Experimental study of excitation functions for the deuteron induced reactions 64Zn(d,2p)64Cu and 64Zn(d,alphan)61Cu using the stacked-foil technique.

There is considerable, and growing, interest in the 64Cu radioisotope for application in Nuclear Medicine for PET imaging and targeted radiotherapy of tumours. We are investigating the cyclotron production of this isotope by way of deuteron bombardment of enriched 64Zn target material. In this study, experimental excitation functions for both the 64Zn(d,2p)64Cu and 64Zn(d,alphan)61Cu reactions up to 18.2 MeV deuteron energy have been measured using the stacked-foil technique. The deuteron energies in the various foils were calculated with the SRIM 2003 code and gamma-ray spectrometry was used to measure the activities of the various radioisotopes produced. Monitor foils were used to determine the deuteron beam current on the target stack. Theoretical excitation functions, calculated both with the Empire II code and with an updated version of the Alice code, were compared with the experimental results and a reasonable agreement was found. The experimental work was performed at the MC40 Cyclotron at the European Commission's Joint Research Centre at Ispra, Italy.     

Development of a large scale production of Cu from Zn at the high energy proton accelerator: Closing the Zn cycle

A number of research irradiations of ⁶⁸Zn was carried out at Brookhaven Linac Isotope Producer aiming to develop a practical approach to produce the radioisotope ⁶⁷Cu through the high energy ⁶⁸Zn(p,2p)⁶⁷Cu reaction. Disks of enriched zinc were prepared by electrodeposition of ⁶⁸Zn on aluminum or titanium substrate and isolated in the aluminum capsule for irradition. Irradiations were carried out with 128, 105 and 92 MeV protons for at least 24 h. After irradiation the disk was chemically processed to measure production yield and specific activity of ⁶⁷Cu and to reclaim the target material. The recovered ⁶⁸Zn was irradiated and processed again. The chemical procedure comprised BioRad cation exchange, Chelex-100 and anion exchange columns. Reduction of the oxidation degree of copper allowed for more efficient Cu/Co/Zn separation on the anion exchange column. No radionuclides other than copper isotopes were detected in the final product. The chemical yield of ⁶⁷Cu reached 92-95% under remote handling conditions in a hot box. Production yield of ⁶⁷Cu averaged 29.2 μCi/[μA−h×g ⁶⁸Zn] (1.08 MBq/[μA−h×g ⁶⁸Zn]) in 24 h irradiations. The best specific activity achieved was 18.6 mCi/μg (688.2 MBq/μg).     

Nuclear data for production of the therapeutic radionuclides 32P, 64Cu, 67Cu, 89Sr, 90Y and 153Sm via the (n,p) reaction: evaluation of excitation function and its validation via integral cross-section measurement using a 14 MeV d(Be) neutron source.

Nuclear data for production of the therapeutic radionuclides 32P, 64Cu, 67Cu, 89Sr, 90Y and 153Sm via (n,p) reactions on the target nuclei 32S, 64Zn, 67Zn, 89Y, (90)Zr and 153Eu, respectively, are discussed. The available information on each excitation function was analysed. From the recommended data set for each reaction the average integrated cross section for a standard 14 MeV d(Be) neutron field was deduced. The spectrum-averaged cross section was also measured experimentally. A comparison of the integrated value with the integral measurement served to validate the excitation function within about 15%. A fast neutron source appears to be much more effective than a fission reactor for production of the above-mentioned radionuclides in a no-carrier-added form via the (n,p) process. In particular, the possibility of production of high specific activity 153Sm is discussed.     

Cyclotron production of 64Cu by deuteron irradiation of 64Zn.

The short-lived (12.7h half-life) (64)Cu radioisotope is both a beta(+) and a beta(-) emitter. This property makes (64)Cu 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 (64)Cu production by deuteron irradiation of natural zinc, we report here the production of this radioisotope by deuteron irradiation of enriched (64)Zn. In addition, yields of other radioisotopes such as (61)Cu, (67)Cu, (65)Zn, (69m)Zn, (66)Ga and (67)Ga, 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.     

Investigation of the natZn(p,x)62Zn nuclear process up to 70 MeV: a new 62Zn/62Cu generator

The excitation function of the ^natZn(p,x)⁶²Zn nuclear process was measured by the stacked-foil technique up to a proton energy of 70 MeV to obtain accurate data for production of the ‘mother nuclide’ (⁶²Zn) of the PET related β⁺ emitting radioisotope ⁶²Cu. Investigations were also made on the ⁶⁶Zn(p,x)⁶²Zn and ^natZn(p,xn)⁶⁶Ga processes and on the ⁶⁶Zn(p,n)⁶⁶Ga reaction using ^natZn and highly enriched ⁶⁶Zn. The excitation functions were compared with the published data. Thick target yields for the ^natZn(p,x)⁶²Zn and ^natCu(p,xn)⁶²Zn processes were also calculated up to 70 MeV. On the basis of these calculations the ^natZn+p process results in higher yield for ⁶²Zn above 50 MeV than the ^natCu+p process. The latter process is presently used for practical production of ⁶²Zn. In an energy window from 70 to 30 MeV the available EOB yield of the ^natZn+p reactions is around 19 mCi/μA h (0.7 GBq/μAh) that makes the ^natZn(p,x)⁶²Zn process a good candidate for routine generator production.     

Study of the excitation function for the deuteron induced reaction on 64Ni(d,2n) for the production of the medical radioisotope 64Cu

The production of ⁶⁴Cu, a radioisotope of considerable interest for the application in nuclear medicine for PET imaging and radioimmunotherapy, was investigated by deuteron bombardment of enriched ⁶⁴Ni target up to E_d=20.5 MeV. The experimental excitation function for the reaction ⁶⁴Ni(d,2n)⁶⁴Cu was measured using the stacked foil irradiation technique followed by HPGe γ-ray analysis at 1346 keV and is compared with earlier literature values. Cross-section data for the ⁶⁴Ni(d,p)⁶⁵Ni reaction are determined for the first time. Thick target yields are derived and compared with results of other production routes.     

Averaged cross sections for the reactions (68)Zn(n,p)(68g)Cu and (68)Zn(n,p)(68m)Cu for a (235)U fission neutron spectrum.

Making use of the method developed in our laboratory for the simultaneous determination of cross sections leading to both the ground and metastable states, we have measured the (68)Zn(n,p)(68g)Cu and (68)Zn(n,p)(68m)Cu reactions, using Zn enriched to 99.4% in its isotope (68)Zn. The measured cross sections are (15.04+/-0.35) and (3.69+/-0.30)microb for the ground and metastable state, respectively. However, a direct determination of the cross section leading to the metastable state gives a value of (4.75+/-0.38)microb. A possible reason for this discrepancy-which is outside experimental uncertainties-is that some tabulated values used in our calculations for the decay parameters of (68g)Cu and (68m)Cu, have either larger than quoted, or unknown systematic, uncertainties.     

Comments on the feasibility of 61Cu production by proton irradiation of (nat)Zn on a medical cyclotron.

Feasibility of 61Cu production in high radionuclidic purity form via (nat)Zn(p,x) 61Cu nuclear process is discussed. Based on the experimentally available cross-sections of the (nat)Zn(p,x) 61Cu, (nat)Zn(p,x) 60Cu and (nat)Zn(p,x) 64Cu nuclear processes the usefulness of the (nat)Zn(p,x) 61Cu process for high-scale production is questionable in the 22 --> 12 MeV energy range.     

Calculations for the excitation functions of the 63Cu(p,n)63Zn, 63Cu(p, 2n)62Zn and 65Cu(p,n)65Zn reactions.

Calculations for the excitation functions of 63Cu(p, n)63Zn, 63Cu(p, 2n)65Zn and 65Cu(p, n)65Zn reactions have been carried out in 3-30 MeV energy range using statistical and pre-equilibrium nuclear reaction models. The calculations have been compared with reported measurements and discussed.     

Production of no-carrier added 67Cu

Copper-67 has been produced at the BLIP by ⁶⁸Zn(p, 2p) and ⁷⁰Zn(p, α) reactions with 193 MeV protons and at the HFBR using the ⁶⁷Zn(n, p) route. The effective cross-sections of ^natZn(p, 2pxn)^61,64,67Cu reactions were measured at 200 MeV and compared with predicted values obtained from semi-empirical formulae given by Silberberg and Tsao. From these cross-sections, the fraction of ⁶⁴Cu in the final ⁶⁷Cu preparations was estimated and compared with the experimental values. A procedure has been developed consisting of electrodeposition and ion-exchange for isolation of no-carrier-added radiocopper from a Zn target. The method is adaptable for remote hot cell operation. The overall radiochemical yield of ⁶⁷Cu and the separation factors from a Zn target and other radionuclides were evaluated. The saturation yield of ⁶⁷Cu produced by the fast neutron ⁶⁷Zn(n, p) reaction and the corresponding cross-section were remeasured. Experiments have been initiated to attach ⁶⁷Cu to monoclonal antibodies for immunotherapy applications.     

New calculation of excitation functions of proton-induced reactions in some medical isotopes of Cu, Zn and Ga.

The new calculations on the excitation functions of 61Ni(p,n)61Cu, 62Ni(p,n)62Cu, 64Ni(p,n)64Cu, 63Cu(p,2n)62Zn, 63Cu(p,n)63Zn, 65Cu(p,n)65Zn, 66Zn(p,n)66Ga, 67Zn(p,2n)66Ga, 67Zn(p,n)67Ga and 68Zn(p,n)68Ga reactions have been carried out in the 5-30 MeV proton energy range. The calculations involve the cascade exciton model, preequilibrium nuclear reaction model and exciton model. The calculated results are compared with the experimental data taken from the literature.     

A new separation procedure for 67Cu from proton irradiated Zn

Cu-67 has been produced since 1985 at the Brookhaven Linac Isotope Producer (BLIP) by irradiation of natural Zn targets with 200 MeV protons. Since the electrodeposition method used previously for isolation of Cu was slow (24–48 h) and unreliable for remote operation, a new, faster and more reliable method has been devised. It is based on (1) selective extraction of Cu dithizonate into organic solvent from a 0.5 M HCl solution of the bulk Zn target; (2) back extraction of Cu into aqueous phase; (3) removal of Ga by isopropyl ether treatment; and (4) final purification by anion exchange separation from other trace radiocontaminants. This procedure has been successfully adapted to remote hot cell operation, takes about 5–7 h to complete the processing of a typical BLIP irradiated ZnO target, and has resulted in better deliverable yields and specific activity. The overall ⁶⁷Cu recovery is about 90% under remote conditions. For several ⁶⁷Cu production runs with this procedure, the average Zn separation factor was 1.1 × 10⁻⁶ and average ⁶⁷Cu specific activity was 5 mCi/μg.     

Effective separation method of 64Cu from 67Ga waste product with a solvent extraction and chromatography

A simple chemical process with a solvent extraction was investigated as an effective separation method for ⁶⁴Cu radionuclide from waste production, which is collected as solution after extracting ⁶⁷Ga and recovering ⁶⁸Zn target materials. For the production of radionuclide ⁶⁷Ga, the enriched ⁶⁸Zn material electroplated on Cu backing plate is usually exposed to energetic protons. The protons produce ⁶⁷Ga including other radionuclides, such as ⁵⁷Ni, ^57,55Co, ^64,67Cu by several nuclear reactions. After extracting ⁶⁷Ga and recovering ⁶⁸Zn through several steps of chemical processes, the residual solution is usually discarded even though it contains other species of radioisotopes. In this study, a simple chemical process having a high separation efficiency of ⁶⁴Cu from the waste solution was investigated. With this method, a promising radiotracer as a diagnostic in PET and a therapeutic in radio-immunotherapy, ⁶⁴Cu was estimated to be produced as high as 1,200 mCi at EOB within 3 h chemical processing after extraction of ⁶⁷Ga and ⁶⁸Zn.     

High purity production and potential applications of copper-60 and copper-61.

Previously we described the high yield production of 64Cu using a target system designed specifically for low energy, biomedical cyclotrons. In this study, the use of this target system for the production of 60Cu and 61Cu is described and the utility of these isotopes in the labeling of biomolecules for tumor and hypoxia imaging is demonstrated. 60Cu and 61Cu were produced by the 60Ni(p,n)60Cu, 61Ni(p,n)61Cu, and 60Ni(d,n)61Cu nuclear reactions. The nickel target (>99% enriched or natural nickel) was plated onto a gold disk as described previously (54-225 microm thickness) and irradiated (14.7 MeV proton beam and 8.1 MeV deuteron beam). The copper isotopes were separated from the nickel via ion exchange chromatography and the radioisotopic purity was assessed by gamma spectroscopy. Yields of up to 865 mCi of 60Cu have been achieved using enriched 60Ni. 61Cu has been produced with a maximum yield of 144 mCi using enriched 61Ni and 72 mCi using enriched 60Ni. Specific activities (using enriched material) ranged from 80 to 300 mCi/microg Cu for 60Cu and from 20 to 81 mCi/microg Cu for 61Cu. Bombardments of natural Ni targets were performed using both protons and deuterons. Yields and radioisotopic impurities were determined and compared with that for enriched materials. 60Cu was used to radiolabel diacetyl-bis(N4-methylthiosemicarbazone), ATSM. 60Cu-ATSM was injected into rats that had an occluded left anterior descending coronary artery. Uptake of 60Cu-ATSM in the hypoxic region of the heart was visualized clearly using autoradiography. In addition, 60Cu-ATSM was injected into dogs and excellent images of the heart and heart walls were obtained using positron emission tomography (PET). 61Cu was labeled to 1,4,8,11-tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid-octreotide (TETA-octreotide) and the PET images of tumor-bearing rats were obtained up to 2 h postinjection. After decay of the 61Cu, the same rat was injected with 64Cu-TETA-octreotide and the images were compared. The tumor images obtained using 61Cu were found to be superior to those using 64Cu as predicted based on the larger abundance of positrons emitted by 61Cu vs. 64Cu.     

Preparation of [61Cu]-2-acetylpyridine thiosemicarbazone complex as a possible PET tracer for malignancies.

Due to the interesting anti-proliferative properties of copper-thiosemicarbazone complexes, the production of a (61)Cu-labeled thiosemicarbazone, i.e. 2-acetylpyridine thiosemicarbazone (APTS) was investigated. Copper-61 (T(1/2)=3.33 h) was produced via the (64)Zn(p,alpha)(61)Cu nuclear reaction using a natural zinc target irradiated with 22 MeV protons for 500 microAh. The (61)Cu was separated from the irradiated target material by a two-step method and converted to acetate; this yielded a final activity of 222 GBq (6.0 Ci), with a radiochemical yield of >95%. The (61)Cu-acetate was mixed with 2-acetylpyridine thiosemicarbazone for 30 min at room temperature to yield [(61)Cu]APTS with a radiochemical yield of more than 80%. Colorimetric methods showed that residual chemical impurities in the product were below the accepted limits. Radio thin layer chromatography (RTLC) showed a radiochemical purity of more than 99% after C(18) column chromatography. A specific activity of about 370-740 MBq/mmol (10-20 Ci/mmol) was obtained. The stability of the final product was checked in the absence and presence of human serum at 37 degrees C for up to 3 h. The partition coefficient of the final complex was also determined.     

Nuclear model analysis of excitation functions of proton and deuteron induced reactions on 64Zn and 3He- and α-particle induced reactions on 59Co leading to the formation of copper-61: Comparison of major production routes

Cross section data for formation of the medically important radionuclide ⁶¹Cu (T_½=3.33 h) in proton and deuteron induced reactions on enriched ⁶⁴Zn and in ³He- and α-particle induced reactions on ⁵⁹Co were analyzed by using the nuclear model calculational codes, EMPIRE and TALYS. A well-defined statistical procedure was then employed to derive the recommended excitation functions, and therefrom to obtain integral yields. A comparison of major production routes of ⁶¹Cu was done.     

Cross-section measurements for (n, 2n), (n, p) and (n, n′α) reactions on gallium isotopes in the neutron energy range of 13.5–14.6 MeV

Cross-sections for (n, 2n), (n, p) and (n, n'alpha) reactions have been measured on gallium isotopes at the neutron energies of 13.5-14.6MeV using the activation technique. Data are reported for the following reactions: 69Ga(n, 2n) 68Ga, 69Ga(n, p) 69mZn, 71Ga(n, p) (71m)Zn, and 71Ga(n, n'alpha) 67Cu. The neutron fluences were determined using the monitor reaction 93Nb(n, 2n) 92mNb.     

The yields, branching ratios and angular distributions of 6–7 MeV photons produced in the F(p,αγ)O reaction

The yields and branching ratios of 6.13, 6.92 and 7.12 MeV photons produced in the 19F(p,álphagamma)16O reaction were measured for incident proton energies between 340.46 and 3490 keV. The experimental data were recorded and analysed to show photon features. The branching ratios of 6.13, 6.92 and 7.12 MeV gamma-rays are different for different incident proton energies. The maximum yield of 6-7 MeV gamma-rays was found at Ep = 2.63 MeV. The angular distributions for 6.13 and 7.12 MeV gamma-rays in the Ep = 340.46 keV resonance were also measured and show to be isotropic within experimental uncertainty.     

α-Particle and γ-ray spectrometry of a plutonium solution for impurity determination

A highly enriched ²⁴⁰Pu solution was measured by α-particle and γ-ray spectrometry to determine other radionuclides present in the material as impurities. Low activities of ²³⁸Pu, ²⁴¹Am, ²⁴³Cm and ²⁴⁴Cm were determined by measuring thin sources, made from the original solution, in a high-resolution alpha-particle spectrometer. The sources were prepared by evaporating the plutonium solution on quartz plates in a vacuum chamber. From the ingrowth of ²⁴¹Am in the original solution, the amount of ²⁴¹Pu could be calculated. After radiochemical separation of ²⁴¹Am, the plutonium was measured by high-efficiency alpha-particle spectrometry to determine the amount of ²³⁸Pu. The enriched ²⁴⁰Pu material was also measured by high-resolution gamma-ray spectrometry, using two different HPGe detectors to determine the impurities of ²³⁹Pu and ²⁴¹Am. The preparation of the sources and the measurement methods are described and discussed. The measured impurities, given in % of the ²⁴⁰Pu activity, are compared with the values on the certificate.