Student: Connor Townsend
1st supervisor: Michelle Ma, King’s College London
2nd supervisor: Samantha Terry, King’s College London
Aim of the PhD Project:
- Develop new hybrid hydroxypyridinone/tetraazamacrocycle chelators for versatile complexation of a range of clinically useful radioactive metals (for PET, SPECT and radiotherapy);
- Identify the most promising chelator that can bind a range of radiometal ions rapidly, with high kinetic and thermodynamic stability;
- Attach the most promising chelator to a peptide that targets prostate cancer;
- Evaluate the in vitro and in vivo biology of radiometal-labelled chelator-peptide derivatives, including PET, SPECT and biodistribution experiments in a mouse model of prostate cancer.
Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT), allow quantitative whole-body molecular imaging of cancer. One class of PET and SPECT molecular radiopharmaceuticals incorporates a radioactive metal bound via a chelator attached to a peptide or protein, which targets cell-surface receptors of diseased cells. Systemic Peptide Receptor Radionuclide Therapy (PRRT) of cancer incorporates ß – or ï¡- emitting radiometals into the same molecular architectures to deliver targeted therapeutic radiation.
In nuclear medicine, there are advantages in using the same chelator for complexation of different radioactive metal ions: (i) a single chelator-peptide conjugate can be used for PET, SPECT and radiotherapy, reducing synthesis and product development times; (ii) there is a general (sometimes erroneous) tenet that the pharmacokinetic properties and biodistribution of two different metal complexes of the same chelator-peptide derivative will be identical. In the case of the latter, this has enabled development of “theranostic” imaging/radiotherapeutic agents, where the imaging derivative is used to predict efficacy and determine dosimetry for the therapeutic derivative.
For example, DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) is a macrocyclic chelator that has been clinically utilised for radiolabelling many peptides and proteins with the PET metals 68Ga and 64Cu, the SPECT metal 111In, the ï¢-emitters 177Lu and 90Y, and the ï¡-emitters, 213Bi and 225Ac. Whilst this has allowed development of both PET and radiotherapeutic radiopharmaceuticals using the same DOTA-peptide derivative, DOTA is not an optimal chelator for many of these radiomtals. In the case of 64Cu derivatives, the complex demonstrates kinetic lability, leading to release of 64Cu in vivo. In the case of other derivatives, kinetic barriers to complexation require the use of harsh reaction conditions to incorporate the metal ion into the radiopharmaceutical, and these conditions are incompatible with some biomolecules.
We have demonstrated that a tripodal tris(3-hydroxypyridin-4-one) (THP) rapidly and stably binds 68Ga, and that this chemistry is suitable for kit-based labelling, leading to development of a prostate cancer radiopharmaceutical that is currently in clinical trials (Figure 1). Hydroxypyridinones have affinity for other, clinically useful imaging and radiotherapeutic radioisotopes , however, THP has only six O ligand donors and is too small to incorporate larger, oxophilic metal ions with coordination geometries between 6 – 9.
In this project, the student will develop hybrid hydroxypyridinone/tetraazamacrocycle chelators, and explore the coordination chemistry and radiolabelling of these chelators with a range of metal ions with medically useful radioisotopes, including 68Ga3+, 89Zr4+, 111In3+, 177Lu3+, 201Tl3+, 212Pb2+, 213Bi3+ and 225Ac3+ (1 – 5). These metal ions have high affinities for hydroxypyridinones and related species. The student will identify the best chelator – in this case, the chelator that can simply and stably coordinate several different radiometallic isotopes – for bioconjugation development. They will attach this chelator to a peptide targeting the prostate-specific membrane antigen (PSMA) receptor that is overexpressed in prostate cancer. The student will radiolabel this compound with two – three different radiometals, and undertake in vitro and in vivo experiments to evaluate the biological behaviour of these different metal-chelator bioconjugates.
Ultimately, the student will use outcomes from biological studies of different metal-chelator-PSMAt derivatives, as well as results from characterisation of the coordination geometries of the different metal chelator complexes to evaluate whether differences in coordination chemistry between different metal complexes affect the biological behaviour of these species.
This project will require the candidate to develop skills in small molecule, peptide, inorganic and radiochemical synthesis, in vitro biology including radiobiology, and preclinical in vivo experiments using small animals, including PET and SPECT scanning, and radiotherapy studies.
(1) Cinzia Imberti, Samantha Y. A. Terry, Carleen Cullinane, Fiona Clarke, Georgina H. Cornish, Nisha K. Ramakrishnan, Peter Roselt, Andrew P. Cope, Rodney J. Hicks, Philip J. Blower, Michelle T. Ma, Enhancing PET signal at target tissue in vivo: dendritic and multimeric tris(hydroxypyridinone) conjugates for molecular imaging of v 3 integrin expression with gallium-68, Bioconjugate Chemistry, 2017, 28, 481-495.