**1. Introduction**

Two main methods for producing radioisotopes or their generators for nuclear medicine are widely used today: in nuclear reactors and cyclotrons. Another possible way of their production is photonuclear method. Production of radioactive isotopes for different purposes by this method was widely investigated in the 1970–1980s, and today the growing number of studies on medical isotopes production by photonuclear method can be observed. Due to the development of this method, nowadays <sup>47</sup>Sc, <sup>67</sup>Cu, and <sup>99</sup>Mo/99mTc generator as well as light isotopes <sup>11</sup>C, <sup>13</sup>N, <sup>15</sup>O, <sup>18</sup>F for positron emission tomography (PET) are already obtained in electron accelerators on a regular basis, and the production of <sup>225</sup>Ac, <sup>177</sup>Lu, <sup>111</sup>In, <sup>105</sup>Rh, and <sup>44</sup>Ti/44Sc generator is currently being investigated [1].

Radioactive isotopes <sup>55</sup>Co, <sup>57</sup>Co, and 58mCo are considered to be used in nuclear medicine, as they are not too well known and well-studied but are promising. The most attention is paid to <sup>55</sup>Co (T1/2 = 17.5 h, 77% β + , Emax<sup>β</sup> <sup>+</sup> = 1498 keV), which is auspicious for studying slow processes in an organism by PET. At the dawn of nuclear medicine, it was reported that <sup>55</sup>Co complexes could be used for the diagnostics of lung cancer and for the visualization of tumors [2–4]. It was shown in contemporary studies that <sup>55</sup>Co-EDTA is suitable for use in nephrological research [5] and for the visualization of prostate cancer [6] as well as for the detection of distant metastasis in close vicinity of the bladder and kidneys [7]. It is important to mention that the chemical properties of <sup>55</sup>Co(II) and its behavior in an organism are similar to that of PET-isotope <sup>64</sup>Cu(II) (T1/2 = 12.7 h, 17.4% β + , Emax<sup>β</sup> <sup>+</sup> = 653 keV) and also of Ca(II), the latter being present in body but lacking suitable radioactive isotopes for its visualization [8–10]. In comparison to <sup>64</sup>Cu(II), <sup>55</sup>Co has the following advantages: first, compounds labeled with <sup>55</sup>Co tend to be absorbed less by the

**Citation:** Kazakov, A.G.; Babenya, J.S.; Ekatova, T.Y.; Belyshev, S.S.; Khankin, V.V.; Kuznetsov, A.A.; Vinokurov, S.E.; Myasoedov, B.F. Yields of Photo-Proton Reactions on Nuclei of Nickel and Separation of Cobalt Isotopes from Irradiated Targets. *Molecules* **2022**, *27*, 1524. https://doi.org/10.3390/ molecules27051524

Academic Editors: Alessandra Boschi and Petra Martini

Received: 25 January 2022 Accepted: 21 February 2022 Published: 24 February 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

liver than compounds labeled with <sup>64</sup>Cu. Second, the higher yield of positrons produced by <sup>55</sup>Co results in less activity of the drug and/or less time required for PET diagnostics. Using <sup>55</sup>Co in PET as an indicator of calcium allows one to visualize the affected tissue in patients with traumatic brain injury and to estimate neuronal damage with strokes and brain tumors [11–13]. As for other medical isotopes of Co, 58mCo (T1/2 = 9.04 h) is Auger emitter and thus is suitable for Auger therapy, and <sup>57</sup>Co (T1/2 = 271.8 d, E<sup>γ</sup> = 122 keV) is suitable for preclinical research and the study of pharmacokinetics of drugs based on cobalt due to the long half-life of this isotope and the high yield of produced gamma-quanta [14]. by 55Co results in less activity of the drug and/or less time required for PET diagnostics. Using 55Co in PET as an indicator of calcium allows one to visualize the affected tissue in patients with traumatic brain injury and to estimate neuronal damage with strokes and brain tumors [11–13]. As for other medical isotopes of Co, 58mCo (T1/2 = 9.04 h) is Auger emitter and thus is suitable for Auger therapy, and 57Co (T1/2 = 271.8 d, Eγ = 122 keV) is suitable for preclinical research and the study of pharmacokinetics of drugs based on cobalt due to the long half-life of this isotope and the high yield of produced gamma-quanta [14].

radioactive isotopes for its visualization [8–10]. In comparison to 64Cu(II), 55Co has the following advantages: first, compounds labeled with 55Co tend to be absorbed less by the liver than compounds labeled with 64Cu. Second, the higher yield of positrons produced

*Molecules* **2022**, *27*, x FOR PEER REVIEW 2 of 12

In spite of the advantages listed above, the use of cobalt isotopes in medicine is limited by the difficulties of their production (Figure 1). <sup>55</sup>Co is mainly produced in cyclotrons by nuclear reactions <sup>54</sup>Fe(d,n)55Co, <sup>56</sup>Fe(p,2n)55Co, and <sup>58</sup>Ni(p,α) <sup>55</sup>Co [15]. However, all listed ways of production require enriched targets, which would also prevent long-lived radioactive impurities <sup>56</sup>Co (T1/2 = 77.27 d) and <sup>57</sup>Co from forming [16]. According to calculations, when a target made of 100% <sup>54</sup>Fe is irradiated with deuterons, a yield of up to 30 MBq/µA·h can be achieved, while the content of long-lived cobalt isotopes is minimal [15]. In the case of irradiation of 100% <sup>56</sup>Fe with protons, a significantly higher yield can be achieved up to 180 MBq/µA·h; however, the content of <sup>56</sup>Co will also be higher. Finally, for the <sup>58</sup>Ni(p,α) <sup>55</sup>Co reaction using an enriched target, the maximum yield is 13 MBq/µA·h, and the impurity content is minimal. Thus, <sup>54</sup>Fe(d,n)55Co is the most promising reaction for use in nuclear medicine among cyclotron ones. In spite of the advantages listed above, the use of cobalt isotopes in medicine is limited by the difficulties of their production (Figure 1). 55Co is mainly produced in cyclotrons by nuclear reactions 54Fe(d,n)55Co, 56Fe(p,2n)55Co, and 58Ni(p,α)55Co [15]. However, all listed ways of production require enriched targets, which would also prevent long-lived radioactive impurities 56Cо (T1/2 = 77.27 d) and 57Cо from forming [16]. According to calculations, when a target made of 100% 54Fe is irradiated with deuterons, a yield of up to 30 MBq/μA·h can be achieved, while the content of long-lived cobalt isotopes is minimal [15]. In the case of irradiation of 100% 56Fe with protons, a significantly higher yield can be achieved up to 180 MBq/μA·h; however, the content of 56Co will also be higher. Finally, for the 58Ni(p,α)55Co reaction using an enriched target, the maximum yield is 13 MBq/μA·h, and the impurity content is minimal. Thus, 54Fe(d,n)55Co is the most promising reaction for use in nuclear medicine among cyclotron ones.

Cobalt isotopes (including 55Co) can also be obtained using an electron accelerator—by irradiation of nickel. Currently, data on yields of photo-proton reactions on nickel nuclei, leading to the formation of medical isotopes of cobalt, is limited. In works [17,18], flux-weighted average cross-sections of reactions natNi(γ,pxn) in energy range of 55 to 75 MeV were determined. It was established that cross-sections of natNi(γ,pxn)55Co in this range varied insignificantly. However, there are no data on the yields of nuclear reactions in these works, which makes it impossible to evaluate the possibility of obtaining cobalt isotopes in sufficient quantities for nuclear medicine using electron accel-Cobalt isotopes (including <sup>55</sup>Co) can also be obtained using an electron accelerator—by irradiation of nickel. Currently, data on yields of photo-proton reactions on nickel nuclei, leading to the formation of medical isotopes of cobalt, is limited. In works [17,18], fluxweighted average cross-sections of reactions natNi(γ,pxn) in energy range of 55 to 75 MeV were determined. It was established that cross-sections of natNi(γ,pxn)55Co in this range varied insignificantly. However, there are no data on the yields of nuclear reactions in these works, which makes it impossible to evaluate the possibility of obtaining cobalt isotopes in sufficient quantities for nuclear medicine using electron accelerators.

erators. No methods of separation of cobalt isotopes produced in an electron accelerator can be found in the literature. At the same time, there are works dedicated to the separation of cobalt isotopes from cyclotron-irradiated nickel targets. In these works, Ni(II) and Co(II) were separated using anion exchange resin Dowex AG-1X8 [11,14,19–27] and using extraction chromatography sorbent based on diglycolamide, where Co(II) was obtained in 3 M HCl [28]. The best results were achieved in the last case, the yield of cobalt was 92%, separation factors of cobalt from different impurities varied from 8·102 to 2·104, No methods of separation of cobalt isotopes produced in an electron accelerator can be found in the literature. At the same time, there are works dedicated to the separation of cobalt isotopes from cyclotron-irradiated nickel targets. In these works, Ni(II) and Co(II) were separated using anion exchange resin Dowex AG-1X8 [11,14,19–27] and using extraction chromatography sorbent based on diglycolamide, where Co(II) was obtained in 3 M HCl [28]. The best results were achieved in the last case, the yield of cobalt was 92%, separation factors of cobalt from different impurities varied from 8·10<sup>2</sup> to 2·10<sup>4</sup> , and the process lasted for 2 h. It is worth mentioning that the main task of these works was more difficult than just separation of cobalt and nickel: first, irradiation of nickel also results in the formation of copper isotopes; second, nickel was usually applied via electrodeposition as a coating to a metal plate, irradiation of which also led to impurities. To produce cobalt isotopes for nuclear medicine purposes, it is necessary to develop a technique with higher

yield, higher Ni/Co separation factors, and less time of separation, allowing one to obtain cobalt in diluted HCl medium.

Thus, the purpose of this work was to determine yields of photonuclear reactions on nickel nuclei and also to develop a fast, simple, and effective method of carrier-free cobalt isotopes separation from nickel targets.
