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Imaging Chemistry and Biology (pre-2019)

New platforms for 99mTc-labelled multimeric molecular SPECT imaging agents: bifunctional dithiocarbamate and diphosphine chelators

Project ID: 2016_201

Student: Ingebjorg Hungnes

1st supervisor: Phil Blower, King’s College London
2nd supervisor: Michelle Ma, King’s College London
Additional supervisors: Samantha Terry, James Wilton-Ely, Paul Pringle, Graeme Hogarth

The generator-produced isotope, technetium-99m (99mTc), is the workhorse isotope in diagnostic SPECT imaging. The alarm caused among the nuclear medicine community by the recent shortages of 99mTc due to nuclear reactor shutdowns testifies to the importance that this isotope still holds, and draws attention to the need for new research to exploit it in the new generation of molecular imaging with biomolecules. With worldwide investment in new production facilities for 99Mo/99mTc coincident with the recent clinical impact of molecular imaging of peptide receptor expression, innovations in ligand systems that will provide 99mTc-labelled molecular imaging agents that are simple to prepare in a radiopharmacy are particularly timely.

Dithiocarbamate and diphosphine chelators have been successfully utilised for radiopharmaceutical syntheses of myocardial imaging agents but have not been functionalised to enable conjugation to proteins and peptides that are suitable for molecular imaging. This project aims to synthesise new dithiocarbamate and diphosphine chelators that can be functionalised with multiple copies of a targeting peptide and radiolabelled with 99mTc to provide new molecular SPECT contrast agents (Figure). This project will build on preliminary work in our laboratory (Figure A, B) (Bordoloi et al. Dalton Trans., 2015, 44, 4963) to assess the ability of these new radiotracers to target peptide receptors in vivo and delineate diseased tissue using SPECT imaging. Lastly, the project aims to radiolabel the new conjugates with the radiotherapeutic -emitter, 188Re, and characterise the radiobiology of the new agents in vitro and in vivo to assess their therapeutic potential.

The project also involves collaboration with Prof Pringle and the University of Bristol’s EPSRC CDT Chemical Synthesis programme, and will provide students with opportunity to undertake work at the University of Bristol, synthesising new diphosphine chelators. The project provides scope for the PhD student to develop skills in chemical synthesis, radiochemistry, inorganic chemistry, SPECT imaging, cell culture, radiobiology and small animal handling.

Figure. Description is in the caption.

(A) Structure of 99mTC-N(DTCBP)2(M=Tc); (B) SPECT/CT showing uptake of (99rnTc-N (DTCBP)2) in calcified mesenteric artery in rat model; (C) Peptide conjugate of dithiocarbamate ligands coordinated to Tc/Re; (D) Peptide conjugate of diphosphine ligands coordinated to Tc/Re.

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