ARTICLE IN PRESS

Applied Radiation and Isotopes 64 (2006) 10011005 www.elsevier.com/locate/apradiso

Cyclotron production of

64

Cu by deuteron irradiation of

64

Zn

K. Abbasa,, J. Kozempela,b, M. Bonardic, F. Groppic, A. Alfaranoa, U. Holzwartha, F. Simonellia, H. Hofmana, W. Horstmanna, E. Menapaced, L. Les eticky b, N. Gibsona
a

Institute for Health and Consumer Protection, Joint Research Centre, European Commission, TP 500, I-21020 Ispra (VA), Italy b Charles University Prague, Faculty of Science, Department of Organic and Nuclear Chemistry, 128 43 Prague, Czech Republic c LASA, Radiochemistry Laboratory, University and INFN, via F.lli Cervi 201, I-20090 Segrate (MI), Italy d ENEA, Applied Physics Division, Bologna, Italy Received 12 July 2005; received in revised form 25 November 2005; accepted 30 December 2005

Abstract The short-lived (12.7 h half-life) 64Cu radioisotope is both a b+ and a b emitter. This property makes 64Cu a promising candidate for novel medical applications, since it can be used simultaneously for therapeutic application of radiolabelled biomolecules and for diagnosis with PET. Following previous work on 64Cu production by deuteron irradiation of natural zinc, we report here the production of this radioisotope by deuteron irradiation of enriched 64Zn. In addition, yields of other radioisotopes such as 61Cu, 67Cu, 65Zn, 69mZn, 66 Ga and 67Ga, which were co-produced in this process, were also measured. The evaporation code ALICE-91 and the transport code SRIM 2003 were used to determine the excitation functions and the stopping power, respectively. All the nuclear reactions yielding the above-mentioned radioisotopes were taken into account in the calculations both for the natural and enriched Zn targets. The experimental and calculated yields were shown to be in reasonable agreement. The work was carried out at the Scanditronix MC-40 Cyclotron of the Institute for Health and Consumer Protection of the Joint Research Centre of the European Commission (Ispra site, Italy). The irradiations were carried out with 19.5 MeV deuterons, the maximum deuteron energy obtainable with the MC-40 cyclotron. r 2006 Elsevier Ltd. All rights reserved.
Keywords:
64

Cu;

61

Cu;

66

Ga;

67

Ga; Target yield; Radioisotope production; Cyclotron; PET; Therapy

1. Introduction The characteristics of 64Cu (12.7 h half-life, 39% b 578 keV end point, 61% b+/EC, with a g-ray emission at 1345.84 keV at 0.473% branching ratio, in addition to the 511 keV annihilation peak), make 64Cu a radioisotope suitable for labelling of a wide range of radiopharmaceuticals, for both PET imaging, and radioimmunotherapy (Firestone et al., 1998). The maximum range of b+ particle with 653 keV end point energy in soft tissue is $2.7 mm and the average range is $1 mm. Cu(II) forms a class of stable complexes and chelates with dithiocarbamates (DTC) like ethylmethyl-DTC, with thiosemicarbazones like PTSM, ATSM, and especially with azamacrocyclic chelants (cyclens), like DOTA, DOTP and SarAr. Over the
Corresponding author. Tel.: +39 0332785673/9466; fax: +39 0332785388. E-mail address: kamel.abbas@jrc.it (K. Abbas).

past several years, the behaviour of these compounds of copper has been investigated in cell cultures, rats and humans (Sun and Anderson, 2004). The usual method for 64Cu production is based on nil proton irradiation of 64Ni using cyclotrons (Szelecse et al., 1993; McCarthy et al., 1997). The method based on fast neutron irradiation of 64Zn through 64Zn(n,p) reaction has been studied and revealed a low yield and contamination with 67Cu (Hetherington et al., 1986; Zinn et al., 1994) while the method of thermal neutron irradiation of 63Cu in a nuclear reactor leads to low specic activity. Among the possible methods for production of NCA 64Cu (and 61Cu), deuteron irradiation of natural zinc targets has been reported (Neirincks, 1977; Abbas et al., 2001; Groppi et al., 2004; Bonardi et al., 2001; Hilgers et al., 2003) and revealed that 64Cu is co-produced with several other radioisotopes including 66Ga and 67Ga. Therefore, handling of the irradiated Zn target has to be performed in highly radiation-shielded cells.

0969-8043/$ - see front matter r 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.apradiso.2005.12.021

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1002 K. Abbas et al. / Applied Radiation and Isotopes 64 (2006) 10011005

In the present paper, we have studied the cyclotron production of 64Cu by deuteron irradiation of enriched 64 Zn, in order to avoid the co-production of Ga and other undesired radioisotopes. In case of future commercialisation of 64Cu-based radiopharmaceuticals, the cost of 64Zn is much lower than that of 64Ni, therefore this method may be cost effective. Moreover, this method would reduce the radioactive waste stream as compared with irradiation of natural Zn. Following theoretical calculations using the evaporation code Alice 91 (Blann, 1996) and SRIM 2003 (Ziegler, 2003) for excitation functions and stopping power predictions, respectively, irradiation of enriched 64Zn at 19.5 MeV deuteron were carried out and the results are reported in this paper. The work was performed at the Cyclotron Laboratory of the Institute for Health and Consumer Protection of the Joint Research Centre of the European Commission (Ispra site, Italy). 2. Production of
64

Ga radioisotope is already in use in medical applications. However, via deuteron irradiation of natural Zn, 67Ga is co-produced with 66Ga and the two radioisotopes cannot be chemically separated, therefore a long decay period is required to reduce the 66Ga activity. In fact, the main dose rate from an activated natural zinc is generated by the Ga radioisotopes, so if 67Ga is not required, the production of these radioisotopes simply causes extra shielding requirements and radioactive waste. For instance, a sample disc of 1 cm diameter containing 37 MBq each of 64Cu, 66Ga and 67 Ga would generate a dose rate at 10 cm of about 880 mSv/ h of which 93% is due to the Ga radioisotopes. In case of an additional 37 MBq of 61Cu in the sample disc, the contribution of Ga radioisotopes in the generated dose rate is estimated at 70%. 61Cu has, however, a much shorter half-life and decays away rapidly. These dose rates are estimated using MicroShield software (version 5.03a, Grove Software Inc, USA). 2.2. Approach for reduction of Ga radioisotopes One of the possibilities of reducing the co-production of Ga radioisotopes is to irradiate the natural Zn at low deuteron energies. According to Table 1, by performing an irradiation at 14 MeV instead of 19.5 MeV, the production yield of 64Cu which at low energy takes place mostly through the 66Zn(d,a)64Cu reaction would be reduced by factor 2.5 while the reduction factors for the production of 66 Ga and 67Ga would be 3.8 and 1.7, respectively (Fig. 1). In addition, the 61Cu production would be reduced by a factor of 5.1 although its production does not cause problems due to its relatively short half-life (3.4 h). As summarised in Table 1, the 66Ga and 67Ga radioisotopes are created from the 66Zn, 67Zn and 68Zn isotopic components of natural Zn. Therefore, it is possible to produce pure 64Cu free of Ga radioisotopes by deuteron irradiation of 64Zn through the 64Zn(d,2p) reaction. The calculated thick target yields of 64Cu, 61Cu and 65Zn for the case of deuteron irradiation of pure 64Zn are given in Table 2, together with the corresponding yields for natural Zn. In addition to avoiding the production of Ga radioisotopes, deuteron irradiation of 64Zn should, in theory, increase the thick target yield of 64Cu. In this work, the deuteron irradiation of 64Zn of 99.4% isotopic purity was performed to verify the theoretical predictions. 3. Experimental 3.1. Target material The 64Zn target consisted of a 7 mm diameter disk with a thickness of 32573 mm (232 mg/cm2) purchased from ISOFLEX Inc., USA with the following isotopic distribution (atom percent): 64Zn: 99.470.1, 66Zn: 0.39, 67Zn: 0.04, 68 Zn: 0.15 and 70Zn: o0.02%. 48V activity produced in a disk of pure Ti (99.6% purity, 3074 mm thickness and 7 mm diameter, Good Fellow) via nat: Tid; x48 V reaction

67

Cu by deuteron irradiation of zinc

2.1. Deuteron irradiation of natural zinc The primary products from deuteron irradiation of natural zinc include 64Cu, 61Cu, 67Cu, 65Zn, 69mZn, 66Ga, 67 Ga, where the production of a given radioisotope may be optimised by adjusting some irradiation parameters, such as the energy of the projectile or the target thickness. The yields (A) are calculated as   1 Z Ep dE A N v I 1 elt sE E dE , dx E Th where Nv is the number of target atoms for the desired reaction per unit volume, I is the beam intensity, l is the radioactive constant of the produced isotope l ln2=T 1=2 , t is the duration of the irradiation, Ep is the beam energy, ETh is the reaction threshold energy, s(E) is the excitation function and dE =dxE is the stopping power of the target material. Table 1 shows the calculated thick target yields of different radioisotopes versus the energy for deuteron irradiation of natural zinc. The natural isotopic composition of zinc is taken into account in these calculations. The yields of 67Cu, 65Zn and 69mZn radioisotopes were calculated only for the energy of 19.5 MeV deuterons as they are very low at lower energies. The experimental studies regarding deuterons irradiation of natural Zn (Neirincks 1977; Abbas et al., 2001; Groppi et al., 2004; Bonardi et al., 2001; Hilgers et al., 2003) reported results in good agreement with those shown in Table 1, with signicant quantities of 66Ga and 67Ga radioisotopes coproduced with the desired 64Cu radioisotope. 66Ga emits rather intense and high-energy g-rays, 1039 keV (38.4%) and 2752 keV (23.5%), which consequently requires adequate shielding to protect the operators during radiochemical separations. Ga radioisotopes can be easily chemically separated from Zn or Cu materials, and the

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K. Abbas et al. / Applied Radiation and Isotopes 64 (2006) 10011005 Table 1 Theoretical thick target yields of energiesa Radioisotopes and nuclear reactions (half-life) 1003

61

Cu,

64

Cu,

67

Cu,

65

Zn,

69m

Zn,

66

Ga and

67

Ga for the process of natural Zn irradiation at various deuteron beam

Threshold energy (MeV)

Deuteron energy (MeV) 19.5 18 17 16 15 14 13 12 11 10

Thick target yield (MBq/mA h) Cu (12.71 h) Zn(d,2p) 66 Zn(d,a) 67 Zn(d,an) 68 Zn(d,a2n) Sum
64 61 64 67 67 64

2.1 0 0 10.3

14.12 8.60 3.36 0.01 26.09 179.20 0.01 0 0.01 0.29 0 0.29 28.06 109.12 0.29 109.41 15.28 3.78 0.21 19.27

9.65 8.53 2.55 0 20.73 133.56

7.08 8.41 2.04 17.53 104.61

4.89 8.24 1.59 14.72 78.02

3.20 7.99 1.20 12.39 54.87

1.89 7.65 8.55 10.39 35.41

0.98 7.07 0.56 8.61 20.92

0.43 6.24 0.33 7.00 10.28

0.13 5.28 0.15 5.56 3.34

0.02 4.19 0.05 4.26 0.75

Cu (3.41 h) Zn(d,an)

1.4 2.1 12.6

Cu (2.58 d) Zn(d,2p) 68 Zn(d,2pn) Sum Zn (244.3 d) Zn(d,p) 66 Zn(d,p2n) Sum

64 65

0 13.7

Zn (13.8 h) Zn(d,p) 66 Ga ( 9.4 h) 66 Zn(d,2n) 67 Zn(d,3n) Sum

68

69m

0 8.4 15.6

85.06 0.03 85.09 13.53 3.38 0.05 16.96

69.50 0 69.50 12.39 3.07 0.02 15.48

54.77 0 54.77 11.29 2.73 0 14.02

40.82 0 40.82 10.19 2.36 0 12.55

28.51 0 28.51 9.10 1.98 0 11.08

17.93 0 17.93 8.03 1.60 0 9.63

9.50 0 9.50 6.99 1.25 0 8.24

3.72 0 3.72 5.99 0.93 0 6.92

0.72 0 0.72 4.99 0.65 0 5.64

Ga (3.3 d) Zn(d,n) 67 Zn(d,2n) 68 Zn(d,3n) Sum

66 a

67

0 4.1 14.6
67 65 69m

Yields of

Cu,

Zn and

Zn were calculated only for deuteron energy of 19.5 MeV.

200 Theoretical Thick Target Yield (MBq/A.h) 180 160 140 120 100 80 60 40 20 0 8 12 16 d Energy (MeV) 20 24
64Cu 67Ga 66Ga 61Cu

was used to accurately determine the integrated deuteron current. The excitation function of this reaction was taken from the IAEA library (IAEA-TECDOC-1211, 2001). The 64 Zn and Ti disks were superimposed and placed on an Al target holder equipped with an Al collimator of 6 mm aperture. Following irradiation, the activity measurements were carried by g-ray spectrometry using a calibrated HPGe detector (EG&G Ortec, USA) with intrinsic efciency of 25% and the Gamma Vision acquisition system(Model A66-B32, Version 5.10, EG&G Ortec, USA). 3.2. Cyclotron irradiation The JRC Cyclotron is a Scanditronix MC 40 model able to accelerate positive ions such as protons, deuterons, alphas and 3He2+ at variable energies. The facility includes three irradiation halls with seven external beam-lines and laboratories for radioactive material handling, including

Fig. 1. Calculations showing the possibility of reduction of Ga radioisotopes relative to 64Cu by irradiating at 14 MeV instead of 19.5 MeV.

ARTICLE IN PRESS
1004 K. Abbas et al. / Applied Radiation and Isotopes 64 (2006) 10011005 Table 2 Theoretical results for the thick target yields for 64Cu, 61Cu and 65Zn through 19.5 MeV deuteron irradiation of pure 64Zn and comparison to irradiation of natural Zn Radioisotope
64 61 65

Nuclear reaction
64 64 64 64

Thick target yield (irradiation of 100% pure 64Zn) (MBq/mA h) 29.05 368.72 0.59

Thick target yield (irradiation of natural Zn) (MBq/mA h) 26.09 179.20 0.29

Cu Cu Zn

Zn(d,2p) Zn(d,an) Zn(d,p), Zn(d,n) and b+

glove boxes for radiochemical preparations. For the present work, the irradiation was carried out with deuterons of 19.5 MeV energy at a current of 0.737 0.02 mA for 150 min. The energy of the deuteron beam exiting the Ti monitoring foil after being transmitted through the 64Zn target was calculated as 1270.2 MeV. The cross section of the nat: Tid; x48 V reaction at 12 MeV deuteron is 245 mb (IAEA-TECDOC-1211, 2001). During the irradiation, the target was indirectly cooled by contact with a cooling nger connected to the water-cooling system of the Cyclotron. To allow a homogeneous irradiation and to avoid any local over-heating of the sample, the beam was collimated such that only the central region of the Gaussian beam reached the target. By comparing the current calculated from the 48V activity produced in the Ti foil with that obtained from the electrically isolated Faraday cup, we estimated that 60% of the total beam reached the target. 4. Results At 2 h after the end of bombardment, the contact dose rate of the target system (still mounted on the beam line), was greater than 50 mSv/h. To comply with the ALARA principle, the target was left for 12 h to decay, then after it was dismantled from its holder. The foils of 64Zn and Ti were separated inside a dedicated glove box and the activities were measured at different time intervals by g-ray spectrometry. Fig. 2 shows two g-ray spectra (spectra a and b) of the activated 64Zn. Spectrum b, in which 61Cu is signicantly decayed, was acquired 20 h after the acquisition of spectrum a. In both spectra, most of the g-ray peaks of 64Cu, 61Cu, 66Ga, 67Ga, 65Zn and 69mZn are well resolved. The 184 keV g-ray peak is characteristic of both 67 Ga and 67Cu radioisotopes. Taking into account the calculations in Table 1 and considering the reactions yielding 67Cu and 67Ga, the contribution of 67Cu with respect to 67Ga to the 184 keV g-ray peak is estimated at a maximum of 0.2%. Radioisotopes such as 58Co, 24Na were produced from impurities in the target. In addition to its gray peak of 1346 keV, 64Cu is also identied by its half-life by acquiring several g-ray spectra over 4 days. The measured half-life was 13.0270.33 h compared with the published value of 12.770.1 h. (Firestone et al., 1998), the difference being attributable to the experimental uncertain-

1E+6
67

annihilation peak Cu + 67 Ga
61

Radiaoactivity [counts]

1E+5 1E+4 1E+3 1E+2 1E+1 1E+0 0

Cu
67

spectrum a (upper) spectrum b (lower)

65 66 58

Ga
69m

61

Cu Cu Co 61 Cu
61

Zn

61

Ga

Zn
61

Cu

Cu

64

Cu

66

66 Ga Ga

66

Ga

300

600 900 Energy [keV]

1200

1500

Fig. 2. g-ray spectra (spectra a and b) of the deuteron irradiated 64Zn disk. Spectrum b, which shows decay of 61Cu with respect to 64Cu, was acquired after 20 h with respect to spectrum a.

ties. Fig. 2 also indicates that it is possible to choose a suitable decay time before proceeding with the separation of 64Cu with a minimum presence of 61Cu (3.4 h half-life), though 61Cu would enhance a PET signal since it is also a positron-emitting radioisotope. Table 2 presents a summary of all radioisotopes produced and the calculated target yields for 64Cu, 61Cu and 65Zn. Note that the measured yields in the present work are not thick target yields since the energy of deuterons transmitted through the 64Zn disk is 12 MeV, which is above the threshold energies for the nuclear reactions considered. Using Table 1, the calculated yields to be compared with the experimental ones are obtained by subtracting the calculated thick target yields at 12 MeV from those at 19.5 MeV deuterons. The measured yields are in good agreement with the theoretical calculations as given in Table 3. Traces of 66 Ga and 67Ga are produced from the activation of impurities of 66Zn and 67Zn present in the 99.4% enriched 64 Zn as given in Table 1. The measured yields of 66Ga and 67 Ga are 1.70 and 0.09 MBq/mA h, respectively. 5. Conclusion In the present work, the rst experimental and theoretical studies of the production of 64Cu by the route of deuteron irradiation of 64Zn are reported. The experimental yield was found to be in good agreement with the theory. As predicted by the calculations, in the case of

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K. Abbas et al. / Applied Radiation and Isotopes 64 (2006) 10011005 Table 3 Experimental results of the yields of 64Cu, thick), together with predicted yields Radioisotope
64 61

1005

61

Cu,

65

Zn,

66

Ga and

67

Ga through 19.5 MeV deuteron irradiation of

64

Zn target (99.4% purity and 300 mm

Reported half-life

Measured half-life (h) 13.0270.33 3.3670.06 Not measured 13.5970.18 9.4970.03 Not measured

Theoretical yield (MBq/mA h)

Experimental yield (MBq/mA h) 36.10 130.60 0.40 0.06 1.70 0.09

Cu Cu 65 Zn 69m Zn 66 Ga 67 Ga

12.71 h 3.41 h 244 d 13.76 h 9.49 h 3.2612 d

27.99 345.47 0.58 0 0 0

irradiating 64Zn, Ga radioisotopes are produced in much lower quantities than in the case of irradiating natural Zn, which facilitates the handling and processing of the activated target. The 36 MBq/mA h yield of 64Cu obtained in 64Zn(d,2p)64Cu reaction, as measured in this work, is lower than the reported yield of 236 MBq/mA h obtained niy et al., 1993), from 64Ni(p,n)64Cu reaction (Szelecse however an irradiation at deuteron energy greater than 19.5 MeV would in theory increase this yield to some extent. Further, this work provided, for the rst time, experimental and theoretical yields for the reactions 64 Zn(d,an)61Cu and 64Zn(d,p)65Zn together with 64 Zn(d,n)65Ga followed by b+ decay. When a natural Zn target is used, calculations have shown a relative increase in the yield of 64Cu over other coproduced radioisotopes when deuteron energy decreased from 19.5 to 14 MeV. However, due to the high yields of these radioisotope impurities, the relative gain in the 64Cu yield is still insufcient for routine production of 64Cu, and therefore the use of highly enriched 64Zn target is essential. In future work, we plan to carry out radiochemical separation and purication of 64Cu in order to increase the accuracy of the results of this work and measure the specic activity of the pure 64Cu produced with the present method. Moreover, future work will aim at a determination of the excitation function of the 64Zn(d,2p)64Cu reaction using the stack foil technique. References
Abbas, K., Birattari, C., Bonardi, M., Groppi, F., Menapace, E., Shaw, D., Severgnini, M., Stroosnijder, M.F., 2001. Cyclotron production of NCA 64Cu from deuteron irradiation of zinc target. J. Labelled Compd. Radiopharm. 44 (Suppl. 1), 802. Blann, M., 1996. New precompound decay model. Phys. Rev. C 54 (3), 1341.

Bonardi, M., Birattari, C., Abbas, K., Groppi, F., Severgnini, M., Shaw, D., Menapace, E., Stroosnijder, M.F., 2001. A new method for NCA 64 Cu production. Eur. J. Nucl. Med. 28, 1262. Firestone, R.B., Baglin, C.M., Chu, F.S.Y., 1998. Table of Isotopes, eighth ed. Wiley, New York, USA Update on CD-ROM, ISBN: 0-47124699-9. Groppi, F., Bonardi, M., Birattari, C., Gini, L., Mainardi, C., Menapace, E., Abbas, K., Holzwarth, U., Stroosnijder, M.F., 2004. Thin-target excitation functions and optimisation of NCA 64Cu and 66,67Ga production by deuteron induced nuclear reactions on natural zinc target, for radiometabolic therapy and for PET. Nucl. Instr. Meth. B, 213, 373. Hetherington, E.L., Sorby, P.J., Camarkaris, J., 1986. The production of high specic activity 61Cu for medical diagnosis. Appl. Radiat. Isot. 37, 1242. Hilgers, K., Stoll, T., Skakun, Y., Coenen, H.H., Qaim, S.M., 2003. Cross section measurements of the nuclear reactions nat: Znd; x64 Cu, 66 Zn(d,a)64Cu and technical developments for small scale production of 67Cu via 70Zn(p,a)67Cu process. Appl. Radiat. Isot. 59, 343. IAEA-TECDOC-1211, 2001. Charged-particle cross-section database for medical radioisotope production. Co-ordinated Research Project (19951999). IAEA, Vienna, Austria, May 2001. Available from / http://www-nds.iaea.org/medicalS. McCarthy, D.W., Shefer, R.E., Klinkowstein, R.E., Bass, L.A., Margeneau, W.H., Cutler, C.S., Anderson, C.J., Welch, M.J., 1997. Efcient production of high specic activity 64Cu using a biomedical cyclotron. Nucl. Med. Biol. 24, 35. Neirincks, R.D., 1977. Simultaneous production of 67Cu, 64Cu and 67Ga and labelling of 67Cu and 64Cu. Appl. Radiat. Isot. 28, 802. Sun, X., Anderson, C.J., 2004. Production and Applications of 64Cu Radiopharmaceuticals. Methods Enzymol. 386, 237. niy, F., Blessing, G., Qaim, S.M., 1993. Excitation functions of Szelecse proton induced nuclear reactions on enriched 61Ni and 64Ni: possibility of production of n.c.a. 61Cu and 64Cu at a small cyclotron. Appl. Radiat. Isot. 44, 575. Ziegler, J.F., 2003. SRIM 2003 code. Available from /http://www.srim.orgS. Zinn, K.R., Chaudhuri, T.R., Cheng, T.P., Morris, J.S., Meyer Jr., 1994. Production of no carrier added 61Cu from Zn metal irradiated under boron shielding. Cancer 73, 774.