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      Production of copper-64 using a hospital cyclotron: targetry, purification and quality analysis

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          Abstract

          Supplemental Digital Content is available in the text.

          Objectives

          To construct and evaluate a 64Cu production system that minimises the amount of costly 64Ni, radionuclidic impurities and nonradioactive metal contamination and maximises radiochemical and radionuclidic purity and molar activity; and to report analytical and quality control methods that can be used within typical PET radiochemistry production facilities to measure metal ion concentrations and radiometal molar activities.

          Methods

          Low volume was ensured by dissolving the irradiated nickel in a low volume of hydrochloric acid (<1 mL) using the concave gold target backing as a reaction vessel in a custom-built target holder. Removal of contaminating 55Co and nonradioactive trace metals was ensured by adding an intermediate hydrochloric acid concentration step during the conventional ion-exchange elution process. The radionuclidic purity of the product was determined by half-life measurements, gamma spectroscopy and ion radiochromatography. Trace metal contamination and molar activity were determined by ion chromatography.

          Results and conclusions

          On a small scale, suitable for preclinical research, the process produced typically 3.2 GBq 64Cu in 2 mL solution from 9.4 ± 2.1 mg nickel-64 electroplated onto a gold target backing. The product had high molar activity (121.5 GBq/µmol), was free of trace metal contamination detectable by ion chromatography and has been used for many preclinical and clinical PET imaging applications.

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          Most cited references53

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          Imaging tumour hypoxia with positron emission tomography

          Hypoxia, a hallmark of most solid tumours, is a negative prognostic factor due to its association with an aggressive tumour phenotype and therapeutic resistance. Given its prominent role in oncology, accurate detection of hypoxia is important, as it impacts on prognosis and could influence treatment planning. A variety of approaches have been explored over the years for detecting and monitoring changes in hypoxia in tumours, including biological markers and noninvasive imaging techniques. Positron emission tomography (PET) is the preferred method for imaging tumour hypoxia due to its high specificity and sensitivity to probe physiological processes in vivo, as well as the ability to provide information about intracellular oxygenation levels. This review provides an overview of imaging hypoxia with PET, with an emphasis on the advantages and limitations of the currently available hypoxia radiotracers.
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            Visualization of Tumor-Immune Interaction - Target-Specific Imaging of S100A8/A9 Reveals Pre-Metastatic Niche Establishment

            Background Systemic cancer spread is preceded by the establishment of a permissive microenvironment in the target tissue of metastasis - the premetastatic niche. As crucial players in establishment of the pre-metastatic niche, myeloid derived suppressor cells (MDSC) release S100A8/A9, an exosomal protein that contributes to metastasis, angiogenesis, and immune suppression. We report the application of antibody-based single-photon emission computed tomography (SPECT) for detection of S100A8/A9 in vivo as an imaging marker for pre-metastatic tissue priming. Methods A syngeneic model system for invasive breast cancer with (4T1.2) or without (67NR) the tendency to form lung metastasis was established in BALB/c mice. A SPECT-probe has been generated and tested for visualization of S100A9 release. Tumor-associated changes in numbers and fuction of immune cells in pre-metastatic tissue were evaluated by flow cytometry and confocal microscopy. Results S100A8/A9 imaging reflected MDSC abundance and the establishment of an immunosuppressive environment in pre-metastatic lung tissue (activity 4T1.2 vs. healthy control: 0.95 vs. 0.45 %ID; p<0.001). The S100A8/A9 imaging signal in the pre-metastatic lung correlated with the subsequent metastatic tumor burden in the same organ (r2=0.788; p<0.0001). CCL2 blockade and the consecutive inhibition of premetastatic niche establishment was clearly depicted by S100A9-SPECT (lung activity untreated vs. treated: 2 vs, 1.4 %ID). Conclusion We report S100A8/A9 as a potent imaging biomarker for tumor-mediated immune remodeling with potential applications in basic research and clinical oncology.
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              Efficient production of high specific activity 64Cu using a biomedical cyclotron.

              Copper-64 (T 1/2 = 12.7 h) is an intermediate-lived positron-emitting radionuclide that is a useful radiotracer for positron emission tomography (PET) as well as a promising radiotherapy agent for the treatment for cancer. Currently, copper-64 suitable for biomedical studies is produced in the fast neutron flux trap (irradiation of zinc with fast neutrons) at the Missouri University Research Reactor. Access to the fast neutron flux trap is only possible on a weekly basis, making the availability of this tracer very limited. In order to significantly increase the availability of this intermediate-lived radiotracer, we have investigated and developed a method for the efficient production of high specific activity Cu-64 using a small biomedical cyclotron. It has been suggested that it may be possible to produce Cu-64 on a small biomedical cyclotron utilizing the 64Ni(p,n)64Cu nuclear reaction. We have irradiated both natural nickel and enriched (95% and 98%) Ni-64 plated on gold disks. Nickel has been electroplated successfully at thicknesses of approximately 20-300 mm and bombarded with proton currents of 15-45 microA. A special water-cooled target had been designed to facilitate the irradiations on a biomedical cyclotron up to 60 microA. We have shown that it is possible to separate Cu-64 from Ni-64 and other reaction byproducts rapidly and efficiently by using ion exchange chromatography. Production runs using 19-55 mg of 95% enriched Ni-64 have yielded 150-600 mCi of Cu-64 (2.3-5.0 mCi/microAh) with specific activities of 94-310 mci/microgram Cu. The cyclotron produced Cu-64 had been used to radiolabel PTSM [pyruvaldehyde bis-(N4-methylthiosemicarbazone), used to quantify myocardial, cerebral, renal, and tumor blood flow], MAb 1A3 [monoclonal antibody MAb to colon cancer], and octreotide. A recycling technique for the costly Ni-64 target material has been developed. This technique allows the nickel eluted off the column to be recovered and reused in the electroplating of new targets with an overall efficiency of greater than 90%.
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                Author and article information

                Journal
                Nucl Med Commun
                Nucl Med Commun
                NMC
                Nuclear Medicine Communications
                Lippincott Williams & Wilkins
                0143-3636
                1473-5628
                05 May 2021
                September 2021
                : 42
                : 9
                : 1024-1038
                Affiliations
                [a ]School of Biomedical Engineering and Imaging Sciences, King’s College London, School of Biomedical Engineering and Imaging Sciences, St Thomas’ Hospital
                [b ]National Physical Laboratory, Teddington, Middlesex, London, UK
                Author notes
                Correspondence to Philip J. Blower, DPhil, School of Biomedical Engineering and Imaging Sciences, Kings College London, St Thomas’ Hospital, 4 th Floor Lambeth Wing, London SE1 7EH, UK, Tel: +44 20 7188 9513; e-mail: philip.blower@ 123456kcl.ac.uk
                Article
                00012
                10.1097/MNM.0000000000001422
                8357037
                34397988
                d0f26b2e-54d6-488b-9cfd-d9a082eca47d
                Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

                History
                : 17 November 2020
                : 09 March 2021
                Categories
                Original Articles
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                copper-64,purification,quality control,solid targetry
                copper-64, purification, quality control, solid targetry

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