*2.2. Reactor-Based Production*

<sup>67</sup>Cu can be produced in a reactor via the <sup>67</sup>Zn(n,p)67Cu nuclear reaction with fast neutrons and, after the separation process, it is possible to obtain <sup>67</sup>Cu in a n.c.a. form. The enrichment of the <sup>67</sup>Zn target material is crucial to obtain quantities of <sup>67</sup>Cu suitable for medical application. In natural zinc, the abundance of <sup>67</sup>Zn is only 4.04%, while <sup>64</sup>Zn contributes to 49.17% [7] and the neutron cross-section for the <sup>64</sup>Zn(n,p)64Cu nuclear reaction is much higher, hence the amount of <sup>64</sup>Cu produced is an order of magnitude higher than that of <sup>67</sup>Cu. The use of enriched <sup>67</sup>Zn not only limits the contribution of <sup>64</sup>Cu but also increases the irradiation yield of <sup>67</sup>Cu. However, due to the low cross section value, the <sup>67</sup>Zn(n,p)67Cu nuclear reaction requires a high flux of fast neutrons exceeding 10<sup>14</sup> n cm−<sup>2</sup> s −1 [3,39–41]. In the fast neutron flux of 4.4 <sup>×</sup> <sup>10</sup><sup>14</sup> n cm−<sup>2</sup> s −1 (En > 1 MeV) the saturation yield of <sup>67</sup>Cu at the EOB was 4.14 <sup>±</sup> 0.37 GBq/mg of <sup>67</sup>Zn, these values were dependent on the neutron flux and the position of the target in the reactor [37,40]. When the thermal and the fast neutron fluxes were 1.3 <sup>×</sup> <sup>10</sup><sup>12</sup> n cm−<sup>2</sup> s <sup>−</sup><sup>1</sup> and 1.5 <sup>×</sup> <sup>10</sup><sup>12</sup> n cm−<sup>2</sup> s −1 , respectively, only 630 kBq/mg Zn of <sup>67</sup>Cu was produced after a 5 h irradiation of target containing around 50 mg of 93.4% enriched <sup>67</sup>ZnO. In the obtained mixture of <sup>64</sup>Cu and <sup>67</sup>Cu, the latter contributed to less than 30% of the total radioactivity. In order to increase the amount of <sup>67</sup>Cu produced by this reaction, irradiation in a nuclear reactor with higher fast neutron flux, and for longer periods of irradiation are required [42]. More detailed summation of reported neutron irradiation yields for the <sup>67</sup>Zn(n,p)67Cu nuclear reaction has been previously reported [43,44].

In nuclear reactors with a high ratio of thermal to fast neutrons, the coproduction of <sup>65</sup>Zn (t1/2 = 243.93 d) is unavoidable because of the presence of <sup>64</sup>Zn, particularly in the natural zinc target material, and the relatively high cross section of <sup>64</sup>Zn(n,γ) <sup>65</sup>Zn nuclear reaction with thermal neutrons. Although <sup>65</sup>Zn can be separated from <sup>67</sup>Cu during the target processing, due to its long half-life, <sup>65</sup>Zn contaminates the recycled target material. Thermal neutron shielding made of materials with high neutron capture cross sections, such as boron, cadmium or hafnium, may reduce this contamination [45–47]. A boron nitride shield of 3.48 g/cm<sup>3</sup> density and around 4 mm thickness reduced the thermal flux in the sample holder from about 10<sup>13</sup> n/cm2/s to approximately 10<sup>10</sup> n/cm2/s, resulting in a production of about 11 times higher for <sup>67</sup>Cu than <sup>65</sup>Zn and in reducing the <sup>65</sup>Zn production in <sup>67</sup>Zn targets by a factor of 66 [45]. Other reported by-products included <sup>58</sup>Co produced via the <sup>58</sup>Ni(n,p)58Co reaction, <sup>67</sup>Ga, and interestingly, <sup>182</sup>Ta, which can be produced via thermal neutron capture on <sup>181</sup>Ta present in the target material [45]. Potentially, all these contaminants can be removed in the chemical separation of <sup>67</sup>Cu.

The measurements of the <sup>71</sup>Ga(n,n + α) <sup>67</sup>Cu nuclear reaction show an increasing trend from 13 MeV to 20 MeV, reaching a maximum value of ca. 20 mb [20]. Because of these quite low cross section values, <sup>71</sup>Ga targets are impracticable for <sup>67</sup>Cu production.

#### *2.3. Targetry 2.3. Targetry*  In the charged-particle induced nuclear reactions, enriched Zn is the most commonly

In the charged-particle induced nuclear reactions, enriched Zn is the most commonly used target material, although Ni has also been used with α-beams. The acceleratorbased production requires the use of highly enriched target material to achieve high radionuclidic and chemical purity of the product thus making the target very expensive and necessitating target recovery and recycling to minimize the production costs. Targets composed by a set of thin foils in the well-know "stacked-foils" configuration have been used in preliminary studies for nuclear cross section measurements, with enriched Zn foils produced by electrodeposition [48] or by lamination from Zn metal powder [16]. In the accelerator production of <sup>67</sup>Cu, mainly thick solid targets have been used, either in the form of metallic foil/coin or in the oxide form [13], despite the low melting point of Zn. used target material, although Ni has also been used with α-beams. The accelerator-based production requires the use of highly enriched target material to achieve high radionuclidic and chemical purity of the product thus making the target very expensive and necessitating target recovery and recycling to minimize the production costs. Targets composed by a set of thin foils in the well-know "stacked-foils" configuration have been used in preliminary studies for nuclear cross section measurements, with enriched Zn foils produced by electrodeposition [48] or by lamination from Zn metal powder [16]. In the accelerator production of 67Cu, mainly thick solid targets have been used, either in the form of metallic foil/coin or in the oxide form [13], despite the low melting point of Zn. A multilayer target configuration, based on the use of both 68Zn and 70Zn enriched

in 67Zn targets by a factor of 66 [45]. Other reported by-products included 58Co produced via the 58Ni(n,p)58Co reaction, 67Ga, and interestingly, 182Ta, which can be produced via thermal neutron capture on 181Ta present in the target material [45]. Potentially, all these

quite low cross section values, 71Ga targets are impracticable for 67Cu production.

The measurements of the 71Ga(n,n + α)67Cu nuclear reaction show an increasing trend from 13 MeV to 20 MeV, reaching a maximum value of ca. 20 mb [20]. Because of these

*Molecules* **2022**, *27*, x FOR PEER REVIEW 5 of 19

contaminants can be removed in the chemical separation of 67Cu.

A multilayer target configuration, based on the use of both <sup>68</sup>Zn and <sup>70</sup>Zn enriched materials, has been recently patented for <sup>67</sup>Cu proton induced production [21]. This target configuration, shown in Figure 1, is beneficial with an increase of 48% in the <sup>67</sup>Cu production and a 12% decrease of <sup>64</sup>Cu coproduction, with respect to a thick monolayer of <sup>68</sup>Zn in the energy range 70–35 MeV and 24 h irradiation (Table 3). In addition to this, in the low energy range (E < 30 MeV), it is possible to add another <sup>70</sup>Zn layer to exploit the (p,α) reaction to increase the <sup>67</sup>Cu yield. It is important to underline that, in this final <sup>70</sup>Zn layer (covering the low-energy region), there is no coproduction of <sup>64</sup>Cu. In the patent, it is suggested to apply a radiochemical process to each target layer individually, in order to recover each enriched material separately (68Zn and <sup>70</sup>Zn). Moreover, the user can decide to combine the final solutions (containing the <sup>67</sup>Cu/64Cu mix of radionuclides and the pure <sup>67</sup>Cu) or to use them separately to label the desired radiopharmaceuticals. materials, has been recently patented for 67Cu proton induced production [21]. This target configuration, shown in Figure 1, is beneficial with an increase of 48% in the 67Cu production and a 12% decrease of 64Cu coproduction, with respect to a thick monolayer of 68Zn in the energy range 70–35 MeV and 24 h irradiation (Table 3). In addition to this, in the low energy range (E < 30 MeV), it is possible to add another 70Zn layer to exploit the (p,α) reaction to increase the 67Cu yield. It is important to underline that, in this final 70Zn layer (covering the low-energy region), there is no coproduction of 64Cu. In the patent, it is suggested to apply a radiochemical process to each target layer individually, in order to recover each enriched material separately (68Zn and 70Zn). Moreover, the user can decide to combine the final solutions (containing the 67Cu/64Cu mix of radionuclides and the pure 67Cu) or to use them separately to label the desired radiopharmaceuticals.

**Figure 1.** Plot of the nuclear cross section ratio for the production of 67Cu and 64Cu radionuclides: the continuous line is the IAEA recommended value for 68Zn targets; the dashed line refers to the measured values for 70Zn targets. The vertical dashed lines refer to the favorable energy range for 67Cu production. A scheme of the multi-layer target configuration described in the international INFN patent is shown at the bottom [21]. **Figure 1.** Plot of the nuclear cross section ratio for the production of <sup>67</sup>Cu and <sup>64</sup>Cu radionuclides: the continuous line is the IAEA recommended value for <sup>68</sup>Zn targets; the dashed line refers to the measured values for <sup>70</sup>Zn targets. The vertical dashed lines refer to the favorable energy range for <sup>67</sup>Cu production. A scheme of the multi-layer target configuration described in the international INFN patent is shown at the bottom [21].

Electroplating of enriched Zn or Ni on a gold, titanium, aluminum, or gold-plated copper backing is the most popular target fabrication technique. With this method, the target thickness can be adapted to the optimal specific beam energy range and thicknesses up to 80 mm have been reported [6,13,49,50]. For the production of <sup>67</sup>Cu via the <sup>64</sup>Ni(α,p)67Cu nuclear reaction, Ohya et al., used enriched <sup>64</sup>Ni target material (64Ni 99.07%) [50]. Sublimation and the casting process have also been used to produce massive zinc ingot targets (50–100 g) for photonuclear production [10,31].

Zinc oxide targets have been used for both photonuclear- and nuclear reactor-based production of <sup>67</sup>Cu. Recently, ZnO was pressed and wrapped in aluminum foil and used as a target for the photonuclear production [24]. In the targets for neutron irradiation in nuclear reactors, zinc oxide powder was encapsulated in a quartz ampule and aluminum cans or sealed in a polyethylene bag and sandwiched between two Ni foils [6,51–54].

natZnO nanoparticles were compared to natZnO powder in the target irradiation at a fast neutron flux. Both targets of the same mass, 1.0 g each, were irradiated for 30 min in the fast neutron flux of 1.4 <sup>×</sup> <sup>10</sup><sup>13</sup> <sup>n</sup>·cm−<sup>2</sup> s −1 , showing an increase in the <sup>67</sup>Cu activity produced that almost doubled (0.0168 MBq vs. 0.0326 MBq) when natZnO nanoparticles target was used [51].
