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.

分子成像是非侵入性临床诊断的关键工具之一，并打开了个性化患者治疗的可能性。尤其是正电子发射断层扫描（PET）正在迅速扩展，目前正在整个英国安装新的宠物成像中心。生物医学研究提供了越来越多的活性分子，这些分子靶向人体中的疾病部位，因此可以通过标记正电子发射同位素标记成像剂的原理作为成像剂。然而，尽管18-F放射性核素的可用性广泛，但目前18-F-FDG是诊所中唯一常规使用的宠物示踪剂。这主要是由于需要专门设备制造18-F标记成像剂的多步骤过程的复杂性。当前的标记方法也可能对敏感的生物分子有害，因此通常将小的前体分子标记，然后将其附着在活性生物分子上以创建成像剂。该项目将开发一种新的18-F标记方法，用于使用金属铝结合氟化物，而不是迄今为止采用的主要方法。一个步骤的标记程序将使临床医生可以将18-F-氟化物直接添加到包含生物分子的准备好的套件中，以准备成像剂。在标签中使用特殊聚合物珠的潜力可能比常规溶液方法获得更高的标记与未标记前体的比例。这具有更好的对比度，并减少由于存在未标记的过量生物分子而引起的患者反应问题。所涉及的化学不需要专门的设备，基于套件的方法更快，有助于最大程度地减少辐射工人对放射性核素的暴露。为了实现我们的目标，我们正在为氟化物设计金属结合位点，该位点将允许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连接感兴趣的生物分子的方法相结合，以保持其到达体内目标位点的能力。另外，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本身并没有必要的分辨率来观察络合物在像细胞一样小的物体中的复合物的行为。通过提供大量改进的标签，我们的新系统将有助于发现新的有效的生物分子，并促进在诊所中采用正电子发射断层扫描，而无需使用昂贵的专业设备。铝涉及的配体化学的最终好处是，它也有可能与其他金属宠物放射性核素一起使用。