# Molecular Imaging with \({}^{68}\)Ga Radio-Nanomaterials: Shedding Light on Nanoparticles
## 2 \({}^{68}\)Gallium
### \({}^{68}\)Ge/\({}^{68}\)Ga Generators  
Generators are devices used to produce useful short-lived daughter radionuclides from a long-lived radionuclide. These devices are often termed as \"cows\". Repeated separations of the daughter product are termed editions and the process is colloquially referred to as \"milking\". A \({}^{68}\)Ge/\({}^{68}\)Ga generator is used to extract \({}^{68}\)Ga from its parent isotope \({}^{68}\)Ge. \({}^{68}\)Ge decays by electron capture to \({}^{68}\)Ga that can then be eluted from the generator every few hours. As \({}^{68}\)Ge has a relatively long half-life (T\({}_{1/2}\) = 270.8 days), the use of the generator spans several months. The first \({}^{68}\)Ge/\({}^{68}\)Ga generator was described in 1960 using liquid-liquid extraction chemistry [24]. Several \({}^{68}\)Ga compounds, were synthesized with extraction product of this generator and used to scan intracranial lesions [25]. Later in the 1960s, the liquid-liquid extraction chemistry was substituted by a solid-phase-based ion exchange system. Trail-breaking studies used alumina (Al\({}_{2}\)O\({}_{3}\)) to retain \({}^{68}\)Ge, while \({}^{68}\)Ga could be eluted from the column using ethylenediaminetetraacetic acid (EDTA) [26; 27]. Solid-phase chromatographic generators offered compelling radiochemical properties, being able to repeatedly elute in 95% yield and as little as 1.4 \(\times\) 10\({}^{-5}\)% of \({}^{68}\)Ge [28]. This system was economically convenient as a \({}^{68}\)Ga-EDTA source. However, eluate was troublesome for subsequent radiolabelingprocesses because of the high thermodynamical stability of the \({}^{68}\)Ga-EDTA complex [29]. In the late 1970s, the impact of \({}^{68}\)Ga in nuclear imaging started to evanesce due to the inability of the available generators to meet the requirements of \({}^{68}\)Ga radiopharmaceutical syntheses. Furthermore, \({}^{99\mathrm{m}}\)Tc- and \({}^{18}\)F-based imaging were rapidly developing and gaining clinical significance. This blend of difficulties motivated the quest for second-generation \"ionic\" generators. Pioneer Russian radiochemists developed a new type of \({}^{68}\)Ge/\({}^{68}\)Ga generator that became commercially available at the beginning of the 21 st century [30]. Most common \({}^{68}\)Ge/\({}^{68}\)Ga generators commercially available nowadays are based on hydrochloric acid and elute \({}^{68}\)Ga in cationic form (\({}^{68}\)Ga\({}^{3+}\)) rather than inert \({}^{68}\)Ga complexes [29; 30]. \"Fresh\" generators elute yields 70-80%, decreasing over time. The rapid insertion of these generators to clinical environments raised concern on safety of eluate products for routine clinical use. \({}^{68}\)Ge breakthrough (ranging 0.01-0.001%), proton excess coming from hydrochloric acid used for elution and metallic impurities should be eliminated, as well as elution under current Good Manufacturing Practices (cGMP) conditions to ensure safe use. To achieve this, a \"post-processing\" or extra purification process is sought. This may be accomplished by: (i) fractionating eluate and selecting the fraction with the highest \({}^{68}\)Ga concentration; (ii) selectively trapping the anionic chloro-complexes of \({}^{68}\)Ga\({}^{3+}\) using an anion-exchange resin; or (iii) using a cation exchange cartridge to selectively retain \({}^{68}\)Ga by elution using diluted HCl [30; 31; 32]. Current commercially available generators are inorganic oxide-based (SnO\({}_{2}\) or TiO\({}_{2}\)) or use an organic resin [28]. Eckert and Ziegler (Berlin, Germany) commercialized clinically approved generators with a modified titanium oxide column eluted with 0.1 M HCl. Low specific volume of \({}^{68}\)Ga eluate is obtained and column packing material dissolution is a source of metal impurities. \({}^{68}\)Ga yield is greater than 60% of nominal activity and \({}^{68}\)Ge breakthrough is 0.0001% for fresh generators, slightly increasing as generator ages.