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An inorganic kit-based approach to F-18 labeling of biomolecules for multimodal fluorescence/PET imaging

基于无机试剂盒的生物分子 F-18 标记方法，用于多模式荧光/PET 成像

基本信息

批准号：
EP/I021949/1
负责人：
Rebekka Hueting
金额：
$ 43.17万
依托单位：
King's College London
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2011
资助国家：
英国
起止时间：
2011 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FI021949%2F1
关键词：
inorganic kit based approach 18

项目摘要

Molecular imaging is one of the key tools for non-invasive clinical diagnosis and opens up the possibility of personalising patient treatment. Positron Emission Tomography (PET) in particular is expanding rapidly and new PET imaging centres are currently being installed across the UK. Biomedical research provides increasing numbers of active molecules that target disease sites in the body and thus could in principle function as imaging agents by labeling with a positron emitting isotope. However, 18-F-FDG is currently the only routinely used PET tracer in the clinic, despite the wide availability of the 18-F radionuclide. This is mainly due to the complexity of the multistep-procedures requiring specialized equipment to make the 18-F labeled imaging agents. The current labeling methods also can be harmful to sensitive biomolecules and thus a small precursor molecule is often labeled that is then attached to an active biomolecule to create the imaging agent. This project will develop a new 18-F-labeling method for sensitive biomolecules which uses the metal aluminium to bind fluoride, rather than carbon-fluorine bond formation which has been the main approach adopted hitherto. The one step labeling procedure will allow clinicians to add the 18-F-fluoride directly into a prepared kit containing the biomolecule in order to prepare the imaging agent. The use of special polymer beads in the labeling has the potential of achieving a higher ratio of labeled to unlabeled precursor than conventional solution methods. This has the advantage of giving better contrast in-vivo and reducing the problems of patient reaction caused by the presence of unlabelled excess biomolecule. The chemistry involved requires no specialised equipment and the faster, kit-based method helps to minimise the exposure of radiation workers to the radionuclide. To achieve our aim, we are designing metal binding sites for fluoride that will allow radiolabeling under conditions that do not harm sensitive biomolecules and proteins. We also propose to combine this approach with methods to attach biomolecules of interest in a way that preserves their ability to reach the target site in the body. Additionally, the compounds we propose are intrinsically fluorescent, so that the potential imaging agents can also be evaluated in living cells using fluorescence microscopy, since PET imaging on its own does not have the resolution necessary to observe the behaviour of the complexes in something as small as a cell. By offering much improved labeling, our new system will facilitate the discovery of new potent biomolecules and facilitate the adoption of Positron Emission Tomography in the clinic without the need for expensive, specialized equipment. A final benefit of the ligand chemistry involved for aluminium is that it also has the potential to be used with other metallic PET radionuclides.

分子成像是无创临床诊断的关键工具之一，为个性化患者治疗开辟了可能性。尤其是正电子发射断层扫描 (PET) 正在迅速扩张，目前英国各地正在安装新的 PET 成像中心。生物医学研究提供了越来越多的针对体内疾病部位的活性分子，因此原则上可以通过用正电子发射同位素标记来充当成像剂。然而，尽管 18-F 放射性核素广泛可用，但 18-F-FDG 是目前临床上唯一常规使用的 PET 示踪剂。这主要是由于需要专门设备来制造 18-F 标记显像剂的多步骤程序的复杂性。目前的标记方法也可能对敏感的生物分子有害，因此通常标记小的前体分子，然后将其附着到活性生物分子上以产生成像剂。该项目将开发一种新的敏感生物分子18F标记方法，该方法使用金属铝结合氟化物，而不是迄今为止采用的主要方法碳氟键形成。一步标记程序将允许临床医生将 18-F-氟化物直接添加到含有生物分子的准备好的试剂盒中，以制备显像剂。与传统溶液方法相比，在标记中使用特殊聚合物珠有可能实现更高的标记前体与未标记前体的比例。这样做的优点是可以在体内提供更好的对比度，并减少因未标记的过量生物分子的存在而引起的患者反应问题。所涉及的化学过程不需要专门的设备，而且更快、基于试剂盒的方法有助于最大限度地减少辐射工作人员对放射性核素的暴露。为了实现我们的目标，我们正在设计氟化物的金属结合位点，以便在不损害敏感生物分子和蛋白质的条件下进行放射性标记。我们还建议将这种方法与附着感兴趣的生物分子的方法结合起来，以保留它们到达体内目标部位的能力。此外，我们提出的化合物本质上是荧光的，因此也可以使用荧光显微镜在活细胞中评估潜在的成像剂，因为 PET 成像本身不具备观察细胞等小物体中复合物行为所需的分辨率。通过提供大大改进的标签，我们的新系统将促进新的有效生物分子的发现，并促进正电子发射断层扫描在临床中的采用，而无需昂贵的专用设备。铝配体化学的最后一个好处是它还有可能与其他金属 PET 放射性核素一起使用。