Aim of the PhD Project:
- Develop new chelators capable of radiolabelling Scandium-44 at room temperature and neutral pH.
- Validate the kinetic stability of the Scandium-44 complexes against biological competitors.
- Develop a bifunctional chelator for targeting Scandium-44 in a prostate cancer model.
This project sets out to develop the next generation of chelators for scandium-44, which can be rapidly radiolabelled under physiological conditions for facile translation into current technology used within the clinic/radiopharmacy. The development of new chelators that can complex scandium-44 is essential to facilitate translation and widen the scope of applications for these PET radionuclides. Radiolabelling under mild conditions, at neutral pH and low temperatures is important as it will simplify the procedure from radionuclide production to patient by removing multiple synthetic steps currently used in a hospital radiopharmacy or PET centre to produce a tracer for imaging. This will also allow for the use of targeting moieties, such as proteins, that are sensitive to harsh radiolabelling conditions.
Scandium-44: 44Sc is a positron emitting isotope which has great potential that is not yet used in clinical PET. With a half-life of 3.9 hours, 44Sc can be used to study longer time course biological processes than Gallium-68, and it can be transported further from the manufacturing site. In addition to this, another isotope of scandium, 47Sc, emits β– (half-life 3.3 days, 162 KeV), and can be used as a therapeutic agent for treatment of cancers. The combination of these two radionuclides would make a powerful theranostic tool: the distribution of the therapeutic agent could be followed exactly using the PET agent. Scandium is thus a versatile radiometal that could be widely used in the future. Sc(III) has a flexible coordination number; complexes with coordination 3 to 9 have been reported, although octahedral 6 coordinate complexes are the most common. Optimal chelation of scandium has not, until recently, been widely explored. Since 2012 several papers have been published exploring the chelation of 44Sc by common chelators. DOTA forms stable complexes (logKSc-DOTA = 27.0) that remain stable to human serum over extended periods of time. However, labelling requires heating and extended reaction times (e.g. 70oC for 30 minutes).Labelling at RT was shown to be possible with labelling times > 24 hours. Acyclic chelators have been shown to bind scandium more rapidly than DOTA, although some chelators showed reduced stability when compared to cyclic chelators. Overall, the limited development of 44Sc chelators has shown that this radiometal has potential, with stable complexes formed under mild conditions but to date there are no ideal 44Sc chelators. Complex will need to be stable for longer periods of time to be widely used in medical applications.
In this project we will develop a series of chelators, that show various coordination modes for binding scandium-44, find the ideal system for radiolabelling at neutral pH and kinetic stability, while being able to functionalise with proteins for imaging cancer.
We will validate the targeting of these scandium-44 tracers in a prostate cancer model, and compare them to the gallium-68 counterparts that are in the clinic.
The PhD candidate will be expected to have a degree in chemical sciences, biochemistry or cancer biology with a willingness to undertake organic chemistry, inorganic radiochemistry, tissue culture and in vivo studies.