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

诊断和跟踪疾病发展和/或治疗的最常用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发射正电子的放射性核素：这种不稳定的元素会坍缩，释放出正电子辐射，甚至在整个身体内部都能看到。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，可以在病人体内检测到18F作为标签。然而，到目前为止，18F的使用在很大程度上被限制在小分子药物上——大多数获得许可的18F“放射性示踪剂”都是小分子的。尽管已经有了一些有用的实验方法，可以将18F附着在更复杂的分子上，包括新一代蛋白质药物（生物制剂）。然而，目前的大多数方法都引入了大量的附加基团（“疤痕”-通常在许多拷贝中），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：虽然我们可以用这些老方法标记这些分子，但我们不能确定标记后它们的行为方式是否相同。这反过来又会在生成的数据中产生伪影的可能性，从而阻碍了对这类重要分子行为的更深入理解，并阻止了PET在理解复杂生物学和生理学方面的更广泛应用。在这个提议中，我们将开发新的方法，允许18F以“无疤痕”的方式插入到蛋白质中，以产生更纯的18F蛋白。这将使它们的使用形式基本上与它们的自然形式几乎相同。这种更高的纯度和精度可能会提供一种重要的工具，使生物和医学科学得到发展，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.