Production of Gallium-68 with Medium to Low Energy Cyclotrons: What Opportunities for the Development of PET Radiotracers in Senegal?

This study focuses on the development possibilities of radiotracers used in PET in Senegal. This is a literature review that develops the production of 68-Gallium (68Ga[Ga]) via a medium to low energy cyclotron. It shows the possibility of producing 68Ga[Ga] with a simple production reaction using a target of 68Zn. This reaction provides high production yields, at the end of the bombardment (EOB), reaching up to 80 times the activity of a generator. PET imaging may offer better sensitivity and spatial resolution compared to SPECT which is currently used in Senegal. The acquisition of this type of medium to low energy accelerator in Senegal may constitute an important phase in the development of radiotracers with the objective of installing a PET imaging. However, solutions must be provided to minimize the presence of isotopic impurities.


Introduction
Gallium (Ga) is a chemical element belonging to the family of post-transition metals (group 13 of the periodic table of the elements). It is a silvery-looking metal with a melting point of 29.8˚C [1] [2]. Gallium has two stable isotopes, 69 Ga and 71 Ga (61.1% and 39.9% of natural gallium, respectively). 68 Ga [Ga] (physical half-life of 67.71 minutes) combines two decay modes: electron capture (10% to 12%) and beta + decay (88 to 90%) ( Table 1) to give 68 Zinc. While PET is becoming more and more accessible, 68 Ga [Ga] has the advantage of being a metal and therefore of offering possibilities different from those of halogens, by its way of binding to other atoms (chemistry of coordination), which makes it more versatile.
Taking these considerations into account, Jensen and Clark [9] have developed an innovative method to meet the growing demand for 68 Ga[Ga]. This method consisted in producing 68 Ga[Ga] via a cyclotron with a liquid target consisting of a solution of 68 ZnCl 2 [9]. Since then, other research groups have attempted to optimize the production of 68 Ga[Ga] with a liquid target [5] [10]. Although the production of 68 Ga[Ga] via a liquid target is facilitated by the target preparation process, the activity of 68 Ga[Ga] available at the end of production is not significantly higher than that produced by the generator. To overcome the limitations seen with the use of a liquid target, a solid (enriched) target can dramatically improve the overall production of 68 Ga [Ga]. Precisely, the objective of this bibliographical synthesis is therefore to highlight the production of 68 Ga[Ga] via a cyclotron by the use of a solid target (nature of the target, irradiation and production rate, quality of the radioelement produced, various impurities ob-served…).
( Figure 1), the reactions 65 Cu (α, n) 68 Ga and 68 Zn (p, n) 68 Ga are the best to produce 68 Ga[Ga] from of a medium to low energy accelerator.
In addition, among these two nuclear reactions, the irradiation of Zn by protons ( 68 Zn[Zn] (p, n) 68 Ga[Ga]) is the preferred one (the one we have also chosen) according to several studies because it leads to a higher production yield with less impurities and uses protons, the simplest of all cyclotron projectiles [5] [11] [13] [15].

Production of 68 Ga[Ga] via a Cyclotron Using a Solid
Target  Thus, 68 Zn[Zn] pellets of different diameter and thickness were prepared (diameter: 6 to 10 mm and thickness: 0.51 to 0.55 mm). The target carrier was made of aluminum, so it was only weakly activated by the proton beam from the cyclotron according to these authors. In addition, aluminum, due to its thermal conductivity properties [17] [18], allowed efficient cooling of the target during irradiation.
In another study, Lin et al. [8] used an enriched 68 Zn[Zn] target (60 -120 mg) with a diameter of 7 mm. The target was electrodeposited on a platinum disc and then it was transferred and mounted in the cyclotron PETtrace via the module Comecer EDS/PTS (Castel Bolognese RA, Italy).

Target Irradiation and Production Efficiency
Aiman H. Alnahwi et al. [16] used irradiations with a beam current between 5 and 35 μA on the squeezed 68 Zn[Zn] target with an energy ranging from 13 to 14.5 MeV for a duration of 90 minutes. The irradiations were first carried out on a 6 mm target for which the production yield (corrected for the decay) was 2.6 GBq/μA·h. The activity of 68 Ga[Ga] increased when the current applied to the target was greater (input 1 -3). The highest production yields were obtained with the 8-and 10-mm targets (entries 4 -5). Using a current of 35 μA, 145 ± 6 GBq (at EOB: end of bombardment) was produced (input 6) ( Table 3) [11] reported that their values, calculated with the cross sections (5.809 GBq/μAh), were in agreement with these data.

Dissolving the Target
After facilitated transport via magnetic media (Automated Target Transfer System [12]), immediate dissolution of the target should be performed for rapid transfer to the purification column. 7N nitric acid HNO 3 can be used for target dissolution. Another particularly interesting method for extracting radioisotopes of gallium from zinc targets is the thermal diffusion method described by Tolmachev and Lundqvist [19]. A similar method was also employed by Zeisler et al. [20]. Entries 1 -5, n = 1; entry 6, n = 2.

Purification of 68 Ga[Ga]
The automated purification process implemented by Aiman H. Alnahwi et al.  [8]). The last purification step, carried out with the CUBCX resin [21], has already been validated internally.

Metallic and Isotopic Impurities
Aiman H. Alnahwi et al. [16] described the presence of metal impurities after purification. For all batches tested, metallic impurities were below the general limit of 10 ppm and 20 ppm for heavy metals (USP and Ph. Eur. can be kept below 2% using a particle energy of 13 MeV. For example, the

Conclusion
The acquisition of a medium to low energy cyclotron can be a huge opportunity for developing African countries including Senegal. The production technique is quite accessible. Obtaining gallium could initiate the development of new PET radiotracers hitherto unused, particularly 68 Ga[Ga]-PSMA (prostate specific membrane antigen), now essential in the diagnosis of prostate cancer. The objective of developing these radiotracers and the installation of a PET are today major challenges and issues for Senegal. Thus, the production of 68 Ga[Ga] via a cyclotron therefore constitutes an innovative and interesting method with high production yields. However, it must be optimized to reduce or even eliminate isotopic impurities.