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      Cyclotron production of 43Sc for PET imaging

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          Abstract

          Background

          Recently, significant interest in 44Sc as a tracer for positron emission tomography (PET) imaging has been observed. Unfortunately, the co-emission by 44Sc of high-energy γ rays ( E γ = 1157, 1499 keV) causes a dangerous increase of the radiation dose to the patients and clinical staff. However, it is possible to produce another radionuclide of scandium— 43Sc—having properties similar to 44Sc but is characterized by much lower energy of the concurrent gamma emissions. This work presents the production route of 43Sc by α irradiation of natural calcium, its separation and purification processes, and the labeling of [DOTA,Tyr3] octreotate (DOTATATE) bioconjugate.

          Methods

          Natural CaCO 3 and enriched [ 40Ca]CaCO 3 were irradiated with alpha particles for 1 h in an energy range of 14.8–30 MeV at a beam current of 0.5 or 0.25 μA. In order to find the optimum method for the separation of 43Sc from irradiated calcium targets, three processes previously developed for 44Sc were tested. Radiolabeling experiments were performed with DOTATATE radiobioconjugate, and the stability of the obtained 43Sc-DOTATATE was tested in human serum.

          Results

          Studies of natCaCO 3 target irradiation by alpha particles show that the optimum alpha particle energies are in the range of 24–27 MeV, giving 102 MBq/μA/h of 43Sc radioactivity which creates the opportunity to produce several GBq of 43Sc. The separation experiments performed indicate that, as with 44Sc, due to the simplicity of the operations and because of the chemical purity of the 43Sc obtained, the best separation process is when UTEVA resin is used. The DOTATATE conjugate was labeled by the obtained 43Sc with a yield >98 % at elevated temperature.

          Conclusions

          Tens of GBq activities of 43Sc of high radionuclidic purity can be obtainable for clinical applications by irradiation of natural calcium with an alpha beam.

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          Most cited references27

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          Copper-64 radiopharmaceuticals for PET imaging of cancer: advances in preclinical and clinical research.

          Copper-64 (T(1/2) = 12.7 hours; beta(+), 0.653 MeV [17.8 %]; beta(-), 0.579 MeV [38.4 %]) has decay characteristics that allow for positron emission tomography (PET) imaging and targeted radiotherapy of cancer. The well-established coordination chemistry of copper allows for its reaction with a wide variety of chelator systems that can potentially be linked to peptides and other biologically relevant small molecules, antibodies, proteins, and nanoparticles. The 12.7-hours half-life of 64Cu provides the flexibility to image both smaller molecules and larger, slower clearing proteins and nanoparticles. In a practical sense, the radionuclide or the 64Cu-radiopharmaceuticals can be easily shipped for PET imaging studies at sites remote to the production facility. Due to the versatility of 64Cu, there has been an abundance of novel research in this area over the past 20 years, primarily in the area of PET imaging, but also for the targeted radiotherapy of cancer. The biologic activity of the hypoxia imaging agent, 60/64Cu-ATSM, has been described in great detail in animal models and in clinical PET studies. An investigational new drug application for 64Cu-ATSM was recently approved by the U.S. Food and Drug Administration (FDA) in the United States, paving the way for a multicenter trial to validate the utility of this agent, with the hopeful result being FDA approval for routine clinical use. This article discusses state-of-the-art cancer imaging with 64Cu radiopharmaceuticals, including 64Cu-ATSM for imaging hypoxia, 64Cu-labeled peptides for tumor-receptor targeting, (64)Cu-labeled monoclonal antibodies for targeting tumor antigens, and 64Cu-labeled nanoparticles for cancer targeting. The emphasis of this article will be on the new scientific discoveries involving (64)Cu radiopharmaceuticals, as well as the translation of these into human studies.
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            Are radiogallium-labelled DOTA-conjugated somatostatin analogues superior to those labelled with other radiometals?

            Gallium-68 is a metallic positron emitter with a half-life of 68 min that is ideal for the in vivo use of small molecules, such as [68Ga-DOTA,Tyr3]octreotide, in the diagnostic imaging of somatostatin receptor-positive tumours. In preclinical studies it has shown a striking superiority over its 111In-labelled congener. The purpose of this study was to evaluate whether third-generation somatostatin-based, radiogallium-labelled peptides show the same superiority. Peptides were synthesised on solid phase. The receptor affinity was determined by in vitro receptor autoradiography. The internalisation rate was studied in AR4-2J and hsst-HEK-transfected cell lines. The pharmacokinetics was studied in a rat xenograft tumour model, AR4-2J. All peptides showed high affinities on hsst2, with the highest affinity for the Ga(III)-complexed peptides. On hsst3 the situation was reversed, with a trend towards lower affinity of the Ga(III) peptides. A significantly increased internalisation rate was found in sst2-expressing cells for all 67Ga-labelled peptides. Internalisation into HEK-sst3 was usually faster for the 111In-labelled peptides. No internalisation was found into sst5. Biodistribution studies employing [67Ga-DOTA,1-Nal3]octreotide in comparison to [111In-DOTA,1-Nal3]octreotide and [67Ga-DOTA,Tyr3]octreotide showed a significantly higher and receptor-mediated uptake of the two 67Ga-labelled peptides in the tumour and somatostatin receptor-positive tissues. A patient study illustrated the potential advantage of a broad receptor subtype profile radiopeptide over a high-affinity sst2-selective radiopeptide. This study demonstrates that 67/68Ga-DOTA-octapeptides show distinctly better preclinical, pharmacological performances than the 111In-labelled peptides, especially on sst2-expressing cells and the corresponding animal models. They may be excellent candidates for further development for clinical studies.
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              Macrocyclic complexes of scandium radionuclides as precursors for diagnostic and therapeutic radiopharmaceuticals.

              The aim of this study was to evaluate new ligands which can be applied for labeling biomolecules with scandium radionuclides. Two radionuclides of scandium, (47)Sc and (44)Sc, are perspective radioisotopes for radiotherapy and diagnostic imaging. (47)Sc decays with a half-life of 3.35 days and a maximum β(-) energy of 600 keV and could be an alternative to carrier added (177)Lu radionuclide for targeted radionuclide therapy. Another scandium radionuclide (44)Sc (t(1/2) = 3.92 h) is an ideal β(+) emitter for PET diagnosis. It can be obtained as a daughter of the long-lived (44)Ti (t(1/2) = 60.4 y) from (44)Ti/(44)Sc generator. For complexation of scandium radionuclides macrocyclic ligands having a cavity size similar to Sc(3+) ionic radius were selected: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7 triacetic acid (NOTA), 1,4,7-triazacyclodecane-1,4,7 triacetic acid and 1,4,7-triazacycloundecane triacetic acid, and analogs of NOTA with 10, 11 and 12 atoms of the carbon in the ring. Our results have shown that from the studied macrocyclic ligands studied DOTA is most efficient for binding scandium radionuclides (44)Sc and (47)Sc to biomolecules. The determined stability constant of Sc-DOTA complex logK = 27.0 is comparable with stability constants for Y(3+) and heaviest lanthanides but is higher than those for In(3+) and Ga(3+). Also (46)Sc-DOTATATE conjugate exhibits high stability in-vitro studies. The (13)C NMR studies have shown that Sc-DOTA like Lu-DOTA forms in solution complexes with eight-coordination geometry. The lipophilicity of Sc-DOTATATE is nearly identical to that of Lu-DOTATATE, which suggests similar receptor affinity of both radioconjugates.
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                Author and article information

                Contributors
                +48 22 5041357 , a.bilewicz@ichtj.waw.pl
                Journal
                EJNMMI Phys
                EJNMMI Phys
                EJNMMI Physics
                Springer International Publishing (Cham )
                2197-7364
                4 December 2015
                4 December 2015
                December 2015
                : 2
                : 33
                Affiliations
                [ ]Institute of Nuclear Chemistry and Technology, Dorodna 16, 03-195 Warsaw, Poland
                [ ]Department of Nuclear Physics, University of Silesia, Katowice, Poland
                [ ]Heavy Ion Laboratory, University of Warsaw, Warsaw, Poland
                [ ]Nuclear Security Unit, Joint Research Centre, Institute for Transuranium Elements, European Commission, Ispra, Italy
                [ ]Nuclear Decommissioning Unit, Joint Research Centre, Ispra Site Management Directorate, European Commission, Ispra, Italy
                [ ]Synektik S.A., Research and Development Center, Warsaw, Poland
                Article
                136
                10.1186/s40658-015-0136-x
                4670438
                26637486
                f9fccd56-20f2-4f84-9a8f-5a6c00662ef9
                © Walczak et al. 2015

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 30 September 2015
                : 27 November 2015
                Categories
                Original Research
                Custom metadata
                © The Author(s) 2015

                scandium-43,cyclotron production,calcium target,alpha irradiation,pet radiopharmaceuticals

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