**2. Production Methods of <sup>67</sup>Cu**

*2.1. Accelerator-Based Production*

2.1.1. Charged-Particle Induced Reactions

While 64/61/60Cu radionuclides can be produced via low energy medical cyclotrons [11], for <sup>67</sup>Cu production, intermediate proton energies are needed, as shown by the well-known cross sections on zinc targets. The main route is the <sup>68</sup>Zn(p,2p)67Cu reaction, studied for decades, whose excitation function has been recommended by the International Atomic Energy Agency (IAEA) [12]. This production method is feasible at intermediate protonbeams (E < 100 MeV), but it can be exploited also at higher energies [13]. The use of enriched <sup>68</sup>Zn targets is mandatory to reduce the coproduction of other Cu-radionuclides affecting the radionuclidic purity (RNP) of the final product [14]. However, the coproduction of <sup>64</sup>Cu cannot be avoided, as also indicated by the <sup>68</sup>Zn(p,x)64Cu cross section reported by the IAEA up to 100 MeV.

At low-energy proton beams, the <sup>70</sup>Zn(p,α) <sup>67</sup>Cu reaction is feasible up to 30 MeV, without the coproduction of <sup>64</sup>Cu [15]. Due to the low value of the cross section (the maximum at 15 MeV is ca. 15 mb), this production route provides quite a low yield, i.e., 5.76 MBq/µAh for the 30–10 MeV energy range (corresponding to a 1.84 mm thick target). On the other hand, when using <sup>70</sup>Zn targets and higher proton energies, it is possible to reach a higher <sup>67</sup>Cu yield, though with the coproduction of <sup>64</sup>Cu [16,17].

Considering gallium as target material, it is possible to investigate the use of <sup>71</sup>Ga, whose natural abundance is 39.892% [7]. The cross section of the <sup>71</sup>Ga(p,x)67Cu nuclear reaction is very low, about 2.6 mb at 33 MeV, and so far few literature data are covering the 20–60 MeV energy range [18]; however, the low cross section makes this route of <sup>67</sup>Cu production not feasible.

In order to estimate the influence of various parameters in the proton-based production of <sup>67</sup>Cu, we used the IAEA tool ISOTOPIA [19] and the recommended nuclear cross sections for calculations; when the IAEA cross sections values were not available, a fit of the literature data were used [20]. The <sup>67</sup>Cu activity was calculated for 62 h irradiation, equivalent to a <sup>67</sup>Cu Saturation Factor SF = 50% and a <sup>64</sup>Cu SF = 97%. Results are shown in Table 2, calculated at the end of bombardment (EOB) and 24 h after the EOB [13]. Table 2 also presents the <sup>67</sup>Cu yield when 70 MeV protons are exploited on a multi-layer target composed of enriched <sup>68</sup>Zn and <sup>70</sup>Zn layers, a configuration that optimizes <sup>67</sup>Cu production and minimizes <sup>64</sup>Cu coproduction [21].


**Table 2.** <sup>67</sup>Cu and <sup>64</sup>Cu production yields obtained using proton-beams on <sup>70</sup>Zn and <sup>68</sup>Zn enriched materials for each target material individually and the multi-layer target configuration (I = 1 µA; TIRR = 62 h).

Deuteron beams can also be exploited for <sup>67</sup>Cu production. As in the case of proton beams, the use of enriched targets is mandatory to limit the coproduction of contaminant Cu-radionuclides. In addition to this, when using natZn targets, the low production cross section [20] also leads to a low <sup>67</sup>Cu yield. The reported data on the <sup>70</sup>Zn(d,x)67Cu cross section include a measurement from 2012 [22] and a recent work of 2021, describing an experimental campaign up to 29 MeV [23]. The use of <sup>70</sup>Zn targets seems promising in the energy window 26–16 MeV, giving a <sup>67</sup>Cu yield of 6.4 MBq/µAh [23]. In order to use higher deuteron beam energies it is important to measure the <sup>70</sup>Zn(d,x)64Cu cross section ( <sup>64</sup>Cu threshold energy is ETHR = 26.5 MeV [7]), whose values are not reported in the literature [20].

Among the charged-particle induced reactions, the α-beams have also been explored. The main <sup>67</sup>Cu production route relies on the use of enriched <sup>64</sup>Ni targets (natural abundance 0.9255%). The enrichment level of the target material is again a key parameter, because of the coproduction of <sup>64</sup>Cu through the natNi(α,x)64Cu reaction. Recently published new data of the <sup>64</sup>Ni(α,p)67Cu reaction up to 50 MeV [24] are in agreement with previous results [25–28]. This latest work also reports the <sup>67</sup>Cu yield, after 24 h irradiation and 30 µA of beam current.

To compare the α-based production route with proton- and deuteron-induced nuclear reactions, Table 3 presents the calculated <sup>67</sup>Cu (and <sup>64</sup>Cu) production yields, assuming 100% enriched targets and the same irradiation conditions (67Cu SF = 24%, <sup>64</sup>Cu SF = 73%). The <sup>61</sup>Cu and <sup>60</sup>Cu contaminants are not included in the calculations, since their half-lives are significantly shorter than <sup>67</sup>Cu half-life; thus, their impact on the RNP is relevant only soon after the EOB.


**Table 3.** <sup>67</sup>Cu and <sup>64</sup>Cu production yields obtained by using proton-, deuteron-, and α-beams on <sup>70</sup>Zn, <sup>68</sup>Zn, and <sup>64</sup>Ni enriched target materials assuming I = 30 µA and TIRR = 24 h.

The calculations reported in Table 3 show that the most convenient route to obtain pure <sup>67</sup>Cu (without <sup>64</sup>Cu coproduction) is by using deuteron beams and <sup>70</sup>Zn targets. Moreover, the use of α-beams and <sup>64</sup>Ni targets provides pure <sup>67</sup>Cu. Intense linear accelerators (ca. mA current) for α-particles, requiring specific targets able to withstand such high currents that are still to be designed, are soon foreseen but not yet available. The proton-induced reactions with a <sup>68</sup>Zn target and a 68/70Zn multi-layer target configuration seem to be a promising option if some <sup>64</sup>Cu coproduction is acceptable, since these routes provide a larger <sup>67</sup>Cu yield in comparison with the <sup>70</sup>Zn(d,x)67Cu route. In all cases, by changing the projectile type and/or its energy and/or the target material, it is possible to adapt the <sup>67</sup>Cu production yield and the profile of contaminants.
