# Highly Enriched Uranium-Free Medical Radioisotope Production Methods: An Integrative Review
## 1 Introduction  
Hospitals, clinics, and health centers make daily use of a wide range of highly complex diagnoses and treatments resulting from technological advances achieved in the last decades, with nuclear medicine being an area that benefits from such advances. In nuclear medicine, radiopharmaceuticals, which are compounds containing radionuclides (or radioisotopes) bound to pharmaceutical drugs [1], are administered to patients via intravenous or oral injections. Depending on their properties, these organic molecules allow the radionuclides to be fixed in specific human body organs. The radioisotope corpuscular and/or the electromagnetic radiation it emits in this organ is used for imaging or treatment purposes [2]. Radiouclides emitting either \(\beta^{+}\) particles and/or \(\gamma\)-rays are usually employed in diagnoses. On the other hand, Auger electrons and \(\beta^{-}\)-emitter radioisotopes are administered in therapy [3]. Medical radioisotopes must have half-lives long enough to allow image acquisition or therapeutic effects, but their half-lives must be short enough to minimize the patient's exposure to ionizing radiation [4]. In this sense, not all radioisotopes are appropriate to be used in radiopharmaceuticals. Some examples of medical radioisotopes are the \({}^{99\text{m}}\)Tc (half-life of approximately 6 h), \({}^{18}\)F (half-life of 1.83 h), and \({}^{64}\)Cu (half-life of 12.7 h). Moreover, \({}^{99\text{m}}\)Tc, the most used radioisotope in nuclear medicine, is a \(\gamma\)-ray-emitter radioisotope; its emitted radiation is detected through a gamma camera in a SPECT (single photon emission tomography)equipment, enabling internal imaging of the patient for diagnostic purposes [5]. Routine clinical applications of \({}^{99\text{m}}\)Tc include bone scintigraphy [6], myocardial perfusion [7], ventriculography [8], brain [9], sentinel node [10], immunoscintigraphy [11], blood-pool labeling [12], sulfur colloid [13], and Meckel's diverticulum [14] scan procedures. On the other hand, \({}^{18}\)F is a \(\beta^{+}\)-emitter radioisotope applied in positron emission tomography (PET) for the early detection and diagnosis of Hodgkin lymphoma [15], and colorectal, head and neck, lung, cervical, and ovarian cancers [16]. Finally, \({}^{64}\)Cu is a \(\beta^{-}\) (39 %) and \(\beta^{+}\) (61 %) emitter used for both PET imaging [17; 18; 19] and cancer therapy [20]. Currently, most of the radioisotope demand is met by two production methods: the fission of highly enriched uranium (HEU) in research reactors, or the acceleration of electrically charged particles (usually protons) in cyclotrons, toward gaseous, liquid, or solid targets, depending on the radioisotope to be produced [21]. Cyclotrons are most often utilized to produce short-life, neutron-deficient, \(\beta^{+}\)-emitter radioisotopes, which are mainly used for PET scans. Because of their short half-lives, these radioisotopes need to be used right after production. Hence, they are mostly produced in medical cyclotrons and are immediately utilized in the same sites in which these facilities are installed [22]. On the other hand, long-lived \(\beta^{-}\) and \(\gamma\)-ray-emitter radioisotopes, generally applied to internal radiotherapy and SPECT scans, respectively, are primarily produced in research reactors. In addition to enabling large-scale production, research reactors also offer logistic advantages. Because most of the radioisotopes produced in these facilities have longer half-lives, if compared to those typically produced in cyclotrons [22], they can be widely distributed before being used. However, as it will be soon discussed, this comes at the cost of transporting highly radioactive material over long distances. In a research reactor, a flux of up to \(10^{14}\) neutrons/cm\({}^{2}\)s hits an HEU target [23], starting the uranium fission.