Therapeutic Radiopharmaceuticals Labelled with New Emerging Radionuclides (F22053)
The images of [64Cu]ATSM (18.5 MBq) in healthy male rabbits 3 hours post injection
CRP at a Glance
This Coordinated Research Project (CRP) will identify important technical issues related to the production and quality control of emerging new radionuclides for use in the development of therapeutic radiopharmaceuticals. 67Cu, 186Re and 47Sc radionuclides have been selected based on their theranostic potential and their dual production routes through reactors and cyclotrons, target availability, and high specific activity production. Based on potential demand of Member States a collaborated research is needed for the establishment of standardized production, quality control and other important issues including preparation of technical protocols and guidelines for ultimate radiopharmaceutical development. The CRP is focused on production methods of the 67Cu, 186Re and 47Sc radioisotopes as Theranostic Radionuclides for possible radiopharmaceutical development as well as research purposes.
Radiopharmaceuticals are the important tool in Nuclear medicine application based on the use of specific radionuclides in the appropriate form for diagnosis and therapeutic applications. Therapeutic radiopharmaceuticals however are used in less extent due to many factors such as availability, low specific activity, insufficient targetry/recovery protocols and target material expenses. Despite these, many therapeutic radioisotopes have found their way into practice in form of radiopharmaceuticals including 131I, 90Y, 153Sm, 177Lu, 188Re, 186Re, etc. However, the availability and quality factors have limited the development of more therapeutic radiopharmaceuticals. These radionuclides can be produced by irradiating targets in Research Reactors and/or in accelerators, in particular Cyclotrons.
Radionuclide therapy (RT) based on the concept of delivering cytotoxic levels of radiation to disease sites is one of the rapidly growing fields of nuclear medicine. Unlike conventional external beam therapy, RT targets diseases at the cellular level rather than at a gross anatomical level. This concept involves a site-specific accumulation of a radionuclide followed by induction of cytotoxicity through the emission of particulate radiations. A therapeutic effect can manifest through the emission of β− particles, α particles, or Auger electrons (e−).
Although the high linear energy transfer (LET) is a characteristic property of α-particles, which produce very high-localized ionization densities in cells, however due to the lack of proper production routes and availability of alpha emitter radionuclides their application is limited. On the other hand, beta-emitters are at the moment the most important component in the development of therapeutic radiopharmaceuticals. For instance, low to medium energy β− particles are low LET radiation and considered more effective for treating small tumours, while high energy β− particles are more appropriate for treatment of larger tumours.
Several factors must be considered in choosing a particular radioisotope for therapeutic applications, such as physical half- life, energy of the particle emission, type of particle emission, specific activity, and the cost and availability of the radioisotope. The half-life must match the pharmacokinetics of the radioactive drug, specifically for uptake and clearance from normal versus targeted tissues, in order to maximize the dose to the target and minimize dose to normal tissue. One other important issue in choosing appropriate radioisotopes for the development of therapeutic radiopharmaceuticals is the possibility of performing both “therapy” and “diagnosis” applications based on the decay characteristics, usually known as “Theranostics”. For instance, a single radionuclide can possess both decay characters such as 177Lu (with photon emission and betta decay), or two radioisotopes for the same element exist with different decay characters (such as 67Cu as a betta emitter and 64Cu as a positron emitter) used for dual purposes.
Images of the theranostic 64Cu-DOTA-PR81 monoclonal antibody in a MUC1 positive tumour in animal model
In its continuous effort to stimulate progress in medical applications of radionuclides, IAEA, recently organized a Technical Meeting (TM) (titled; Preparation of CRP on Therapeutic Radiopharmaceuticals Labelled with New Emerging Radionuclides, October 2014, Vienna, Austria) to discuss the proposal for arranging a CRP focusing on the development of radiopharmaceuticals labelled with new beta emitter radionuclides with Theranostic properties and to evaluate the feasibility of technology transfer to Member States for corresponding production methods. The TM was attended by seven international experts and three external observers. After discussions and technical evaluation of many candidate radionuclides, the scientific team of the TM recommended focusing on 67Cu, 186Re and 47Sc as Emerging Theranostic Radionuclides to formulate a new CRP. These isotopes have been selected based on their theranostic potential and their dual production routes through reactors and cyclotrons, target availability, and high specific activity production. To limit the scope, this required the exclusion of other radionuclides that perhaps have promising therapeutic applications. Criteria for exclusion included, production limitations, lack of interests as well as low availability of starting materials.
The CRP will involve the development of standardized production, quality control and recovery procedures for new emerging beta emitter “Theranostic” radionuclides (67Cu, 186Re and 47Sc) for ultimate use in radiopharmaceutical development.
CRP Overall Objective
To formulate guidelines to enhance and strengthen the expertise and capability of Member States in deploying emerging 67Cu, 186Re and 47Sc therapeutic radioisotopes with “Theranostic” properties from research reactors and accelerators for medical applications in order to meet national needs as well as to assimilate new developments.
Specific research objectives
- Production of 67Cu, 186Re and 47Sc radionuclides using research reactors and accelerators for some participants for research and clinical use.
- Development of targetry procedures for the radionuclide production based on the production methods under unified bench-marking at the CRP group.
- Development of quality control procedures for the produced radionuclides based on the production methods under unified bench-marking at the CRP group.
- Development of target recovery procedures for the future productions based on the production methods under unified bench-marking to optimize the production expenses.
- Development of preliminary procedures for preparation of potential Radiopharmaceuticals of interest based on the mentioned radioisotopes and preclinical studies.
Expected research outcomes
The CRP is expected to enhance the capability of MS for the production and quality control of 67Cu, 186Re and 47Sc radionuclides and preliminary development of possible radiopharmaceuticals for therapeutic applications benefitting from the prepared guidelines in this CRP. Based on the level of their knowledge and expertise in some MS would have initiatives to developing new agents for specific diseases including cancers and arthritis rheumatoid.
The CRP is expected to produce a document containing an international guideline on the practical production (targetry, purification, quality control and recovery) of emerging theranostic 67Cu, 186Re and 47Sc radioisotopes according to the MS demands. Also production of these radionuclides and possible related radiopharmaceuticals in some MS institutes are expected.
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): firstname.lastname@example.org
- SATO, N., et al., First Measurement of the Radionuclide Purity of the Therapeutic Isotope 67Cu Produced by 68Zn(n,x) Reaction Using natC(d,n) Neutrons, J Phys Soc Jpn 83 (2014).
- BIDOKHTI, PS., et al., Nuclear Data Measurement of 186Re Production via Various Reactions. Nuclear Engineering and Technology, 42 (2010) 600-607.
- KOPECKÝ, P., et al., Excitation functions of (p,xn) reaction on natTi: Monitoring of bombardning proton beams, Appl. Radiat. Isot. 44 (1993), 687–692.
- KHANDAKER, MU., et al., Investigations of the natTi(p,x) 43,44m,44g,46,47,48Sc,48V nuclear processes up to 40 MeV, Appl. Radiat. Isot. 67 (2009), 1348–1354.
- HERMANNE, A., et al., Excitation functions for production of 46Sc by deuteron and proton beams in natTi: A basis for additional monitor reactions, Nucl Inst Methods Phys Res, B 338 (2014) 31–41.
- JALILIAN AR, M. et al. Development of a radioscandium immunoconjugate for radioimmunotherapy, Radiochimica Acta, (2012) 100, 215-221.
- MÜLLER, C., et al., Promising Prospects for 44Sc-/47Sc-Based Theragnostics: Application of 47Sc for Radionuclide Tumor Therapy in Mice, J Nucl Med (2014).
- JALILIAN, et al. Preparation and quality control of scandium-46 bleomycin as a possible therapeutic agent, Iran J Nucl Med (2012) 20(1):19-24.
- MAUSNER, L., et al., Production and evaluation of Sc-47 for radioimmunotherapy, J Radiolalled Comp Radiopharm (1993) 32:388-390.
- FAZAELI, Y.,et al. Production, Quality Control and Imaging of 64Cu-ATSM in Healthy Rabbits for Clinical Applications. Iran J Nucl Med (2010);18(2):29-37
- ALIREZAPOUR, B., et al. Development of [64Cu]-DOTA-PR81 radioimmunoconjugate for MUC-1 positive PET imaging. Nucl Med Biol, Accepted Manuscript, Available online 1 August 2015, DOI: http://dx.doi.org/10.1016/j.nucmedbio.2015.07.012