Development of novel acyclic chelates for gallium-68 and scandium-44 radiometals used in PET

Project Description

This proposal sets out to design, synthesize and validate the next generation of chelators for radiometals that are utilised in positron emission tomography. The radiometals; gallium-68 and scandium-44 that are produced on generators the size of a bench top coffee machine, will be the isotopes of focus in this proposal. As the generator production makes PET imaging with these isotopes more available to hospitals/radio pharmacies without access to a large cyclotron. The current issue with radiotracers based on these isotopes is the harsh conditions that are required to radiolabel the DOTA chelator along with the high ligand concentrations causing multiple steps to be performed in the radiopharmacy to pass QC. these novel acyclic chelators will be able to radiolabel the isotopes rapidly radiolabelled under physiological conditions, with the aim of lowering ligand concentrations for easy translation into the radiopharmacy. The development of new chelates that can complex gallium-68 and scandium-44 under mild conditions; at neutral pH and low temperatures is important as it will simplify the procedure to produce a tracer for PET imaging and also allows targeting motifs that are sensitive to harsh conditions to be used. This project will develop a series of bifunctional chelates for the complexation of gallium-68 and scandium-44 and focus on prostate cancer as a model for targeting imaging via the PSMA. The aim of the proposal is to develop these chelators for easy translation to the clinic utilising current kit based technology in the radiopharmacy.
Our preliminary data suggests the use of acyclic chelators, that are modular, to allow for control in complex formation, by using steric bulk, DT3A is novel the ligand of choice for this, based off of amino acids it can be functionalised to create the ideal cavity for the metal and control the kinetic and thermodynamic stability to allow for in vivo application. this system can also be used to introduce sites of functionalisation for bioconjugation to targeting motifs.

The proposal will be split into three work packages:

1) Development of DT3A derivatives and Bifunctional chelates, for gallium-68

Synthesis and validation of DT3A based chelates to provide the for ideal radiolabelling conditions for gallium-68, to allow for translation to kit based format within radiopharmacy.

2) Bioconjugation and biological evaluation of DT3A chelates gallium-68.

To develop bioconjugation techniques for the DT3A ligands to the PSMA targeting motif and validate this in vitro and in in vivo models of prostate cancer.

3) Development of DT3A/Dpaa ligands for scandium-44.

To synthesise novel chelates based on DT3A and Dpaa for scandium-44, which is a under used radioisotope for PET which can provide longitudinal imaging.

Outcomes of the award:
- Synthesis of a series of fully validated DT3A based bifunctional chelates with the ability to complex 68Ga and 44Sc under physiological conditions with high serum stability.
- Efficient bio-conjugation to targeting peptides (PSMA as a model system).
- High radiochemical yields under physiological conditions and ease of purification of the radiolabelled bioconjugate-PSMA-chelate.
- Specific targeting to metastatic prostate cancer in vitro and in vivo using the DT3A ligand set.
- Translate the successful ligands in kit forms for validation in radiopharmacy