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Copper-64 Radiopharmaceuticals for Theranostic Applications (F22067)

Figure 1. Two important copper-chelating agents for biological targeting

CRP at a Glance

This Coordinated Research Project (CRP) will identify important technical issues related to the production and quality control of new theranostic copper-64 radiopharmaceuticals. As the only known radionuclide in the nuclear medicine Cu-64 is simultaneously emitting positron particles used in positron emission tomography (PET) as well as beta particles and Auger electrons used for therapeutic applications. Recent studies showed that Cu-64 in the most simple form (64CuCl2) 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.
The 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.


Figure 2. Fusion coronal images of a tumour-bearing mouse at 18h following tail vein injection of a 64Cu-labeled bombesin analogue

Copper-64 has several unique attributes that make it a multi-purpose radionuclide with many potential applications. It has a complex decay scheme, with electron capture, beta-emission and positron emission branches. The positron emission (18%) has a low energy allowing high resolution images and there are no abundant gamma emissions that impair the imaging properties as with many other positron emitters. The combination of positron and beta-emission (39%) imparts a high local radiation dose at the cellular level making it suitable (at least in principle) for targeted radionuclide therapy, while the electron capture decay (43%) is accompanied by emission of high LET Auger electrons which add to the cytotoxic potency if the radionuclide is located inside cells and particularly within or close to cell nuclei. Thus, it may be described as the archetypal “theranostic” radionuclide, producing excellent PET molecular imaging at low administered doses without major dosimetry or radiobiological concerns, and having potential for radionuclide therapy at high doses, with radionuclide distribution and accurate dosimetry possible using PET imaging during therapy.

Its half-life of 12.8 h makes it versatile – short enough to be useful for tracers with rapid pharmacokinetics such as small molecules and peptides, yet long enough to be useful for tracers with slow pharmacokinetics, for example those associated with monoclonal antibodies, and for the tracking of cell migration.

Its chemistry offers advantages: although it is less substitutional inert than other transition metals, with well-designed macrocyclic chelators it can be stably attached to targeting molecules such as antibodies, peptides, antibody fragments etc. Many years of design and optimisation of these chelators have generated a wide selection of useful bifunctional chelators for this purpose and the radiolabelling process is simple and straightforward.

It is also redox active, and the reduction of Cu(II) to Cu(I) in the biological milieu can be used as a basis for molecular imaging with very simple complexes, allowing blood flow and hypoxia imaging. Copper is an essential naturally occurring metal and its trafficking, accumulation and clearance are tightly controlled in normal health but often disturbed in disease states such as dementia, cancer, inflammation, nutritional abnormalities and inherited diseases of copper metabolism. This creates additional unique potential for Cu-64 in imaging these processes and perhaps exploiting them for therapy. This potential is almost entirely untapped at present.

Figure 3. Sagittal section: Cu-64 acetate in brain of normal mouse showing uptake restricted to choroid plexus/ventricles

With the above radiochemical and chemical attributes, Cu-64 could plausibly be described as the most versatile of all currently available medical imaging and therapeutic radionuclides.

The elevated copper concentration in cancer cells may potentially be used to differentiate healthy from transformed cells. Thus, Cu-64 dichloride has been applied to perform diagnostic PET/CT e.g. in staging of prostate cancer and detection of recurrent disease. High hepatic concentration of the radiopharmaceutical is an issue for use of Cu-64 dichloride PET/CT in clinical routine, but interesting results have been obtained in a recent application in Hodgkin lymphoma.

These data suggest the feasibility of Cu-64 dichloride PET/CT scanning in patients with progressive Hodgkin lymphoma and its potential for tailored radionuclide therapy. In a recent study a high uptake of Cu-64 dichloride in prostate cancer and involved regional lymph nodes was observed.

CRP Overall Objective

To formulate guidelines to enhance and strengthen the expertise and capability of Member States in production, quality control, preclinical and possible clinical application of copper-64 radiopharmaceuticals with “Theranostic” properties in order to meet national needs as well as to assimilate new developments.

Specific research objectives

  1. Evaluate in vivo stability of the two most promising Cu-64 chelating agents (NOTA and sarcophagine derivatives) conjugated to targeting molecules (such as peptides) under different conditions
  2. Build on promising preclinical work on radionuclide therapy with Cu-64 peptides with a view to translation of Cu-64 peptide radionuclide therapy to the clinic
  3. Improve understanding of the biological management and trafficking of copper in health and disease, using Cu-64 chloride and other innovative approaches to deliver Cu-64 and expose it to endogenous copper transport mechanisms
  4. Exploit this understanding to develop applications of Cu-64 chloride in imaging and therapy of disease, including cancers and non-oncological disease, by means of PET imaging studies in animal models and humans
  5. Undertake radiobiological investigations with Cu-64, including cellular toxicity in vitro and in animal tumor models, and possible comparison with currently used therapeutic radionuclides
  6. Measurement of organ and cellular (micro)dosimetry in animal models and in human studies with a view towards planning radionuclide therapy with Cu-64 tracers
  7. Evaluate effects of Cu-64 accumulation in liver, using dosimetry, micro dosimetry and functional measurements in animals and humans

Expected research outcomes

The CRP is expected to enhance the capability of MS for the production and quality control of 64Cu- radiopharmaceuticals (including 64Cu-efficiently-targeting agents and most simple 64CuCl2 radiopharmaceutical) for diagnosis and therapeutic applications at preclinical and clinical level(s).

Expected outputs

The CRP is expected to produce a document containing practical production, quality control and formulation of theranostic Cu-64 radiopharmaceuticals according to the MS demands. Also preliminary set-ups and considerations has been discussed for appropriate clinical studies based on available 64CuCl2 radiopharmaceutical among MS and also 64Cu-efficiently- targeting agents via collaborated research among potential participants.

How to join the CRP?

Please submit your Proposal for Research Contract or Agreement directly to the IAEA’s Research Contracts Administration Section, using the form templates (http://cra.iaea.org/cra/forms.html) on the CRA web site (preferably via email): research.contracts@iaea.org

Selected References

  1. Nanda, PK; et al. “Bombesin Analogues for Gastrin-releasing Peptide Receptor Imaging.” Nucl. Med. Biol., 2012, 39, 461-471.
  2. Baguña Torres J, et al. PET Imaging of Copper Trafficking in a Mouse Model of Alzheimer's Disease. J Nucl Med. 2015 Oct 8. pii: jnumed.115.162370. [Epub ahead of print]
  3. Alirezapour B, et al. Development of [64Cu]-DOTA-PR81 radioimmunoconjugate for MUC-1 positive PET imaging. Nucl Med Biol. 2015 Aug 1. pii: S0969-8051(15)00134-1.