DOI: 10.1007/s10967-007-7143-x Journal of Radioanalytical and Nuclear Chemistry, Vol 277, No.2 (2008) 451–466 Radiochemical separation and quality assessment for the 68Zn target based 64Cu radioisotope production Le Van So,* P Pellegrini, A Katsifis, J Howse, I Greguric Radiopharmaceutical Research Institute, Australian Nuclear Science and Technology Organisation, New Illawarra Road, Lucas Heights , P.M.B 1, Menai NSW 2234, Australia (Received July 31, 2007) The radiochemical separation of the different radionuclides (64Cu, 67Cu, 67Ga, 66Ga, 56Ni, 57Ni, 55Co, 56Co, 57Co, 65Zn, 196Au ) induced in the Ni supported Cu substrate – 68Zn target system, which was bombarded with the 29.0 MeV proton beam, was performed by ion-exchange chromatography using successive isocratic and/or concentration gradient elution techniques The overlapped gamma-ray spectrum analysis method was developed to assess the 67Ga and 67Cu content in the 64Cu product and even in the post-67Ga production 68Zn target solution without the support of radiochemical separation This method was used for the assessment of 64+67Cu radioisotope separation from 67Ga , the quality control of 64Cu product and the determination of the 68Zn (p,2p)67Cu reaction yield The improvement in the targetry and the optimization of proton beam energy for the 68Zn target based 64Cu and 67Ga production were proposed based on the stopping power and range of the incident proton and on the excitation functions, reaction yields and different radionuclides induced in the target system Introduction 64Cu which emits both beta and positron in high abundance (39% β – and 17.4% β +) with a half-life of 12.7 hours can play a role of bi-functional radioisotope for both positron emission tomography (PET) imaging and endoradiotherapy (ERT) The better physical characteristics of low intensity of the high energy gamma-ray (1345.7 keV, 0.47%) and low energy β +emission (653 keV) of 64Cu compared to 61Cu and 62Cu are particularly useful for high resolution PET imaging Its 578 keV energy β–-emission, nearly identical to that of the 67Cu beta-emitter, is suitable for the ERT of small tumours Besides, the electron capture decay with its associated Auger emissions can yield more efficient cell killing when the 64Cu nuclide is deposited in the cell nucleus The combined effect of three decay modes of the 64Cu radioisotope gives a high cell killing efficacy.1 64Cu’s preferable properties involved in physiological pathways1–4 – being almost invariably bound to protein or peptide for transport purposes and for functional use, being sequestered in mettalothionein as Cu(I)-thiolate clusters, the redox and electron/oxygen transfer properties based enzymatic uses – make radioactive copper complex molecules useful (in their own right) as targeting radiopharmaceuticals (the bis[thiosemicarbazone] chelating group based PTSM and ATSM complexes, porphyrins, bleomycin) These compounds displaying the metal-essential biochemical properties of Cu are being used for brain and myocardial imaging studies (PTSM) and for tumour treatment (PTSM and ATSM).1,3 Another use of the Cu radioisotopes is based on the high capability of forming stable coordinative complexes with bifunctional chelators1,2 – acyclic polyaminocarboxylate (DTPA, EDTA), cyclic polyamines (Cyclam) and macrocyclic polyaminocarboxylates (TETA, DOTA, NOTA) The last two groups of chelator–Cu complexes with good in-vivo stability make the Cu radioisotopes amenable to coupling with the targetted molecules such as peptides and antibodies for the in-vivo applications This type of Cu-bifunctional chelator-biomolecule-conjugate further offers more versatile applications in PET imaging and in targeting radiotherapy The 64,67Cu-chelator-antibody conjugates (MAb35-against carcinoembryonic antigen, SEN7 and SWA20-against lung cancer antigen, VG76e, B72.3 antibodies) are the best-known targeting radiopharmaceuticals to this date The 64Cu labeled ligands targeting receptors (64Cu-DOTA-[Pro1, Tyr4]bombesin[1-14] for targeting GRP receptors, 64CuTETA-somatostatin analogs, 64Cu-DOTA-Annexin V.,) are conjugates being widely investigated.1–5 Currently two cyclotron based methods are used for 64Cu production The first is based on the 68Zn target and second on 64Ni The 64Ni target based production process is recently developed and based on the 64Ni(p,n)64Cu reaction.3,5,8,11–14 This production route, which uses a proton beam energy lower than 13 MeV for activation, has the advantages of no side nuclear reactions which could induce radionuclidic impurities in the 64Cu product However, the disadvantage of this process is the use of very expensive enriched 64Ni target The larger cyclotron with proton beam energy not adjustable to lower than 13 MeV is difficult to be used for the 64Ni target based 64Cu production due to the need for a larger amount of 64Ni target and a special target design * E-mail: slv@ansto.gov.au 0236–5731/USD 20.00 © 2008 Akadémiai Kiadó, Budapest Akadémiai Kiadó, Budapest Springer, Dordrecht LE VAN SO et al.: RADIOCHEMICAL SEPARATION AND QUALITY ASSESSMENT In contrast, the 68Zn target based production route was developed more than 10 years ago.15–18 This process was based on the 68Zn(p,αn)64Cu reaction and performed by separating 64Cu from the “waste” solution of the 68Zn(p,2n)67Ga reaction based 67Ga production process This production route seems more economic in the target utilization, because both 67Ga and 64Cu can be produced from the same low cost target However, the different side nuclear reactions inducing several longerlived radionuclides in the 68Zn target and its substrate are the main disadvantages Besides, the potential of 67Ga contamination in 64Cu is high due to the much higher reaction yield and much longer half-life of the 67Ga radionuclide The 68Zn(p,2p)67Cu reaction induced 67Cu and the target substrate contaminated “cold” Cu elemental impurity in the 64Cu product are crucial problems in performing the 68Zn target based production route So, the effective target design, optimal proton beam energy utilization and good radiochemical separation should be the main issues concerned about regarding the 68Zn target based 64Cu production As for the quality assessment the analysis of the overlapping gamma-ray spectra should be developed to identify 67Ga and 67Cu radionuclide contaminations in the 68Zn target based 64Cu product The lack of an analysis method for the evaluation of 67Ga and 67Cu radionuclide contamination may create a pitfall that fails to draw one’s attention on the performance of the 67Ga-64,67Cu separation Above are the reasons why the 68Zn target based 64Cu production and its quality assessment are worthy of further investigation In this paper some important aspects regarding the 68Zn target based 64Cu +67Ga production technology and the quality of the 64Cu product are reported Experimental Reagent and material The commercially available anion-exchange resin AG1-X4 and cation-exchange resin AG50W-X4 (BioRad) with average particle size of 200–400 mesh were used for the radiochemical separations Analytical grade hydrochloric acid and Milli-Q purified water were used for the whole experimental process Isotopically enriched 68Zn target was purchased from Trace-Sciences International Inc USA.27 The target isotopic compositions were 68Zn (>99.4%), 67Zn (0.43%), 66Zn (0.08%), 64Zn (