Final Report Summary - RADIOPHARM METAL ISO (New chemical platforms for targeted radiopharmaceuticals based on generator-produced metal isotopes)
Whole body diagnostic imaging using PET (positron emission tomography) allows clinicians to stage disease in cancer patients and thus assign patients to a course of appropriate therapy. Radioactive, positron-emitting isotopes such as gallium-68 and zirconium-89 are tethered to biomolecules such as proteins or peptides that target diseased tissue, and this radiopharmaceutical can ultimately provide a traceable signal when injected into a patient. The radiopharmaceutical accumulates at diseased tissue, and cameras locate this accumulation, resulting in an image that clinicians extract diagnostic information from.
Whilst gallium-68 and zirconium-89 isotopes have recently become commercially available, there is a lack of chemical platforms that allow this technology to be fully exploited. The radiopharmaceuticals that are derived from these isotopes are complex to synthesise in a hospital radiopharmacy, or the resulting radiopharmaceuticals themselves are not optimal.
To allow for simple and rapid radiolabelling, we have developed a new chemical platform – a tris(hydroxypyridinone) compound – to incorporate these isotopes into biomolecules. This has involved (i) extensive chemical synthesis to produce new bifunctional chelators, that can attach to both a targeting biomolecule and bind either gallium-68 or zirconium-89; (ii) attachment of the new bifunctional chelators to proteins and peptides to provide bioconjugates; (iii) radiosynthesis to bind either gallium-68 or zirconium-89 to the bioconjugates; and (iv) preclinical testing of the final radiotracer to determine where the new radiotracers accumulate in the body, and if they localise selectively at a particular type of tumour.
The new tris(hydroxypyridinone) bifunctional chelators provide facile access to peptide and antibody bioconjugates and these can be radiolabeled rapidly with gallium-68 and zirconium-89 under mild conditions, simply by addition of the radioisotope to the chelators/conjugates. Incorporation of the radioisotope is rapid (< 5 minutes) and yields of the final radiotracer are high. All of the gallium-68 radiotracers target tumour tissue selectively, providing a PET images that exhibits high contrast between tumour tissue and non-diseased tissue. In contrast, the zirconium-89 conjugates are not stable under biological conditions – zirconium-89 dissociates from the bioconjugate in the biological milieu and accumulates in bone.
These new chemical platforms allow simple, efficient preparation of a radiopharmaceutical based on gallium-68. The simplicity and efficiency of labelling at very low concentrations under mild conditions brings, for the first time, the possibility of kit-based gallium-68 tracer production without complex automated synthesis typical of multistep PET radiochemistry. This would greatly increase 68Ga PET access to hospitals, expanding the use of the gallium-68 generator. We are currently collaborating with commercial partners to develop products that will (i) allow other scientists access to these new chemical platforms for their own experiments and (ii) enable clinical translation and development of radiopharmaceutical products based on tris(hydroxypyridinone) compounds.
Whilst gallium-68 and zirconium-89 isotopes have recently become commercially available, there is a lack of chemical platforms that allow this technology to be fully exploited. The radiopharmaceuticals that are derived from these isotopes are complex to synthesise in a hospital radiopharmacy, or the resulting radiopharmaceuticals themselves are not optimal.
To allow for simple and rapid radiolabelling, we have developed a new chemical platform – a tris(hydroxypyridinone) compound – to incorporate these isotopes into biomolecules. This has involved (i) extensive chemical synthesis to produce new bifunctional chelators, that can attach to both a targeting biomolecule and bind either gallium-68 or zirconium-89; (ii) attachment of the new bifunctional chelators to proteins and peptides to provide bioconjugates; (iii) radiosynthesis to bind either gallium-68 or zirconium-89 to the bioconjugates; and (iv) preclinical testing of the final radiotracer to determine where the new radiotracers accumulate in the body, and if they localise selectively at a particular type of tumour.
The new tris(hydroxypyridinone) bifunctional chelators provide facile access to peptide and antibody bioconjugates and these can be radiolabeled rapidly with gallium-68 and zirconium-89 under mild conditions, simply by addition of the radioisotope to the chelators/conjugates. Incorporation of the radioisotope is rapid (< 5 minutes) and yields of the final radiotracer are high. All of the gallium-68 radiotracers target tumour tissue selectively, providing a PET images that exhibits high contrast between tumour tissue and non-diseased tissue. In contrast, the zirconium-89 conjugates are not stable under biological conditions – zirconium-89 dissociates from the bioconjugate in the biological milieu and accumulates in bone.
These new chemical platforms allow simple, efficient preparation of a radiopharmaceutical based on gallium-68. The simplicity and efficiency of labelling at very low concentrations under mild conditions brings, for the first time, the possibility of kit-based gallium-68 tracer production without complex automated synthesis typical of multistep PET radiochemistry. This would greatly increase 68Ga PET access to hospitals, expanding the use of the gallium-68 generator. We are currently collaborating with commercial partners to develop products that will (i) allow other scientists access to these new chemical platforms for their own experiments and (ii) enable clinical translation and development of radiopharmaceutical products based on tris(hydroxypyridinone) compounds.