Development of novel chelates for use in molecular imaging

Lead Research Organisation: Imperial College London
Department Name: Dept of Chemistry


The use of metal complexes in molecular imaging is well established. The availability of technetium-99m from a commercial generator coupled with the properties of this radioisotope (technetium-99m emits 140 keV gamma-ray with 89% abundance) has meant that technetium-99m has become the preferred radioisotope for SPECT imaging. The 6 hour half life is attractive since it allows sufficient time for radiosynthesis and distribution of labelled compounds to imaging centres. The design of chelates and the corresponding metal-complexes plays a significant role in the development of new tracers. The properties of the metal-chelate moiety (e.g. lipophilicity, charge, size) can greatly influence the in vivo characteristics of the final labelled candidate. Another key factor of the design of chelates relates to the radiolabelling conditions utilized - for example, the physiochemical properties of the macromolecule will influence the choice of conditions. For example the pH and temperature can impact on the nature of the macromolecule (aggregation and stability). The labelling conditions (and consequently the design and modification of the chelate) need to be 'tuned' to the properties of the macromolecule. One of the critical properties of the resultant metal-chelate complex is that it is highly stable in vivo. Although, there have been significant developments in the use of chelates in technetium chemistry, recently the requirement to label more complex and larger macromolecules (> 10 kDa) has demonstrated the need to develop alternative chelates. Proposed Programme: (i) Novel chelate synthesis - the IC Chemistry Department and GEHC have considerable experience in this area. The plan is to design chelates which are suited to a broader range of labelling conditions e.g. pH, temperature. Tailored, multifunctional ligands can allow the modification of reactivity and lipophilicity, stablisation of specific oxidation states and investigation of substitution inertness. They can also play an integral role in muting the potential toxicity of a metallodrug to have a positive impact in areas of diagnosis and therapy. To date, ligand coordination to 99mTc has generally utilized N2S2 or N4-donating atoms but within this project, wider and unexplored aspects of Tc coordination chemistry will be investigated in the search for compounds with increased specificity. Chelate motifs to be studied will include P2N2, P4N2, P(=O)2N2, P(=O)4N2, P(=S)2N2 or P(=S)4N2 donor sets, either within a macrocyclic structure or within an open-chained multidentate ligand, such as a functionalised tris(pyrazolyl)borate or similar tripodal species. Another novel facet will involve the incorporation of redox-active groups within the chelate framework i.e. ferrocene, quinolines, dithiolenes, in order to harness and exploit the rich oxidation state chemistry of technetium, focusing on biological and biomedical applications. (ii) Labelling conditions will be developed using Tc-99m. Parameters including reducing agents, pH, temperature, reaction time will be investigated. (iii) Metal-complex stability will be assessed using standard methodology (in vitro & in vivo) and will be compared against existing chelate including bis(amine-oxime), bis-amine-dithiol, tetra-amine and polypyridyl. (iv) Successful chelates will be conjugated onto biomolecules e.g alpha-v-beta-3 inegrin peptide (RGD), Octreotide the somatostatin receptor ligand and other novel macromoles from the GEHC library. Key disease areas for application of these probes will be in oncology, neurology and metabolic disorders. (v) Biological evaluation of the above labelled candidates will be carried out in collaboration with the biology groups. The biological studies will include biodistribution, metabolism and imaging of probe in a suitable animal model. These studies will be carried out at GEHC laboratories.


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