficacy of these new, targeted radiotracers.