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

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：不稳定的元素会崩溃，发射甚至在整个身体内都可以看到的正电子辐射。其中最重要的是 18F 的使用，事实上，英国（以及世界各地）的大多数医院都配备了合适的扫描仪，可以检测 18F 作为患者体内的标签。然而，迄今为止，18F 的使用在很大程度上仅限于其与小分子药物的附着——大多数获得许可的 18F“放射性示踪剂”都是小分子。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，包括新型和下一代蛋白质药物（生物制剂）。然而，目前的大多数方法都会引入大量的额外基团（“疤痕”——通常有许多副本），从而导致生物分子功能的扰动和混合物的产生。这就产生了一个难题：虽然我们可以使用这些旧方法标记这些分子，但我们无法确定它们在标记后的行为是否相同。反过来，这可能会在生成的数据中产生伪影，从而妨碍更深入地了解这一类重要分子的行为方式，并阻止更广泛地应用 PET 来了解复杂的生物学和生理学。在本提案中，我们将开发新方法，允许以“无疤痕”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自然形式几乎相同的形式使用。这种更高的纯度和精度可能会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.