Introduction In the past several years there has been a growing interest in the development of radiopharmaceuticals labeled with metallic radionuclides (Anderson et al. 1999). Of particular interest is the positron emitter Cu-64 (t½ = 12.7 h) for molecular imaging of small molecules as well as peptides and antibodies (Smith 2004). This has led us to the recent implementation of a solid target production facility using commercially available target irradiation station and chemistry modules. Routine production of Cu-64 was achieved with an average production yield of 0.32 mCi/μAh, however purification of Cu-64 has proven to be problematic; with several metallic contaminants compromising subsequent radiolabeling. We report in this work, the step by step procedure which led us to the successful production of low metal contaminant 64Cu with high specific activity and high labeling efficiency. Material and Methods Detailed implementation of our solid target was reported earlier (Poniger et al. 2012). A Nirta Solid Target from IBA was coupled to our 18/9 cyclotron using a 2-meter external beam line. A pneumatic solid target transfer system (STTS) designed by TEMA was use to deliver the irradiated target disks to a dedicated hotcell. Modules from IBA (Pinctada metal) were used for electroplating 64Ni onto a Ag disk and for acid dissolution and purification of the irradiated target. Typical irradiation parameters were 14.9 MeV at 35 μA for 5–6 hours with 64Ni plating’s ranging from 10–60 μm thickness at 6–12 mm. Radionuclidic purities were evaluated by gamma spectroscopy and traces of metallic impurities were determined by ICP-MS or ICP-AES. Labeling efficiency was evaluated by measuring the amount of 64Cu uptake per 20 μg of scFv-cage. Results and Conclusion Initial 64Cu purifications following the manufacturers recommended method resulted in high levels of Cu, Fe and Zn metal contaminants (see TABLE 1, ID 1). Note that little Ag contamination is observed nevertheless the 64Ni is plated directly on a Ag disk. After several productions, visual inspection of the module quickly revealed that the heater block used for heating the back of the Ag target disk was heavily corroded. Replacing the copper heater block with a PEEK heater block drastically reduced the levels of Cu and Fe contaminants. Unfortunately unusually high levels of Zn were still observed regardless of the stringent conditions and ultrapure reagents used during the processing (see TABLE 1, ID 5). In our quest for answers, ICP-MS analysis of the 64Ni plating solution as well as critical stock reagents such as Milli-Q water (18 MΩ cm−1) and 30% HCl TraceSelect Ultra (Sigma) was performed (see TABLE 1, ID 2,3,4). The results were surprising, with high level of Zn found not only in the 64Ni plating solution, but as well in the HCl TraceSelect Ultra. It was hypothesized that the Pinctada’s glass bottles (Kay, 2004) used to store the reagents, especially concentrated acidic solutions were the source of Zn contamination and all glass bottles were replaced by LDPE or PFA types. Our hypothesis was confirmed by subsequent ICP-MS analysis of fresh samples of HCl TraceSelect Ultra and the 64Ni plating solution prepared/stored in plastic containers (see TABLE 1, ID 6,7). We also confirmed by ICP-MS analysis that no contamination occurred when performing a non-radioactive dissolution/purification sequence on the Pinctada module using a blank PTFE target disk in conjunction with the change to plastic reagent storage bottles (see TABLE 1, ID 8). Initially the purification protocol was modified as described by Ometakova et al., 2012 to help reduce the co-elution of Zn contaminants with the 64Cu from the AG1-X8 resin. This change resulted in a significant amount of 64Cu eluting from the resin during the resin washing steps, so that protocol was abandoned and the protocol as described by Thieme et al., 2012 was adopted. By modifying the AG1-X8 resin washing protocol to this new method and eluting the 64Cu from with 0.1M HCl rather than Milli-Q water (see TABLE 1, ID 9), we were able to further reduce metal contaminants, especially Zn. During the course of these experiments, the true specific activity of 64Cu increased from as low as 12 mCi/μmol of Cu (n = 2, TABLE 1, ID 1) to 649 mCi/μmol of Cu (n = 7, TABLE 1, ID 5) and finally to 4412 mCi/μmol of Cu (n = 3, TABLE 1, ID 9). In the same time, the effective specific activity increased from 0.03 ± 0.02 mCi per 20 μg of scFv-cage, to 3.7 ± 0.3 mCi per 20 g of scFv-cage with 64Cu. In conclusion, a significant reduction in Cu, Fe and Zn contaminants was achieved when processing 64Cu using the Pinctada module: i) after replacement of the Cu heater block; ii) after elimination of glass reagent storage containers from the Pinctada module and procedures during preparation of the 64Ni plating solution and iii) after implementation of a new purification protocol (Thieme et al. 2012). Introduction of a 6M HCl wash-up cycle of the module prior to the dissolution procedure was also effective. However in recent 64Cu productions slightly elevated Ag levels have been observed and are under investigation (see TABLE 1, ID 9).

Introduction Copper-64 is an emerging radionuclide with applications in PET molecular imaging and/or internal therapy and it is typically produced by proton irradiation of isotopically enriched 64Ni electrodeposited on a suitable backing substrate. We recently reported a simple and efficient method for the preparation of nickel targets from electrolytic solutions of nickel chloride and boric acid [1]. Herein we report our recent research work on the analysis of metallic impurities in the copper-fraction of the radiochemical separation process. Material and Methods Nickel targets were prepared and processed as previously reported [1]. Briefly, the bath solution was composed of a mixture of natural NiCl2. 6H2O (135 mg/ml) and H3BO3 (15 mg/ml) and Ni was electrodeposited using a gold disk as cathode and a platinum wire as anode. The plating process was carried out at room temperature using 2 ml of bath solution (pH = 3.7) and a constant current density of 60 mA/cm2 for 1 hour. The unirradiated Ni targets were dissolved in 1–2 ml of concentrated (10M) HCl at 90 oC. After complete dissolution of the Ni layer, water was added to dilute the acid to 6M, and the solution was transferred onto a chromatographic column containing AG 1-X8 resin equilibrated with 6M HCl. The Ni , Co and Cu isotopes were separated by using the well-known chromatography of the chloro-complexes. The sample-fractions containing the Cu isotopes (15 ml, 0.1M HCl) were collected in plastic centrifuge tubes previously soaked in 1M HNO3 and rinsed with Milli-Q water (18 MΩ cm). Impurities of B, Co, Ni, Cu and Zn in these samples were determined by inductively coupled plasma-mass spectroscopy (ICP-MS) at the Department of Geosciences (Laboratory of Isotopic Studies) of the National University. Results and Conclusions The mass of Ni deposited in 1 h was 25.0 ± 1.0 mg (n = 3) and the current efficiency was > 75 % in all cases. The pH of the electrolytic solution tended to decrease along the electrodeposition process (3.71.6). The results of ICP-MS analysis of the Cu-fractions from the cold chromatography separation runs are shown in FIG. 1. We were particularly interested in the boron impurities as H3BO3 is used as buffer for electrodeposition of the Ni targets. Except for the Ni impurities that were deter-mined to be in the range of ppm (mg/l), all other analyzed metallic impurities were found to be in the range of ppb (µg/l), including boron. The Co, Ni, Cu and Zn impurities determined in the Cu-fraction in this work using Ni targets electrode-posited from a NiCl2 acidic solution, are in the same order of magnitude compared with that obtained when using targets prepared from an alkaline solution [2], with the advantage of the simplicity of the electrodeposition method from NiCl2 solutions, as the target material is already recovered in the chemical form of NiCl2, enabling a simpler, one step process to prepare a new plating solution when using enriched 64Ni target material for the production of 64Cu.

Introduction In the past several years there has been a growing interest in the development of radiopharmaceuticals labeled with metallic radionuclides (Anderson et al. 1999). Of particular interest is the positron emitter Cu-64 (t½ = 12.7 h) for molecular imaging of small molecules as well as peptides and antibodies (Smith 2004). This has led us to the recent implementation of a solid target production facility using commercially available target irradiation station and chemistry modules. Routine production of Cu-64 was achieved with an average production yield of 0.32 mCi/μAh, however purification of Cu-64 has proven to be problematic; with several metallic contaminants compromising subsequent radiolabeling. We report in this work, the step by step procedure which led us to the successful production of low metal contaminant 64Cu with high specific activity and high labeling efficiency. Material and Methods Detailed implementation of our solid target was reported earlier (Poniger et al. 2012). A Nirta Solid Target from IBA was coupled to our 18/9 cyclotron using a 2-meter external beam line. A pneumatic solid target transfer system (STTS) designed by TEMA was use to deliver the irradiated target disks to a dedicated hotcell. Modules from IBA (Pinctada metal) were used for electroplating 64Ni onto a Ag disk and for acid dissolution and purification of the irradiated target. Typical irradiation parameters were 14.9 MeV at 35 μA for 5–6 hours with 64Ni plating’s ranging from 10–60 μm thickness at 6–12 mm. Radionuclidic purities were evaluated by gamma spectroscopy and traces of metallic impurities were determined by ICP-MS or ICP-AES. Labeling efficiency was evaluated by measuring the amount of 64Cu uptake per 20 μg of scFv-cage. Results and Conclusion Initial 64Cu purifications following the manufacturers recommended method resulted in high levels of Cu, Fe and Zn metal contaminants (see TABLE 1, ID 1). Note that little Ag contamination is observed nevertheless the 64Ni is plated directly on a Ag disk. After several productions, visual inspection of the module quickly revealed that the heater block used for heating the back of the Ag target disk was heavily corroded. Replacing the copper heater block with a PEEK heater block drastically reduced the levels of Cu and Fe contaminants. Unfortunately unusually high levels of Zn were still observed regardless of the stringent conditions and ultrapure reagents used during the processing (see TABLE 1, ID 5). In our quest for answers, ICP-MS analysis of the 64Ni plating solution as well as critical stock reagents such as Milli-Q water (18 MΩ cm−1) and 30% HCl TraceSelect Ultra (Sigma) was performed (see TABLE 1, ID 2,3,4). The results were surprising, with high level of Zn found not only in the 64Ni plating solution, but as well in the HCl TraceSelect Ultra. It was hypothesized that the Pinctada’s glass bottles (Kay, 2004) used to store the reagents, especially concentrated acidic solutions were the source of Zn contamination and all glass bottles were replaced by LDPE or PFA types. Our hypothesis was confirmed by subsequent ICP-MS analysis of fresh samples of HCl TraceSelect Ultra and the 64Ni plating solution prepared/stored in plastic containers (see TABLE 1, ID 6,7). We also confirmed by ICP-MS analysis that no contamination occurred when performing a non-radioactive dissolution/purification sequence on the Pinctada module using a blank PTFE target disk in conjunction with the change to plastic reagent storage bottles (see TABLE 1, ID 8). Initially the purification protocol was modified as described by Ometakova et al., 2012 to help reduce the co-elution of Zn contaminants with the 64Cu from the AG1-X8 resin. This change resulted in a significant amount of 64Cu eluting from the resin during the resin washing steps, so that protocol was abandoned and the protocol as described by Thieme et al., 2012 was adopted. By modifying the AG1-X8 resin washing protocol to this new method and eluting the 64Cu from with 0.1M HCl rather than Milli-Q water (see TABLE 1, ID 9), we were able to further reduce metal contaminants, especially Zn. During the course of these experiments, the true specific activity of 64Cu increased from as low as 12 mCi/μmol of Cu (n = 2, TABLE 1, ID 1) to 649 mCi/μmol of Cu (n = 7, TABLE 1, ID 5) and finally to 4412 mCi/μmol of Cu (n = 3, TABLE 1, ID 9). In the same time, the effective specific activity increased from 0.03 ± 0.02 mCi per 20 μg of scFv-cage, to 3.7 ± 0.3 mCi per 20 g of scFv-cage with 64Cu. In conclusion, a significant reduction in Cu, Fe and Zn contaminants was achieved when processing 64Cu using the Pinctada module: i) after replacement of the Cu heater block; ii) after elimination of glass reagent storage containers from the Pinctada module and procedures during preparation of the 64Ni plating solution and iii) after implementation of a new purification protocol (Thieme et al. 2012). Introduction of a 6M HCl wash-up cycle of the module prior to the dissolution procedure was also effective. However in recent 64Cu productions slightly elevated Ag levels have been observed and are under investigation (see TABLE 1, ID 9).

Introduction Copper-64 is an emerging radionuclide with applications in PET molecular imaging and/or internal therapy and it is typically produced by proton irradiation of isotopically enriched 64Ni electrodeposited on a suitable backing substrate. We recently reported a simple and efficient method for the preparation of nickel targets from electrolytic solutions of nickel chloride and boric acid [1]. Herein we report our recent research work on the analysis of metallic impurities in the copper-fraction of the radiochemical separation process. Material and Methods Nickel targets were prepared and processed as previously reported [1]. Briefly, the bath solution was composed of a mixture of natural NiCl2. 6H2O (135 mg/ml) and H3BO3 (15 mg/ml) and Ni was electrodeposited using a gold disk as cathode and a platinum wire as anode. The plating process was carried out at room temperature using 2 ml of bath solution (pH = 3.7) and a constant current density of 60 mA/cm2 for 1 hour. The unirradiated Ni targets were dissolved in 1–2 ml of concentrated (10M) HCl at 90 oC. After complete dissolution of the Ni layer, water was added to dilute the acid to 6M, and the solution was transferred onto a chromatographic column containing AG 1-X8 resin equilibrated with 6M HCl. The Ni , Co and Cu isotopes were separated by using the well-known chromatography of the chloro-complexes. The sample-fractions containing the Cu isotopes (15 ml, 0.1M HCl) were collected in plastic centrifuge tubes previously soaked in 1M HNO3 and rinsed with Milli-Q water (18 MΩ cm). Impurities of B, Co, Ni, Cu and Zn in these samples were determined by inductively coupled plasma-mass spectroscopy (ICP-MS) at the Department of Geosciences (Laboratory of Isotopic Studies) of the National University. Results and Conclusions The mass of Ni deposited in 1 h was 25.0 ± 1.0 mg (n = 3) and the current efficiency was > 75 % in all cases. The pH of the electrolytic solution tended to decrease along the electrodeposition process (3.71.6). The results of ICP-MS analysis of the Cu-fractions from the cold chromatography separation runs are shown in FIG. 1. We were particularly interested in the boron impurities as H3BO3 is used as buffer for electrodeposition of the Ni targets. Except for the Ni impurities that were deter-mined to be in the range of ppm (mg/l), all other analyzed metallic impurities were found to be in the range of ppb (µg/l), including boron. The Co, Ni, Cu and Zn impurities determined in the Cu-fraction in this work using Ni targets electrode-posited from a NiCl2 acidic solution, are in the same order of magnitude compared with that obtained when using targets prepared from an alkaline solution [2], with the advantage of the simplicity of the electrodeposition method from NiCl2 solutions, as the target material is already recovered in the chemical form of NiCl2, enabling a simpler, one step process to prepare a new plating solution when using enriched 64Ni target material for the production of 64Cu.