Student: Rory Kenrick, Poppy Tobolski
1st Supervisor: Michelle Ma , King’s College London
2nd Supervisor: Nick Long, Imperial College London
Clinical Supervisor: Professor Gary Cook, King’s College London
Aim of the PhD Project:
- Develop new chelators that can complex large radioactive metal ions that are used for for PET, SPECT and radiotherapy;
- Identify the most promising chelator that can bind a diagnostic/therapeutic pair of radioactive metal ions with high stability;
- Attach the most promising chelator to biological targets (antibodies, peptides) for radiolabelling;
- Evaluate the in vitro and in vivo biology of radiometal-labelled bioconjugate derivatives of the most promising chelator.
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 beta- or alpha-emitting radiometals into the same molecular architectures to deliver targeted therapeutic radiation. Gallium-68 (Ga-68) PET agents and lutetium-177 (Lu-177) beta-emitting PRRTs have recently made a huge impact in prostate and neuroendocrine cancer in clinics where they are available. The Ga-68 and Lu-177 agents are used as a diagnostic/therapeutic pair of radiopharmaceuticals, and are often referred to as “theranostic” agents.
Alpha-particles deposit large amounts of energy over a short range, resulting in high cytotoxicity localised at a few cells. Tumours refractory to beta-PRRT and other therapies have demonstrated remission after alpha-PRRT. New radioactive metals that emit alpha-particles are becoming available, but to enable their application in PRRT, new versatile chelator platforms that enable simple radiolabelling of peptides and proteins are required.
Alpha-emitting bismuth-213 (Bi-213, 46 min half-life) is available from an Ac-225/Bi-213 generator. Actinium-225 (Ac-225, 10 day half-life) and thorium-227 (Th-227, 18.7 day half-life) are also alpha-emitters. Alpha-emitting Bi-212 (60 min half-life) is a product of lead-212 (Pb-212) decay (half-life10 days), which is also available from a generator. Pb-212 delivered to target tumour cells acts as an “in vivo generator”, providing a continual source of alpha-particles at the tumour site over time.All these metal ions possess expanded coordination spheres. There are readily available PET and SPECT radioisotopes (Ga-68, Zr-89, In-11, Tl-201) that could be used as diagnostic matches for pairing with these radiotherapeutic metal ions for “theranostic” applications.
Macrocyclic chelators are known to stably encapsulate transition, main group and lanthanide and actinide metal ions, with high kinetic stability. Hydroxypyridinones and hydroxypyridinthiones are well-documented to have high affinity for “hard” metal ions with a high charge density. We have demonstrated that a tripodal tris(3-hydroxypyridin-4-one) (THP) rapidly and stably binds Ga-68, and that this chemistry is suitable for kit-based labelling and receptor-targeted imaging (e.g. Figure 1a), [2,3] leading to development of a prostate cancer radiopharmaceutical that has completed early stage clinical trials.  More recently, we have prepared a hybrid macrocycle-hydroxypyridinone chelator, C-HP, based on cyclen and a 3,4-hydroxypyridinone derivative, and demonstrated that the In-111 complex, [In-111][In(C-HP)] possesses exceptionally high stability in biological media (unpublished work, Figure 1b). We have also prepared a tetrakis(hydroxypyridinone) chelator and shown that it complexes Bi-213 rapidly (< 2 min) under mild conditions (unpublished work, Figure 1c).
In this project, the student will prepare new hydrid chelators that combine macrocyclic aza-crown ethers (known to encapsulate lanthanide and actinide metal ions ), with hydroxypyridinones and hydroxypyridinthiones, and explore the coordination chemistry and radiolabelling of these new chelators with a range of metal ions with medically useful radioisotopes. This includes therapeutic radioisotopes of Pb(II), Bi(III) and Ac(III) and Th(IV) (with a view to assessing applicability with alpha-emitting isotopes) and imaging radioisotopes of Zr(IV), In(III) and Tl(I/III). The student will then select the most promising chelator, for bioconjugation to a peptide or antibody, as we have done with prior novel chelator derivatives. [2,6,7] The student will radiolabel this bioconjugate with selected imaging and therapeutic radiometals, and undertake in vitro and in vivo experiments to evaluate the biological behaviour of these novel, targeted radiotracers.
This project would suit a student with a background in synthetic chemistry, inorganic chemistry, medicinal chemistry or pharmaceutical chemistry.
- Jackson, J. A. et al, Bioconjugates of Chelators with Peptides and Proteins in Nuclear Medicine: Historical Importance, Current Innovations, and Future Challenges. Bioconjugate Chem. 2020, 31, 483–491.
- Imberti, C. et al, Enhancing PET Signal at Target Tissue in Vivo: Dendritic and Multimeric Tris(Hydroxypyridinone) Conjugates for Molecular Imaging of avβ3 Integrin Expression with Gallium-68. Bioconjugate Chem. 2017, 28, 481–495.
- Young, J. D. et al, 68Ga-THP-PSMA: A PET Imaging Agent for Prostate Cancer Offering Rapid, Room-Temperature, One-Step Kit-Based Radiolabeling. J. Nucl. Med. 2017, 58, 1270–1277.
- Kulkarni, M. et al, The Management Impact of 68Gallium-Tris(Hydroxypyridinone) Prostate-Specific Membrane Antigen (68Ga-THP-PSMA) PET-CT Imaging for High-Risk and Biochemically Recurrent Prostate Cancer. Eur. J. Nucl. Med. Mol. Imaging 2020, 47, 674–686.
- Thiele, N. A. et al, An Eighteen-Membered Macrocyclic Ligand for Actinium-225 Targeted Alpha Therapy. Angew. Chem. Int. Ed. 2017, 56, 14712–14717.
- Farleigh, M. et al, New Bifunctional Chelators Incorporating Dibromomaleimide Groups for Radiolabeling of Antibodies with Positron Emission Tomography Imaging Radioisotopes. Bioconjugate Chem. 2021, 32, 1214–1222.
- Hungnes, I. N., et al, in press, One-step, kit-based radiopharmaceuticals for molecular SPECT imaging: a versatile diphosphine chelator for 99mTc radiolabelling of peptides Dalton Trans. 2021, 10.1039/D1DT03177E.