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

Funder: UK Research and InnovationProject code: EP/I021949/1
Funded under: EPSRC Funder Contribution: 338,790 GBP

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

Description

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.

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