# Highly Enriched Uranium-Free Medical Radioisotope Production Methods: An Integrative Review
## 3 Results and Discussion  
Table 11 and Figure 1a show that 81.3% of the selected papers describe the use of cyclotrons for radioisotope production. The reason behind this large number is that cyclotron is a well-established technology. The use of hospital cyclotrons to produce radioisotopes began in the 1950s [84], over 70 years ago, and the largest medical centers in the world already have cyclotrons. Globally, there are more than 1500 cyclotrons [85]. Protons are usually the types of particles accelerated in cyclotrons, justifying their large appearance numbers (34), as indicated in Table 11 and Figure 1b. In addition to cyclotrons, research reactors (without the presence of enriched uranium), linear particle accelerators (LINACS), plasma focus devices, and tandetrons have also been used for radioisotope production in the selected papers. These four production technologies add up to only 18.7% of the papers, as shown in Figure 1a. Figure 2 shows that 53 unique radioisotopes were produced in the selected papers; the most cited medical radioisotopes were \({}^{44}\)Sc, \({}^{66}\)Ga, \({}^{99\text{m}}\)Tc, \({}^{68}\)Ga, \({}^{99}\)Mo, and \({}^{89}\)Zr. Together, they appear in 25% of the selected papers. As shown in Figure 2, the most cited (7 distant citations) radioisotope is the \(\beta^{+}\)-emitter radioisotope \({}^{44}\)Sc. Its half-life is often described to be 3.97 h, but a recent study reported a half-life of 4.04 h [86]. This radioisotope was investigated for PET imaging [87] and might  
Figure 1: Number of papers that utilized (**a**) the determined production technology and (**b**) accelerated particles to produce the intended radioisotope. Figure 2: Number of papers that cited the production of each radioisotope. be a suitable alternative to \({}^{68}\)Ga (with a half-life of 1.13 h) due to its half-life, almost four times greater than \({}^{68}\)Ga, which allows the synthesis of a variety of radiotracers with longer pharmacokinetic profiles [88]. Additionally, \({}^{44}\)Sc has been proposed as a matching pair of \({}^{47}\)Sc (with a half-life of 80.4 h, a \(\beta^{-}\)-emitter that has been proposed for radioimmunotherapy [89]) for PET imaging, dosimetry estimation, and the assessment of radionuclide therapeutic responses [89; 90; 91]. Currently, there are two main routes for \({}^{44}\)Sc production, i.e., via \({}^{44}\)Ti/\({}^{44}\)Sc generators, but due to difficulties in the production of the parent isotope (\({}^{44}\)Ti), in the chemical separation, and the purification process, the applicability of this generator is very limited, making its clinical implementation difficult [92]. Cyclotron production is the other main source of the \({}^{44}\)Sc radioisotope. In the selected papers, the production occurred via irradiation on \({}^{44}\)Ca, \({}^{42}\)Ca, or \({}^{nat}\)Ca targets through \({}^{44}\)Ca(p,n)\({}^{44}\)Sc, \({}^{44}\)Ca(d,2n)\({}^{44}\)Sc, \({}^{42}\)Ca(\(\alpha\), np+pn)\({}^{44}\)Sc, and \({}^{nat}\)Ca(p,n)\({}^{44}\)Sc reaction routes, as indicated in Table 1.  
With three distinct citations, \({}^{99}\)Mo is a \(\beta^{-}\)-emitter radioisotope without direct application in medicine. However, \({}^{99}\)Mo decays into \({}^{99m}\)Tc, the most used radioisotope for SPECT imaging, as mentioned in Section 1. It makes \({}^{99}\)Mo and \({}^{99m}\)Tc the most relevant pair of radioisotopes in nuclear medicine, justifying a total of seven distinct paper citations (four papers cited \({}^{99m}\)Tc and three cited \({}^{99}\)Mo). Figure 2 also shows that two radioisotopes of gallium, namely \({}^{68}\)Ga and \({}^{66}\)Ga, had seven citations combined. Moreover, \({}^{66}\)Ga (with a half-life of 9.49 h) is a \(\beta^{+}\)-emitter used in PET. Its long half-life makes it possible to perform next-day PET imaging, improving the image contrast [93]. \({}^{66}\)Ga has been tested for studies of slow dynamic processes, such as lymphatic transport [94], and imaging of tumor angiogenesis using monoclonal antibodies [95].