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

诊断和跟踪疾病发展和/或治疗的最常见方法之一是使用正电子发射断层扫描(PET)。这有赖于使用合适的发射正电子的放射性核素：不稳定的元素会坍塌，释放出甚至在全身都能看到的正电子辐射。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，以允许检测到18F作为耐心内的标签。然而，到目前为止，18F的使用在很大程度上仅限于它与小分子药物的结合--大多数获得许可的18F-‘放射性示踪剂’是小分子。尽管发展了一些有用的实验方法将18F连接到更复杂的感兴趣的分子上，包括新的和下一代蛋白质药物(生物制品)。然而，这些目前的方法中的大多数都引入了大量的附加基团(“伤疤”--通常是许多副本)，这会导致生物分子的功能受到干扰，并产生混合物。这就产生了一个难题：虽然我们可以用这些较旧的方法标记这些分子，但我们不能确保它们在标记后的行为是相同的。这反过来又在产生的数据中创造了人工制品的可能性，排除了对这类重要分子如何行为的更深层次的理解，并阻止了PET更广泛地应用于理解复杂的生物学和生理学。在这项提议中，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。这将使它们能够以与其自然形态基本相同的形式使用。这种更高的纯度和精确度可能会提供一个重要的工具，使生物和医学科学得以发展，并使这种强大的成像形式得到更广泛的应用。

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.