**4. Discussion**

Comparing with the accelerator-produced mode, the routine production of <sup>67</sup>Cu via the (n,p) reaction in a nuclear reactor is less profitable due to the relatively low yields and expensive <sup>67</sup>Zn target material. Only a limited number of nuclear reactors offer the fast neutron flux higher than 10<sup>14</sup> n cm−<sup>2</sup> s <sup>−</sup><sup>1</sup> and only a few higher than 10<sup>15</sup> n cm−<sup>2</sup> s −1 , which would be preferred for the more efficient production of <sup>67</sup>Cu [40]. For this reason, the reactor route is currently not expected to contribute significantly to the availability of <sup>67</sup>Cu, though reactor produced <sup>67</sup>Cu might be useful as a tracer in research phase on the development of new radiopharmaceuticals or to expand research globally [43]. In contrast, the number of LINACS and cyclotrons with high energy protons is increasing [109,110], thus rapidly filling the <sup>67</sup>Cu availability gap. It is worth to mention that the scarce availability of intense deuteron-beams with energy higher than 9 MeV is curtailing the use of the <sup>70</sup>Zn(d,x)67Cu reaction. A more thorough detailed insight into the economy of charged-particle induced reactions is given in Table 5, where the target material costs were estimated considering the target thicknesses, a hypothetical beam spot area of 1 cm<sup>2</sup> and an average price of enriched <sup>68</sup>Zn about USD 3/mg, <sup>70</sup>Zn about USD 13/mg and <sup>64</sup>Ni about USD 30/mg. Table 5 also reports the estimated cost of <sup>67</sup>Cu activity for each case. However, these estimates did not include the influence of recovery and reuse of the irradiated enriched target material. Obviously, the <sup>67</sup>Cu cost will decrease if the same enriched material will be re-used for several production cycles. The number of these cycles has to be carefully studied, to assure a final <sup>67</sup>Cu product accomplishing the regulatory requirements.

The calculations revealed that when the target material is fully enriched in the desired isotope (i.e., 100% enrichment, unless for the <sup>64</sup>Ni case that is reported from [24] with a 98% enrichment), the convenient route to obtain <sup>67</sup>Cu (without <sup>64</sup>Cu coproduction) is by using deuteron beams and <sup>70</sup>Zn targets. On the other hand, if some <sup>64</sup>Cu coproduction is acceptable for clinical applications, the <sup>68</sup>Zn(p,2p)67Cu reaction seems to be a better option, since it provides a larger <sup>67</sup>Cu yield at a lower price per GBq (mCi) in comparison with the <sup>70</sup>Zn(d,x)67Cu route. The proton-induced reaction on a multi-layer target, composed of <sup>68</sup>Zn and <sup>70</sup>Zn, maximizes the <sup>67</sup>Cu yield at a reasonable price per GBq (or per mCi); however, there is a coproduction of <sup>64</sup>Cu. This route has been previously inhibited by the lack of commercial availability of electron accelerators and the need for an enriched thick target that must be recycled. Electron accelerators are now becoming commercially available and methods for target recycling have been worked out which make this route of production more cost effective. It is important to note that the dose of <sup>67</sup>Cu radioactivity required for one treatment is about 3.7 GBq (100 mCi) [43], but it can vary depending on the specific case and radiopharmaceutical. The <sup>64</sup>Cu coproduction and its impact on the dose delivery has to be carefully considered for each radiopharmaceutical, taking into account the specific biodistribution and timing for wash-out [111]. In general, the limit for the RNP is 99% and the dose increase due to contaminant radionuclides is 10%; however, considering the <sup>64</sup>Cu and <sup>67</sup>Cu decay characteristics (i.e., the emission of β - particles and Auger electrons), preclinical studies with 64/67Cu-radiopharmaceuticals are encouraged to determine the potential impact of this combined therapy.

**Table 5.** <sup>67</sup>Cu activity cost (\$ (USD)/GBq) by using proton-, deuteron-, and alpha-beams on <sup>70</sup>Zn, <sup>68</sup>Zn, and <sup>64</sup>Ni enriched materials, considering I = 30 µA, TIRR = 24 h and enriched targets.


It is worth noting that pure <sup>67</sup>Cu is available using the photo-induced production route [10]. Its major drawback is the need of a large, massive enriched <sup>68</sup>Zn target, having not only an economic impact on the initial investment but also a technological one on the radiochemical processing and target recovery. In addition to this route, it is important to mention the possibility of using an online mass separator to select <sup>67</sup>Cu, to later apply the chemical separation of Cu-isotopes from the collected <sup>67</sup>X radionuclides.

Mass separation, in contrast to the commonly used ion exchange and extraction chromatography, is expected to increase the availability of certain "exotic" radionuclides, among them <sup>67</sup>Cu. This novel approach will be studied within the recently granted EU project (PRISMAP) [112]; however, the efficacy of this process is yet to be shown.
