Production of Gallium-68 with Medium to Low Energy Cyclotrons: What Opportunities for the Development of PET Radiotracers in Senegal? ()
1. 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, 69Ga and 71Ga (61.1% and 39.9% of natural gallium, respectively). 68Ga [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 68Zinc.
The β+ type decay results in the emission of a positron allowing the formation of two annihilation photons, essential for PET (positron emission tomography) imaging [1] [3] [4].
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Table 1. Main emissions of 68Ga[Ga] [1] [3] [4].
While PET is becoming more and more accessible, 68Ga [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.
Currently, 68Ga [Ga] is mainly produced from a 68Ge[Ge]/68Ga[Ga] generator. The 68Ge[Ge]/68Ga[Ga] generator remains practical, because it guarantees the supply of 68Ga [Ga] for several months (68Ge[Ge] physical period: 270.82 days). However, the use of the generator can be limited by its activity (typically 1.85 GBq of nominal activity when new); the minimum interval between elutions (typically 3 - 4 hours); the elution efficiency (~60% - 80%); and the potential for the parent radionuclide to be long-lived (68Ge[Ge]) crosses the column and ends up in the eluate (breakthrough) [5] [6] [7] [8].
Taking these considerations into account, Jensen and Clark [9] have developed an innovative method to meet the growing demand for 68Ga[Ga]. This method consisted in producing 68Ga[Ga] via a cyclotron with a liquid target consisting of a solution of 68ZnCl2 [9]. Since then, other research groups have attempted to optimize the production of 68Ga[Ga] with a liquid target [5] [10]. Although the production of 68Ga[Ga] via a liquid target is facilitated by the target preparation process, the activity of 68Ga[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 68Ga[Ga]. Precisely, the objective of this bibliographical synthesis is therefore to highlight the production of 68Ga[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 observed…).
2. Ways of Producing 68Ga[Ga] from a cyclotron, Medium to Low Energy
Several methods of producing 68Ga[Ga] have been developed using cyclotrons. Considering the type of particles typically accelerated in medium to low energy accelerators, four reactions can efficiently produce 68Ga[Ga], namely:
65Cu (α, n) 68Ga on a copper target, 68Zn (p, n) 68Ga, 68Zn (d, 2n) 68Ga and 70Zn (p, 3n) 68Ga on zinc targets [11] [12].
According to evaluations by Szelecsényi and al. and Sadeghiet al. [11] [13] based on the study of the cross section (maximum values of the cross sections: 882.0 ± 98.5 milli-barns for 17.2 ± 1.2 MeV with α particle on 65Cu[Cu] target et 911.3 ± 99.4 milli-barns for 12.2 ± 1.3 MeV with a proton on 68Zn target) (Figure 1), the reactions 65Cu (α, n) 68Ga and 68Zn (p, n) 68Ga are the best to produce 68Ga[Ga] from of a medium to low energy accelerator.
In addition, among these two nuclear reactions, the irradiation of Zn by protons (68Zn[Zn] (p, n) 68Ga[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].
3. Production of 68Ga[Ga] via a Cyclotron Using a Solid Target of 68Zn[Zn]
3.1. Nature of the Target
Aiman H. Alnahwi et al. [16] developed an automated 68Ga[Ga] radiosynthesis for routine large-scale production using a squeezed 68Zn[Zn] target (target highly enriched to 99.26 in 68Zn[Zn]) (Table 2).
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Figure 1. Cross sections of reactions 65Cu[Cu] (α, n) 68Ga[Ga] and 68Zn[Zn] (p, n) 68Ga[Ga] [11] [14].
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Table 2. Isotopic composition of the target and impurities [16].
Thus, 68Zn[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 68Zn[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).
3.2. 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 68Zn[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 68Ga[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). This value (145 ± 6 GBq in EOB) is superior to the values reported by Lin et al. (Lin, Waligorski, et Lepera 2018) which used an incident energy of 14.5 MeV proton beam with beam currents of 15 à 40 μA and a power equivalent to about 80 times the activity of a generator.
Other authors like Sadeghi et al. [13] obtained interesting yield values for the 68Zn[Zn] (p, n) 68Ga[Ga] nuclear reaction using a solid target of Zn enriched to 97% in 68Zn[Zn]. Their EOB yield reached 5.032 GBq/μAh at 15 MeV with the use of a target of 52 μm thick; with an irradiation time of 0.25 h and a beam current of 150 μA. Szelecsényi et al. [11] reported that their values, calculated with the cross sections (5.809 GBq/μAh), were in agreement with these data.
3.3. 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 HNO3 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].
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Table 3. Production yields [8] [16].
aThe proton beam energies were calculated by Monte Carlo simulation using SRIM. Irradiation time was fixed at 30 min. bTotal recovered activity, corrected at EOB. cIrradiation time was 90 min. dSaturation yield estimated from results reported by Lin et al. [8]. Entries 1 - 5, n = 1; entry 6, n = 2.
3.4. Purification of 68Ga[Ga]
The automated purification process implemented by Aiman H. Alnahwi et al. [16] used a hydroxamate resin. 0.01 N HCl solution (50 mL) was required to remove 68Zn[Zn]. The 68Ga[Ga] was then eluted from the hydroxamate resin with 0.75 N HCl as [68Ga] GaCl3. This provides 68Ga[Ga] with a high radiochemical yield and a lead time of the dissolution and purification method of less than 10 - 12 min (20 min for Lin et al. [8] ). The last purification step, carried out with the CUBCX resin [21], has already been validated internally.
3.5. 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.). The concentrations of impurities of antimony, barium, beryllium, bismuth, cadmium, chromium, cobalt, lead, lithium, molybdenum, selenium, silver, tin, titanium, vanadium were <0.5 ppm. The elements Al, Fe, Mg, Zn and Cu were <4 ppm.
The main isotopic impurities were identified by gamma spectrometry (29, 50 and 72 h post purification) and consisted of 67Ga[Ga] (physical period: 3.26 days) and 66Ga[Ga] (physical period: 9.45 h), as indicated previously by Al-Saleh et al. [22] [23] and their total combined amount was less than 2% at 6 h after irradiation (Energy 13 MeV). 67Ga[Ga] can be produced via the reactions 67Zn[Zn] (p, n) 67Ga[Ga] and 68Zn[Zn] (p, 2n) 67Ga[Ga] with incident proton energy of 2 - 26 MeV and 13 - 29.5 MeV, respectively. 66Ga[Ga] can be produced via 66Zn[Zn] (p, n) 66Ga[Ga] and 67Zn[Zn] (p, 2n) 66Ga[Ga] with incident particle energy of 6 - 26 MeV and 15 - 26 MeV, respectively [24]. According to the experimental measurements reported by Alves et al. [5], the amounts of 67Ga[Ga] and 66Ga[Ga] can be kept below 2% using a particle energy of 13 MeV. For example, the 68Ga[Ga] purities may be 99.97% and 99.99% at EOB for particle energies of 14 and 13 MeV respectively. These values were confirmed by Lin et al. [8] who observed a small fraction (≤0.2%) of 67Ga[Ga] when the target was irradiated for up to 90 min with 14.5 MeV protons.
3.6. Target Recovery
Many authors have not performed a target recovery process, believing it to be more expensive than buying a new target. However, according to an IAEA document [12], 68Zn[Zn] can easily be recovered provided no impurities (e.g. iron) are present. Thus, simple multiple drying with nitric acid can be performed as described below. The procedure includes: 1) dry evaporation; 2) Dilution in concentrated nitric acid (>10 M); 3) Repeat the evaporation; 4) Dilution in 10 mM nitric acid; and 5) Evaporation to dryness or preparation of a ready-to-use solution. >90% recovery of the 68Zn isotope of Zinc is expected. All reagents used must be of high quality, traces of metal.
Buying a new target is worth more than this long and tedious target recovery process.
4. 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 68Ga[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 68Ga[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.