Radical Radiochemistry for Site- and Copy-Controlled 18F-Labeling of Proteins

用于诊断和跟踪疾病的发展和/或治疗的最常见方法之一是使用正电子发射断层扫描（PET）。这依赖于使用合适的正电子发射放射性核素：不稳定的元素，崩溃发射正电子辐射，甚至可以在整个身体内看到。其中最重要的是使用18 F，事实上，英国（和世界各地）的大多数医院都配备了合适的扫描仪，以允许检测18 F作为患者体内的标签。然而，迄今为止，18F的使用主要限于其与小分子药物的连接-大多数许可的18F-“放射性示踪剂”是小分子。尽管开发了一些有用的实验方法将18F连接到更复杂的目标分子上，包括新的和下一代蛋白质药物（生物制剂）。然而，大多数这些现有方法都会引入大量的额外基团（“疤痕”-通常是许多拷贝），导致生物分子功能的干扰和混合物的产生。这就产生了一个难题：因为虽然我们可以用这些老方法标记这些分子，但我们不能确定它们在标记后的行为是否相同。这反过来又会在生成的数据中产生伪影的可能性，从而妨碍了对这类重要分子行为的更深入理解，并阻止了PET更广泛地应用于理解复杂的生物学和生理学。在这项提案中，我们将开发新的方法，允许以“无疤痕”的方式将18F插入蛋白质中，以产生更纯的18F蛋白质。这将使它们能够以基本上与其天然形式几乎相同的形式使用。这种更高的纯度和精度可能提供一种重要的工具，使生物和医学科学能够进步，并更广泛地使用这种强大的成像形式。

One of the most common methods for diagnosing and following the development and/or treatment of disease is to use positron emission tomography (PET). This relies upon the use of suitable positron emitting radionuclides: unstable elements that collapse emitting positron radiation that can bee seen inside even whole bodies. Foremost amongst these is the use of 18F and, indeed, most hospitals in the UK (and around the world) are equipped with suitable scanners to allow the detection of 18 F as a label inside patience. To date, the use of 18F, however has been largely restricted to its attachment to small molecule drugs - most licensed 18F-'radiotracers' are small molecules. This is despite the development of some useful experimental methods for attaching 18F onto more complex molecules of interest, including new and next-generation protein drugs (biologics). Most of these current methods, however, introduce bulky additional groups ('scars' - often in many copies) that lead to perturbation of a biomolecule's function and the creation of mixtures. This creates a conundrum: in that whilst we can label these molecules using these older methods, we cannot be sure that they behave in the same way after labelling. This, in turn, creates the possibility of artefacts in the data that are generated that precludes a deeper understanding of how this important class of molecules behaves and stops the application of PET more generally to understand complex biology and physiology. In this proposal we will develop new methods that allow the insertion of 18F into proteins in a 'scar-free' manner to create more pure 18F-proteins. This will enable their use in a form that is essentially near identical to their natural form. This greater purity and precision is likely to provide an important tool that will allow biological and medical sciences to advance and to use this powerful form of imaging much more widely.