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New approaches to radionuclide imaging of cancer with gallium-68

Student thesis: Doctoral ThesisDoctor of Philosophy

The positron emitting isotope 68Ga is gaining increasing interest in the radionuclide imaging community, due to its favourable decay properties and availability from a generator. Incorporation of 68Ga into biomolecules requires conjugation to a bifunctional chelator. The tris(hydroxypyridinone) ligand THPMe is a valuable chelator for 68Ga, being able to coordinate Ga(III) effectively in extremely mild conditions. These outstanding radiolabelling properties prompted further investigation of THPMe, as a prototype to develop improved tris(hydroxypyridinone) chelators, and as a tool to explore new strategies for cancer imaging with 68Ga.

In the first part of this project, a new tris(hydroxypyridinone) chelator, THPH, was developed, where the N1-methyl group in the hydroxypyridinone ring was replaced by hydrogen. A new synthetic strategy was developed to achieve this. Quantitative 68Ga labelling of THPH was achieved in mild conditions and in vivo stability of the radiolabelled complex demonstrated. Spectrophotometric titration and competition experiments revealed preference for Ga(III) over Fe(III) for both THPMe and THPH, with the latter possessing higher Ga(III) selectivity. A library of THP derivatives is potentially available from an intermediate in THPH synthesis as a result of the new strategy.

In a second part of this work, the ability of THPMe to interfere with 68Ga trafficking in biological systems was investigated. THPMe (24 nmol) was found able to chelate 68Ga in vivo, significantly accelerating its renal excretion in mice. We therefore explored use of THPMe as a blood clearance agent, to increase the tumour-to-blood activity ratio in the context of cancer imaging with 68Ga salts. Initial evaluation of THPMe in a melanoma model lead to inconclusive results, due to inconsistency of 68Ga-acetate biodistribution. However, successive evaluation in a colon cancer xenograft showed a three-fold increase in tumour-to-blood ratio for mice treated with THPMe compared to a control group, demonstrating THPMe potential as a blood clearance agent in this model.

Finally, a new pretargeting strategy for 68Ga imaging with antibodies was investigated, based on the in vivo chelation of 68Ga(III) by a pretargeted THPMe-antibody conjugate. Two THPMe-antibody conjugates were prepared by attachment of THPMe derivatives to non-internalising antibodies and their favourable 68Ga labelling properties and affinity for their target antigen verified. However, in vitro/in vivo evaluation, showed no pretargeting ability for either of these compounds, likely due to a low availability of THPMe-antibody conjugates at the antigen site and to competitive binding of 68Ga by transferrin or other proteins.
Original languageEnglish
Awarding Institution
Award date2018


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