This Coordinated Research Project (CRP) will identify important technical issues related to the production and quality control of new theranostic copper-64 radiopharmaceuticals. Cu-64 is the only known radionuclide in the nuclear medicine transmuting through three different routes namely positron decay, beta decay and electron capture. Consequently these result in emission of positron particles which can be used in positron emission tomography (PET) and beta particles and Auger electrons both of which find use in therapy. Thus, this unique nature allows Cu-64 to be used for both diagnostic and therapeutic purpose in nuclear medicine and has earned it the name 'theranostic' radionuclide. Recent studies showed that Cu-64 in the most simple form (64Cu-CuCl2) as well as linked to a variety of bioactive molecules can be used as theranostic agents in human malignancies such as prostate, glioblastoma, melanoma, breast cancers) and also diagnosis of human copper-associated diseases such as atherosclerosis, Alzheimer’s etc.This CRP is focused on the application of newly-discovered theranostic properties of copper-64 cation as well as developing and evaluation of most promising Cu-64 chelated targeting theranostic agents for therapy and diagnosis of human diseases.
Based on the interesting preliminary data on the application of 64CuCl2 radiopharmaceutical in human cancers for diagnosis and therapy, the working group is focused on thorough preclinical/clinical investigations of the radiopharmaceutical. For these investigations, the priority is to better understand, and exploit for diagnostic and therapeutic purposes and endogenous Cu transport mechanisms. Cancer models to be investigated include prostate cancer, glioblastoma, lymphoma, breast cancer and melanoma. The unique opportunity of 64Cu to target various human cancers such as prostate, glioblastoma and melanoma also offers the opportunity to study the in-vitro and in-vivo behaviour of 64CuCl2 in these disease models. We therefore proposed to also evaluate the Cu-trafficking mechanisms, microdosimetry, radiobiology, etc. in comparison to other existing therapeutic radiopharmaceuticals (where available). A high incidence of receptor expression in either early- or late-stage/metastatic cancers creates potential for development of new and innovative monovalent and bivalent 64Cu radioligands to tailor receptor-specific uptake, optimize localization in cancerous tissues, and minimize uptake in normal tissues to produce high-quality, high-contrast PET images for early diagnosis and staging of human cancers and atherosclerotic plaques. In addition, these agents offer the added opportunity to be used for targeted therapy due to ideal particle emissions for the three decay modes. In these research investigations, we propose usage of selected targeting vectors (mono- or bivalent) to be delivered to participating countries to perform in-vitro and in-vivo evaluation of agents. For example, based upon a thorough review of the literature, the focal points of this CRP are to be peptides (e.g. particularly GRPR targeting, integrin targeting, somatostatin receptor targeting, etc.) and small molecules (e.g. PSMA inhibitors), and antibodies. In view of previous research investigations from numerous research groups around the world, the participants proposed usage of NOTA- or sarcophagine-based complexing agents for further evaluations to conjugate the targeting vectors in order to complex and stabilize the 64Cu metal centre.
64Cu Radiolabelling, in-vitro, and in-vivo Investigations Using Antibody-Based Targeting Vectors.
64Cu Radiolabelling, in-vitro, and in-vivo Investigations Using Bivalent aVb3/GRPR-Targeting Peptides.
64Cu Radiolabelling, in-vitro, and in-vivo Investigations Using PSMA-Targeting Small Molecule.
64Cu Radiolabelling, in-vitro, and in-vivo Investigations Using SSTR-2-Targeting Peptides.
Investigations of 64Cu Agents in Labelling of Mononuclear Leukocytes and Stem Cells.
Preclinical, Dosimetry, and Clinical Investigations Using 64CuCl2 for Theranostic Applications.
Usage of DOTHA2 for Conjugation to Varying Biomolecules.
The outcome of investigations of this CRP has addressed important technical issues associated with the usage of 64CuCl2.
The current CRP also indicated new and emerging technologies for the production of 64CuCl2 using cyclotrons and reactors.
This CRP reported the development of new small molecules and peptide/antibody-based 64Cu-tracers for diagnostic imaging and therapy. These new theranostic agents would be useful in the management of various types of cancers.
The output from this CRP is a technological asset to the IAEA Member States.
The technology transfer from this CRP will benefit the young and upcoming research groups around the globe.
Through this CRP many graduate students contributed to the development of 64Cu-radiopharmaceuticals and they will be a driving force for future production of radioisotopes and radiopharmaceutical activities in the Member States.
Participants of the CRP discussed the different aspects of Cu-64 radiopharmaceuticals during the RCMs that led to the preparation of an IAEA publication already submitted to IAEA publication section.
This Coordinated Research Project (CRP) identified important technical issues associated with the usage of 64CuCl2 as a theranostic agent for administration to human patients presenting with a host of cancer disease. These cancers include but are not limited to prostate, breast, neuroendocrine, uterine, and glioblastoma multiform. In addition, Member States have described interests in radiolabelling investigations of prostate specific membrane antigen (PSMA) and other small molecules. The emerging technological advances for diagnosis of PSMA-expressing prostate cancer in clinical studies provide an important point of focus for participating Member States in the CRP. This CRP focuses primarily upon research strategies developed between the Member States to produce new 64Cu-tracers having potential as theranostic radiopharmaceuticals.