47Sc production development by cyclotron irradiation of 48Ca

The therapeutic radionuclide 47Sc was produced through the 48Ca(p,2n) channel on a proton beam accelerator. The obtained results show that the optimum proton energies are in the range of 24–17 MeV, giving the possibility to produce 47Sc radionuclide containing 7.4% of 48Sc. After activation, the powdery CaCO3 target material was dissolved in HCl and scandium isotopes were isolated from the targets. The performed separation experiments indicate that, due to the simplicity of the operations and the chemical purity of the obtained 47Sc the best separation process is when scandium radioisotopes are separated on the 0.2 µm filter.


Introduction
Only few pairs of radionuclides have been proposed for theranostics applications. These are iodine radioisotopes 123 I and 124 I for imaging, as well as 131 I for therapy. Other examples are 86 Y, 61 Cu and 64 Cu for PET imaging and bemitters 90 Y and 67 Cu for therapy. Recently, scandium radioisotopes were also proposed for theranostics application. Significant attention in 44 Sc and 43 Sc as tracers in positron emission tomography imaging has been observed. 44 Sc was first proposed by Rösch as a potential alternative for 68 Ga in clinical PET diagnosis [1,2]. 44 Sc decays by the emission of low-energy positrons (E b? = 1.47 MeV) with the half-life T 1/2 = 3.97 h which is almost four-fold longer than that of 68 Ga. 44 Sc can be obtained from the 44 Ti/ 44 Sc generator [3] or produced in the 44 Ca(p,n) 44 Sc reaction on small or medium medical cyclotrons that currently supply 18 F to hospitals [4][5][6][7][8][9]. However, the co-emission of highenergy c-rays (E c = 1157, 1499 keV), has to be taken into consideration with regard to radiation dose to the patients and clinical staff. Emission of high-energy c-rays generates also radiolytic decomposition of biomolecules, which is thought to be accompanied by formation of free radicals [10]. Another radionuclide of scandium-43 Sc, shows properties similar to 44 Sc, but emits much lower energy of concurrent gamma. 43 Sc can be produced either by the 43 Ca(p,n) [11], or by 42 Ca(d,n) [12] reaction, but unfortunately the cost of enriched calcium targets is very expensive. The more promising method of 43 Sc production is alpha irradiation of natural calcium target through the 40 Ca(a,p) and 40 Ca(a,n) channels has been mentioned in recently published paper [13].
The method of producing highly active 47 Sc in a nuclear reactor was described by Mausner et al., . An enriched 47 TiO 2 target was irradiated with high energy neutrons (E n [ 1 MeV) to produce 47 Sc via the 47 Ti(n, p) 47 [21]. The former nuclear reaction requires E n [ 1 MeV, while the latter reaction uses more available thermal neutrons. The second advantage of this method is the use of 47 Ca/ 47 Sc generator system to supply 47 Sc activity, but the disadvantage is the requirement of an enriched target. 46 Ca is presently available with only a 30% enrichment and at a very high price, which makes the target cost prohibitive.
Other ways of producing 47 Sc have been based on proton irradiation of nat Ti [22] and c irradiation of 48 Ti in an electron linear accelerator (LINAC) [23]. The production efficiency was lower than in the former cases. Both production routes require also radiochemical separation of 47 Sc from the Ti targets. Recently, new cyclotron method for 47 Sc production by alpha irradiation of 44 Ca enriched target was reported [24]. Unfortunately due to low cross section of the 44 Ca(a,p) 47 Sc reaction production by this method makes difficult to obtain GBq quantities, which are necessary to carry out clinical trials.
Various methods of 47 Sc separation from TiO 2 targets based on tributyl phosphate (TBP) extraction, extraction chromatography or on cation and anion exchange processes have been reported [11,12]. Dissolution in hot concentrated H 2 SO 4 and evaporation of the solution were the most difficult and time-consuming steps in the case of the TiO 2 target, what significantly limits the use of this type of targets. In the case of calcium targets many methods of scandium radionuclide separation have been reported [4,5,8,22]. All proposed methods are simple, fast and allow for high percent of scandium radionuclides and for calcium recovery.
In the present work we propose an alternative way of 47 Sc production through the 48 Ca(p,2n) reaction at medium size cyclotrons (proton energy below 30 MeV). During 48 Ca irradiation the 48 Sc (T 1/2 = 43.67 h) and 46 Sc (T 1/2 = 83.79 days) are also co-produced, therefore the goal of our studies was optimization of the parameters of 48 Ca irradiation for maximization the 47 Sc production with minimal 48 Sc and 46 Sc impurities.

Irradiation of calcium target
Production yield of 47 Sc and 48 Sc radionuclides for proton induced reactions on CaCO 3 with natural isotopic composition were measured as function of proton energy in the range of 60 ? 0 MeV using activation method on stacks. The stack consisted of thin metallic foils with natural isotopic composition interleaved with CaCO 3 targets. The stack was assembled from six groups of Al-Cu-CaCO 3 and five groups of Al-Cu-Ti-CaCO 3 . The stack of targets and foils were mounted in a target holder which was made of aluminum. CaCO 3 powder of analytical grade from POCH S.A. (Gliwice, Poland) were pressed with 232 MPa. Thickness of targets were about 0.35 g/cm 2 . The thickness of monitor reaction Al, Cu and Ti foils (purity 99.0-99.9% supplied by Goodfellow Cambridge Ltd., England) was 0.02 mm for Al, 0.01 mm for Cu and 0.01 mm for Ti. The thin metallic foils were used to monitor intensity and/or energy of proton beam.
Two stacks were irradiated at the extracted proton beam of the AIC-144 cyclotron of the Institute of Nuclear Physics Polish Academy of Sciences Cracow. Irradiations were carried out for 5 h with beam current of about 30 nA and with initial proton bombarding energy of 60 MeV.

Data analysis
The activities of the radioactive products of the targets and monitors were measured nondestructively using the gamma HPGe-detector coupled with Multichannel Analyzers 919E EtherNIM. The photo peak area of c-ray spectra was determined by using MAESTRO Multichannel Analyzer Emulation. The decay data for the monitors and Sc radionuclides, such as half-life (T 1/2 ), c-ray energy (E c ) and c-ray emission probability (I c ), were taken from the Table of Radioactive Isotopes [25].
The proton flux intensity was determined through the monitor reactions: 27 Al(p,x) 22,24 Na, nat Cu(p,x) 56 Co, 62,65 Zn and nat Ti(p,x) 48 V from the measured activities induced in monitor foils at the front position of each CaCO 3 target. The standard cross-sections for the monitor reactions were taken from [26].
The energy degradation along the stacks and effective particle energy in the middle of each foil was calculated using the computer program SRIM version 2008.04 [27]. The estimated uncertainty of the points representing the proton energy ranges from ±0.6 up to ±1.5 MeV.
The following sources of errors were considered to derive the summed up uncertainty in the yield values of 46 Sc, 47 Sc and 48 Sc: statistical error (1-7%), error of the monitor flux (*6%), error due to the sample thickness determination (1-2.5%) and error of efficiency calibration of c-rays spectrometer (*5%). The overall uncertainty in the determined yield was around 12%.

Separation of Sc from the target
Three methods previously elaborated for 43,44 Sc production were tested for separation of 47 Sc from natural Ca target. First of the methods based on application of chelating resin, elaborated in our group [4], consisted of dissolution of the target in 1 M HCl and adsorption of scandium radionuclides on chelating ion exchange resin Chelex 100 of bed size 0.8 9 4.0 cm and conditioned with 5 ml of 1 M HCl. After adsorption of Sc 3? and Ca 2? , the column was washed with 30 ml of 0.01 M HCl in order to remove Ca 2? . The scandium radionuclides were then eluted with 1 M HCl in 0.5 ml fractions. In the second method, described by Valdovinos et al. [8], the irradiated nat CaCO 3 target was dissolved in 1 ml of 9 M HCl solution. The dissolved target solution was passed through a column containing 50 mg of UTEVA resin and after adsorption of scandium radionuclides the column was washed with 5 ml of 9 M HCl. The scandium radionuclides were eluted with a 400 ll portion of H 2 O. The third method which used 47 Sc separation on 0.2 lm filter was recently described by Minegishi et al. [24]. In this method calcium target was dissolved in 0.5 M HCl and next was neutralized by 25% NH 3 solution to pH 10. The obtained Sc solution was then passed through a 0.2 lm filter (Whatmann) to trap Sc radioisotopes. Subsequently, 3 ml of pure water was passed through the filter to wash out residual Ca 2? and NH 4 ? cation. Scandium radionuclides trapped on the filter was eluted by 0.5 M HCl. The methods were tested on proton irradiated natural Ca targets containing 44 Sc,47 Sc and 48 Sc no carrier added radionuclides.

Results and discussion
Up to now for the production of 46,47,48 Sc through the nat Ca(p,xn) 46,47,48 Sc reaction only two groups reported experimental data: first group reported cross section data using nat Ca in calcium formate as the target [28] and a second group a thick target yields for natural calcium metal [6].  47 Sc production in 48 Ca(p,2n) 47 Sc reaction. In the present work results of 47 Sc production via the 48 Ca(p,2n) reaction in energy range 60-0 MeV have been described.
Due to low availability and high cost of 48 Ca we decided to work with natural calcium targets containing 0.187% 48 Ca. Table 1 shows the isotopic compositions of the natural and 48 Ca enriched calcium targets. Table 2 shows results of irradiation of nat CaCO 3 in the energy range 60-0 MeV.
As shown in Table 2 the optimum energy range for the 48 Ca(p, 2n) 47 Sc reaction is 24 ? 17 MeV with the peak at about 20 MeV for CaCO 3 target. The peak for 48 Ca(p,n) 48 Sc reaction is about 11 MeV and is about 33 MeV for 48 Ca(p,3n) 46 Sc reaction. It should be noted that 46 Sc forms also in 46 Ca(p,n) 46 Sc nuclear reaction, but due to the very low abundance of 46 Ca in nat Ca (0.004%) the produced 46 Sc activity is negligible. In the obtained 47 Sc radionuclide the percent of 48 Sc impurity at EOB is 14.7 and decreases after 80.38 h (half-life of 47 Sc) to 7.4%. As shown in Table 2 in this energy range also 20.1 kBq/ lA h of 47 Ca (T 1/2 = 4.5 days) is produced which by the bdecay generates additional 47 Sc activity, therefore the yield of 47 Sc at EOB includes also the activity of 47 Sc generated from 47 Ca decay during the irradiation. The ratio of 46 Sc impurity to 47 Sc was only 0.2% at EOB. Irradiation of thiner CaCO 3 targets could allow to increase the representing points in the proton energy range.
The yields estimated by using the cross section data from Michel et al. [28] are lower by about 25% than in our work. Irradiations of natural Ca metal at 16 MeV proton energy were performed by Severin et al. [6]. This group presented yields at EOB equal to 0.09 for 47 Sc and 0.33 MBq/lA h for 48 Sc. However, direct comparison of obtained experimental yield values is difficult because irradiated Ca targets had different chemical forms. For comparison of measured yields obtained in this work with data obtained by Severin et al. [6], a normalization for the number of Ca atoms in the target was performed. Our yield value 0.31 MBq/lA h for 48 Sc, after the normalization, over the proton energy range 16.6 ? 0 MeV is in good agreement with the yield value obtained by Severin et al. [6]. In the case of 47 Sc we obtained about two times higher yield value than Severin et al. [6]. This difference may result from error in determination of input proton energy on the target. In this proton energy range a small change in energy causes a large change in the efficiency of (p,2n) nuclear reaction.
To find the best method for separation of 47 Sc from the calcium targets three methods previously elaborated for 44 Sc were tested. These methods were compared in respect to Sc separation yield, possibility of separation from other metallic impurities which could negatively affect the effectiveness of 47 Sc bioconjugates labeling and recovery of calcium target (Table 3).
All separation procedures studied are fast and simple. In the case of Chelex 100 and UTEVA resins the target dissolution and separation of scandium radioisotopes were performed in 30 min and the separation process on 0.2 lm filter needs only 15 min. The separation process on 0.2 lm filter gives also highest recovery of scandium isotopes and is much simpler and faster in comparison with other methods studied. It contains only two simple processes: adsorption Sc(OH) 3 on the filter and then dissolution of the precipitate in hydrochloric acid.
Chemical purity of the Sc product is important, since the presence of other metals may interact with the DOTAchelator. The most dangerous is Fe 3? for which forms stronger complexes with DOTA than Sc 3? [29]. Influence of other possible impurities like Zn 2? , Mg 2? , Sr 2? and Co 2? is negligible due to the much lower stability constants of their DOTA complexes [29]. The results of Fe  concentration in dissolved calcium targets and in scandium fractions after separation processes are presented in Table 4. For all the methods studied the concentration of Ca 2? in Sc fractions was less than 1 ppm.
Taking into account the obtained results, we recommend filtration process for the separation of Sc radionuclides from the calcium targets.

Conclusion
The production of 47 Sc in (p,2n) nuclear reaction on natural CaCO 3 target was successfully performed. During proton irradiation of natural calcium target radionuclides of interest 46 Sc, 47 Sc and 48 Sc can be formed only in p,n, p,2n and p,3n reactions on 48 Ca, therefore, the results obtained for natural calcium can be recalculated for enriched 48 Ca targets. The obtained results of production efficiency creates the opportunity to produce GBq activity levels of 47 Sc. The separation process based on precipitation of Sc(OH) 3 and separation on 0.2 lm filter is simple, reliable, efficient and fast and can be easily adapted for remote operation.