47Sc as useful β–-emitter for the radiotheragnostic paradigm: a comparative study of feasible production routes
© The Author(s) 2017
Received: 13 March 2017
Accepted: 12 May 2017
Published: 2 June 2017
Radiotheragnostics makes use of the same molecular targeting vectors, labeled either with a diagnostic or therapeutic radionuclide, ideally of the same chemical element. The matched pair of scandium radionuclides, 44Sc and 47Sc, satisfies the desired physical aspects for PET imaging and radionuclide therapy, respectively. While the production and application of 44Sc was extensively studied, 47Sc is still in its infancy. The aim of the present study was, therefore, to investigate and compare two different methods of 47Sc production, based on the neutron irradiation of enriched 46Ca and 47Ti targets, respectively.
47Sc was produced by thermal neutron irradiation of enriched 46Ca targets via the 46Ca(n,γ)47Ca → 47Sc nuclear reaction and by fast neutron irradiation of 47Ti targets via the 47Ti(n,p)47Sc nuclear reaction, respectively. The product was compared with regard to yield and radionuclidic purity. The chemical separation of 47Sc was optimized in order to obtain a product of sufficient quality determined by labeling experiments using DOTANOC. Finally, preclinical SPECT/CT experiments were performed in tumor-bearing mice and compared with the PET image of the 44Sc labeled counterpart.
Up to 2 GBq 47Sc was produced by thermal neutron irradiation of enriched 46Ca targets. The optimized chemical isolation of 47Sc from the target material allowed formulation of up to 1.5 GBq 47Sc with high radionuclidic purity (>99.99%) in a small volume (~700 μL) useful for labeling purposes. Three consecutive separations were possible by isolating the in-grown 47Sc from the 46/47Ca-containing fraction. 47Sc produced by fast neutron irradiated 47Ti targets resulted in a reduced radionuclidic purity (99.95–88.5%). The chemical purity of the separated 47Sc was determined by radiolabeling experiments using DOTANOC achievable at specific activities of 10 MBq/nmol. In vivo the 47Sc-DOTANOC performed equal to 44Sc-DOTANOC as determined by nuclear imaging.
The production of 47Sc via the 46Ca(n,γ)47Ca nuclear reaction demonstrated significant advantages over the 47Ti production route, as it provided higher quantities of a radionuclidically pure product. The subsequent decay of 47Ca enabled the repeated separation of the 47Sc daughter nuclide from the 47Ca parent nuclide. Based on the results obtained from this work, 47Sc shows potential to be produced in suitable quality for clinical application.
Nuclear data of theragnostic radionuclides for therapy and PET imaging
Diagnostic radionuclide (positron emitter)
Eβ− av [keV]
Eγ [keV] (Iγ [%])
Eβ+ av [keV] (I[%])
Eγ [keV] (Iγ [%])
113 (6.4) 208 (11.0)
This matched pair would present an attractive alternative to 68Ga and 177Lu, which are currently used in clinics for PET imaging and therapy, respectively (Oh et al. 2011). Ga(III) and Lu(III) can be coordinated by 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-complexes (Majkowska-Pilip and Bilewicz 2011), however, they do not share the same coordination chemistry. Lu(III) is coordinated by all carboxyl groups of the octadentate DOTA (Viola-Villegas and Doyle 2009; Parus et al. 2015), while Ga(III) has a preference for the coordination number six, leaving two uncoordinated carboxyl groups in the Ga-DOTA-complex (Viola-Villegas and Doyle 2009; Majkowska-Pilip and Bilewicz 2011). As a result, these structural differences may have an influence on the radioconjugate’s chemical properties and, consequently, on the in vivo kinetics and receptor binding affinity (Reubi et al. 2000; Majkowska-Pilip and Bilewicz 2011). By using chemically identical radionuclides such as 44Sc/47Sc–known to form stable complexes with DOTA–this limitation could be addressed.
The physical half-life of 44Sc of 3.97 h (recently re-determined as 4.04 h (Garcia-Torano et al. 2016), is almost 4-fold longer than that of 68Ga (T1/2 = 68 min) and, hence, allows its use with biomolecules with slower kinetics. Due to the possibility of shipping 44Sc-radiopharmaceuticals over long distances, it can also facilitate logistics as it would allow centralized production and distribution to remote hospitals (Chakravarty et al. 2014; van der Meulen et al. 2015). The increased availability of 44Sc has initiated a number of preclinical in vitro and in vivo studies with DOTA-conjugated biomolecules (Müller et al. 2013a, 2013b; Hernandez et al. 2014) and, recently, labeling of NODAGA (1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid)-functionalized peptides and DTPA (N-[(R)-2-amino-3-(para-isothiocyanato-phenyl)propyl]trans-(S,S)-cyclohexane-1,2-diamine N,N,N’,N”N”-pentaacetic acid)-functionalized antibodies was also demonstrated (Chakravarty et al. 2014; Domnanich et al. 2016).
The emission of low-energy β−-particles from 47Sc (Eβ− av = 162 keV, Table 1) is particularly interesting for targeted radionuclide therapy of small tumors and cancer metastases, similar to the clinically-established 177Lu (Eβ− av = 134 keV, T1/2 = 6.65 d, Table 1). Moreover, the shorter half-life of 47Sc (T1/2 = 3.35 d) would encourage its use, in conjunction with small molecules, with relatively fast pharmacokinetic profiles. In analogy to 177Lu, the decay of 47Sc is characterized by the co-emission of γ-rays with an ideal energy (Eγ = 159 keV, Table 1) for SPECT imaging (Müller et al. 2014a).
The aim of the present study was to optimize the parameters of the previously-reported production process for 47Sc from enriched 46Ca targets (Müller et al. 2014a) in order to reproducibly obtain increased 47Sc yields in a formulation allowing direct preclinical application after radiolabeling and to compare it with the method using 47Ti as target material. 47Sc labeling experiments with DOTANOC were performed as part of the quality control. In the second part of the study the stability of 47Sc-labeled DOTANOC was investigated and SPECT/CT imaging studies were performed in tumor-bearing mice to compare the performance of 47Sc-DOTANOC with the previously obtained PET images of the 44Sc-labeled counterpart. Moreover, comparison of SPECT images obtained with mice injected with 177Lu-DOTANOC were also performed.
Enriched 46CaCO3 (83.09% 40Ca, 1.19% 42Ca, 0.36% 43Ca, 8.55% 44Ca, 5.00 ± 0.50% 46Ca, 1.81% 48Ca, Trace Sciences International, USA) was used as target material for thermal neutron irradiation. Enriched 47TiO2 (0.41% 46Ti, 95.7 ± 0.3% 47Ti, 3.61% 48Ti, 0.15% 49Ti, 0.13% 50Ti, Isoflex, USA) was reduced to 47Ti metal and used as target material for fast neutron irradiation. Prior to irradiation, a precursory scan for trace metals by ICP-OES (Perkin Elmer Optima 3000) was performed.
The chemical separation of Sc from Ca was performed on a N,N,N’,N’-tetra-n-octyldiglycolamide, non-branched resin (DGA, particle size 50–100 μm, TrisKem International, France). SCX cation exchange cartridges (100 mg Bond Elut SCX, particle size 40 μm, Agilent Technologies Inc., USA) or DGA extraction chromatographic resin were used for the preconcentration of Sc. Chemical separations were performed with MilliQ water, hydrochloric acid (HCl, 30% Suprapur, Merck KGaA, Germany) and sodium chloride (NaCl, Trace Select, ≥99.999%, Fluka Analytical, Germany). For the 47TiO2 reduction process, calcium hydride (CaH2, metals basis, Mg <1%, Alfa Aesar, Germany), argon (Ar, 99.9999%, Linde, Germany) and acetic acid (CH3COOH, 100% Suprapur, Merck KGaA, Germany) were used. Nitric acid (HNO3, 65% Suprapur, Merck KGaA, Germany) was required for the preparation of the 46Ca targets. DOTANOC acetate was obtained from ABX GmbH, advanced biochemical compounds, Germany.
Production of 47Sc from enriched 47Ti
The reduction of 47TiO2 was performed at Helmholtz Center for Heavy Ion Research (GSI) in Darmstadt as described elsewhere (Lommel et al. 2014). Briefly, the enriched 47TiO2 was combined with 40% surplus of calcium hydride and the reduction process was performed under constant argon flow at 900 °C for 1 h. Dilute acetic acid was used for the isolation of the reduced 47Ti metal from the co-produced calcium oxide.
To prepare the targets, 0.6–19.9 mg reduced 47Ti powder was placed in a quartz glass ampoule (Suprasil, Heraeus, Germany) and sealed. The targets were irradiated with neutrons at the spallation-induced neutron source, SINQ, at Paul Scherrer Institut (PSI) at a fast neutron flux (>1 MeV) of 3.3–3.5 × 1011 n cm−2 s−1 for 1.5–18.9 days and in the BR2 reactor at SCK.CEN, Mol, Belgium in a reflector channel at a fast neutron flux (>1 MeV) of 5.7 × 1013 n cm−2 s−1 for 7 days. 47Sc was formed via the 47Ti(n,p)47Sc nuclear reaction with fast neutrons.
Production of 47Sc from enriched 46Ca
To prepare the targets, 65–91 mg enriched 46CaCO3 powder was dissolved in concentrated nitric acid and evaporated to complete dryness at 60–70 °C. The 46Ca(NO3)2 residue was taken up in dilute nitric acid (~1 M HNO3) and an aliquot of the aqueous solution (0.14–0.35 mg 46Ca) transferred into a quartz glass ampoule, evaporated to dryness and sealed.
47Sc was produced by the irradiation of the described 46Ca targets with thermal neutrons at the high flux reactor of Institut Laue-Langevin (ILL) in Grenoble, France at a thermal neutron flux of 1.0–1.4 × 1015 n cm−2 s−1, for 4 to 11 days, and at the BR2 reactor at SCK.CEN, Mol, Belgium at a thermal neutron flux of 3.2 × 1014 n cm−2 s−1 for 7 days, respectively. 47Sc was generated by the decay of the formed 47Ca (T1/2 = 4.54 d) occurring during the irradiation, but also after removal of the ampoule from the reactor.
Separation of 47Sc from 46Ca and 47Ca
The renewed generation of 47Sc, by the decay of radioactive 47Ca in the Ca-containing fraction (47Ca and stable 46Ca), enabled subsequent separations after a minimum in-growth time of 3 days.
To identify the nuclide inventory of the samples, γ-ray spectrometry with an N-type high-purity germanium (HPGe) coaxial detector (EURISYS MESURES, France) and the Ortec InterWinner 7.1 software were employed. The aliquot of 47Sc eluate was in the range of 3–15 MBq, while the entire neutron irradiated glass ampoules containing the 47Ti were used for the measurements. The counting time was determined by ensuring the measurement error was <4%. To determine small activities of long-lived radionuclidic impurities, γ-spectrometry measurements of the same samples were performed with an extensive counting time several days post-irradiation.
Radiolabeling for quality control of the produced 47Sc
After quantitative determination of the 47Sc activity in the eluate with a dose calibrator (ISOMED 2010, Nuclear-Medizintechnik Dresden, GmbH, Germany), the required activity for radiolabeling in 0.05 M HCl was withdrawn from the product vial and 0.5 M sodium acetate solution (pH 8) was added to the 47Sc eluate to obtain a pH value of ~4.5. DOTANOC (0.7 mM solution in MilliQ water) was added to the 47Sc solution (~50 MBq) to obtain a specific activity of 10–25 MBq/nmol (2–5 nmol DOTANOC). The reaction mixture was incubated at 95 °C for 15 min. The preparation of 177Lu-DOTANOC (25 MBq/nmol) was carried out under standard labeling conditions (pH 4.5, 95 °C) using no carrier-added 177Lu (purchased from Isotope Technologies Garching GmbH, Germany) (Müller et al. 2013a).
High-performance liquid chromatography (HPLC, Merck Hitachi, LaChrom) with a C-18 reversed-phase column (XterraTM MS, C18, 5 μm, 150 × 4.6 mm; Waters) was used for determination of the radiolabeled fraction of DOTANOC. The detection was performed with a UV (LaChrom L-7400) and radiodetector (Berthold, HPLC Radioactivity Monitor, LB 506B). The mobile phase consisted of MilliQ water containing 0.1% trifluoracetic acid (A) and acetonitrile (B) with a gradient of 95% A and 5% B to 20% A and 80% B, over a period of 15 min, at a flow rate of 1.0 mL/min.
In vitro stability of 47Sc- and 177Lu-labeled DOTANOC
The in vitro stability of 47Sc- and 177Lu-labeled DOTANOC (radiochemical purities >95%) was investigated in phosphate buffered saline (PBS, pH 7.4). An activity of 50 MBq of 47Sc- or 177Lu-DOTANOC was diluted with PBS (pH 7.4) to a total volume of 500 μL and incubated at room temperature for 3 days. Once every 24 h an aliquot was withdrawn to determine the integrity of the labeled compound by means of HPLC.
SPECT/CT imaging with 47Sc- and 177Lu-DOTANOC
In vivo experiments were approved by the local veterinarian department and conducted in accordance with the Swiss law of animal protection. Female, athymic nude mice (CD-1 nude) at the age of 5–6 weeks were obtained from Charles River Laboratories, Sulzfeld, Germany. AR42J cells (rat exocrine pancreatic tumor cells, European Collection of Cell Cultures ECACC, Salisbury, U.K.) were suspended in PBS (5 × 106 cells in 100 μL) and subcutaneously inoculated on each shoulder. SPECT/CT experiments were performed about 2 weeks after tumor cell inoculation, when the tumor reached a size of about 400 mm3.
Imaging studies were performed using a small-animal SPECT camera (NanoSPECT/CT™, Mediso Medical Imaging Systems, Budapest, Hungary) as previously reported (Müller et al. 2014b). The energy peaks for the camera were set at 159.4 keV (± 10%) for the scans with 47Sc and 56.1 keV (± 10%), 112.9 keV (± 10%) and 208.4 keV (± 10%) for the scans with 177Lu. SPECT/CT scans were followed by CT scans. The images were acquired using Nucline Software (version 1.02, Bioscan Inc., Poway, California, US). The reconstruction was performed iteratively with HiSPECT software (version 1.4.3049, Scivis GmbH, Göttingen, Germany). SPECT and CT data were automatically co-registered and the fused datasets were analyzed with the VivoQuant post-processing software (version 2.50, inviCRO Imaging Services and Software, Boston, USA).
The mice were injected intravenously with 47Sc-DOTANOC (12 MBq, 1.2 nmol, 100 μL) and 177Lu-DOTANOC (40 MBq, 1.2 nmol, 100 μL), respectively. The in vivo SPECT/CT scans of 35 min duration were acquired 3 h after injection of 47Sc-DOTANOC. During the scans, the mice were anesthetized by inhalation of a mixture of isoflurane and oxygen. Post-mortem scans of 1.3–3.5 h were performed 6 h after injection of 47Sc- and 177Lu-DOTANOC. The SPECT acquisitions were performed in such a manner to obtain the same total number of counts for each scan.
Production of 47Sc from 47Ti via the (n,p) reaction
Activity and yield of 47Sc at the end of irradiation (EOI) with fast neutrons (>1 MeV) at SINQ (irradiations PSI 1, PSI 2 and PSI 3) and at the BR2 reactor (irradiation SCK.CEN)
m (47Ti) [mg]
A (47Sc) at EOI [MBq]
A (47Sc)saturation [MBq/mg 47Ti 10−13 n cm−2 s−1]
46Sc activity at EOI [%]
Production of 47Sc from 46Ca via the (n,γ) reaction
Activity of 47Sc at the time of separation (A(47Sc)), comparison of the calculated and measured 47Sc saturation yield (A(47Sc)calc and A(47Sc)meas) and of the optimal and measured relative 47Sc activity (a(47Sc)opt and a(47Sc)meas) after irradiation with thermal neutrons at ILL (irradiations ILL 1–5) and BR2 (irradiation SCK.CEN)
A(47Sc) at separation [MBq]
[MBq/mg 46Ca 10−13 n cm−2 s−1]
Separation of 47Sc from 46Ca and 47Ca
After the ampoule was crushed, it was moved to the hot cell containing the production panel (Fig. 2), where the target material was dissolved by repeated application of 6.5 mL 3.0 M HCl. The 47Ca and 47Sc activity was transferred from the crushed glass ampoule to the DGA column, leaving only 1.1 ± 0.5% 47Ca and 3.3 ± 0.4% 47Sc attached to the glass. Direct application of 2 mL 3.0 M HCl quantitatively removed the Ca (47Ca and stable Ca isotopes) from the resin. The collected Ca fraction contained 99.8 ± 0.2% of the total 47Ca activity. The 47Sc activity was eluted from the DGA column with 4 mL 0.1 M HCl and only 1.5 ± 0.6% of the 47Sc activity remained on the column. Using Method A, the solution was concentrated on the SCX cation exchange resin (used as the second column) and eluted with 700 μL 4.8 M NaCl/0.1 M HCl solution (pH 0–0.5), collecting 94.8 ± 2.1% of the total 47Sc activity. When using Method B, the molarity of the 47Sc eluate was increased from 0.1 to 3.0 M HCl and the resulting solution adsorbed on a second smaller DGA column and eluted with 1.7 mL 0.05 M HCl. Fractionized collection revealed that about ~90% of the eluted 47Sc activity was obtained in the first 700 μL (pH ~0).
Radionuclidic purity of 47Sc produced from 46Ca via (n,γ) reaction
The γ-ray spectrum of the neutron-irradiated 46Ca target material (Additional file 1: Figure S2a) showed, exclusively, the γ-lines of 47Sc (159 keV) and the parent nuclide 47Ca (489, 808 and 1297 keV). After chemical separation and concentration of 47Sc on SCX resin (Method A), the radionuclidic purity of the final 47Sc eluate was 99.6 ± 0.7%. When the second DGA column (Method B) was used, the radionuclidic purity increased to 99.99 ± 0.03% (Additional file 1: Figure S2b). The long-lived radionuclidic impurity 46Sc was only present in the eluate obtained from the first separation at a maximum of 0.005% and could be only detected by performing long-term γ-spectrometry measurements several days post separation. The isolated 47Sc which was generated by the decay of 47Ca in the Ca-containing fraction did not contain any 46Sc, due to its entire removal within the first separation.
Radiolabeling and stability of 47Sc labeled DOTANOC
Radiolabeling of 47Sc was reproducible at a specific activity of 10 MBq 47Sc per nmol DOTANOC, with >96% radiochemical purity. Depending on the activity concentration of the 47Sc solution, it was also possible to label at higher specific activity of up to 25 MBq/nmol.
Imaging with 47Sc-DOTANOC in comparison to 44Sc-DOTANOC and 177Lu-DOTANOC
Recently, the use of 47Sc for therapeutic purposes, as part of the 44Sc/47Sc theragnostic radionuclide pair, has attracted considerable attention in the field of nuclear medicine (Rösch and Baum 2011). In the present study we report, to our knowledge, the first reproducible production of MBq to GBq activities of 47Sc by the irradiation of enriched 46Ca target material with thermal neutrons. Concurrently, an alternative production route was investigated, using 47Ti as target material and, by irradiation with fast neutrons, 47Sc was formed via the (n,p) nuclear reaction. Irradiation of enriched 47Ti at the spallation source SINQ (PSI, Switzerland) and the BR2 reactor (SCK.CEN, Mol, Belgium) resulted in the formation of 1.8–10.0 MBq 47Sc/mg 47Ti 10−13 n cm−2 s−1. The production of 47Sc by neutron irradiation of enriched 47Ti target material was performed previously by Mausner and Kolsky in the fission neutron spectrum of the HFIR reactor in Oak Ridge National Laboratory (ORNL) and Brookhaven National Laboratory (BNL) (Kolsky et al. 1998, Mausner, Kolsky et al. 1998) and by Bartoś et al. at the Maria reactor in Świerk, Poland (Bartoś et al. 2012). The reported activity of produced 47Sc was within the range of 1.4–4.2 MBq 47Sc/mg 47Ti 10−13 n cm−2 s−1, which is comparable with the 47Sc radioactivity obtained in our experiment at BR2. The irradiations at SINQ generated higher 47Sc activities, due to the larger proportion of fast neutrons (> 1 MeV) at the spallation source (Lehmann 2016) than at the reactor (Chrysanthopoulou et al. 2014). The production of 85–98 MBq 47Sc/mg 46Ca 10−13 n cm−2 s−1 was feasible via the 46Ca(n,γ)47Ca → 47Sc route with thermal neutrons from nuclear reactors at ILL and BR2, however. The nearly ten-fold higher accessible 47Sc activity from 46Ca irradiations can be attributed to the higher nuclear cross section of the 46Ca(n,γ)47Ca reaction (σ = 0.7 barn) (Magill et al. 2015) in comparison to the 47Ti(n,p)47Sc nuclear reaction (Additional file 1: Figure S4), as well as to an increased flux of thermal neutrons in comparison to fast neutrons. Lower measured relative 47Sc activities than the optimal activities were obtained for the irradiations ILL 1–ILL 5, because the post-irradiation waiting period was too long and the built up 47Sc already started to decay. Shorter waiting periods were prevented due to logistical issues. The waiting period after the irradiation at SCK.CEN, however, was close to the optimum time period, thus the measured relative 47Sc activity obtained from the irradiation at SCK.CEN is in good correlation with the optimal value.
γ-spectra of the irradiated 46Ca indicated the presence of 47Ca and 47Sc, however, due to high dead time a precise determination of both activities before separation was not possible. After chemical separation a product of high radionuclidic purity, containing only 0.005% 46Sc, was obtained (Additional file 1: Figure S2). The acquired radionuclide inventory of 47Ti targets, neutron irradiated at the spallation source SINQ, indicated a higher percentage of 46Sc (Additional file 1: Figure S3), which increased proportionally with irradiation time (3.8–11.5% 46Sc for 1.5–18.9 days irradiation), whereas a significantly smaller amount of 46Sc (0.05%) was produced after 7 days of irradiation at the BR2 reactor (SCK.CEN). Trace activities of 122Sb and 124Sb were identified in the γ-ray spectrum of the irradiated 47Ti ampoule at SINQ (Additional file 1: Figure S3), conceivably produced by neutron activation reactions on natural Sb impurities (Additional file 1: Table S5). The presence of 22Na and 7Be can be attributed to spallation reactions with the capsulation material. The scan for trace metals revealed impurities of Ca, Sr, Sb and Zr in the reduced 47Ti metal (Additional file 1: Table S5), which were probably introduced by the reduction process. Neutron activation reactions were only observed with Sb, but not with any of the other determined impurities, however.
The formation of 46Sc from 47Ti via the 47Ti(n,n + p)46Sc nuclear reaction is known to be only induced by very fast neutrons above the threshold of 10.7 MeV (Additional file 1: Figure S4) (Zerkin 2016). The considerably decreased 46Sc impurity of the sample irradiated at the BR2 reactor can, therefore, be attributed to the lower proportion of very energetic neutrons in the fission spectrum of the BR2 reactor (Chrysanthopoulou et al. 2014), compared to the spallation neutron spectrum in the SINQ (Lehmann 2016). The percentage of 46Sc obtained from the 47Ti irradiation at the BR2 reactor was in agreement with those from previous experiments at ORNL, BNL and the Maria reactor, which was reported to be 0.06–0.64% 46Sc (Kolsky et al. 1998; Mausner et al. 1998; Bartoś et al. 2012). With respect to radiopharmaceutical applications, the ten-fold higher 47Sc production from 46Ca targets, together with the absence of long-lived radionuclidic impurities, intensified our research towards the further development of the more attractive 46Ca route.
In order to meet the requirements for radiopharmaceutical applications, the obtained 47Sc eluate needed to be of high chemical purity and concentrated into a small volume of moderately acidic eluate to facilitate efficient radiolabeling and subsequent in vivo application. Initially, SCX cation exchange resin (Method A) was used and 94.8% ± 2.1% of the total 47Sc activity was recovered in only 700 μL eluate (4.8 M NaCl/0.1 M HCl). The use of this resin is already established for the concentration of the 68Ga eluate from the 68Ge generator (Mueller et al. 2013); however, direct preclinical in vivo application is not feasible due to the high osmolarity of the obtained eluate. In a modification of the separation procedure, a second, smaller DGA column was used (Method B), allowing the elution of ~90% using 700 μL 0.05 M HCl. This enabled labeling and preclinical application as previously shown with 44Sc (Domnanich et al. 2016).
The labeling of DOTANOC with 47Sc was performed to verify a consistent chemical purity of the obtained eluate. Our results demonstrated reproducible radiosynthesis of 47Sc-DOTANOC at specific activities of 10 MBq/nmol, whereas radiolabeling at 25 MBq/nmol proved possible. The obtained results indicated good quality of the produced 47Sc achieving radiolabeling yields, in agreement with the previously-performed 47Sc-radiolabeling of a DOTA-folate conjugate (Müller et al. 2014a).
In PBS 47Sc remained stably coordinated by the DOTA-chelator over 3 days (<6% release), a result which was comparable to the 177Lu-labeled peptide. 47Sc- and 177Lu-DOTANOC were, however, affected by radiolytic decomposition, which decreased the amount of intact product over time. It is likely the radiolytic stability could be enhanced by the addition of radical scavengers, such as ascorbic or gentisic acids, which were previously successfully employed for the stabilization of 90Y- and 177Lu-labeled DOTA-peptides (Liu and Edwards 2001; Liu et al. 2003).
In a proof-of-concept study, 47Sc-DOTANOC was utilized for SPECT/CT imaging of AR42J tumor-bearing mice. The equal distribution profile of 47Sc-DOTANOC and 44Sc-DOTANOC, previously demonstrated using PET/CT, demonstrated the successful realization of the “matched pair” principle using scandium radionuclides. Moreover, the in vivo distribution of 47Sc-DOTANOC was comparable to 177Lu-DOTANOC. Due to the higher percentage of emitted γ-radiation in the case of 47Sc, it is expected that less activity of 47Sc-labeled compounds would be necessary for clinical SPECT as compared to the activity necessary for 177Lu-labeled counterparts.
The reproducible production of activities of up to 2 GBq 47Sc at high radionuclidic purity via the 46Ca(n,γ)47Ca nuclear reaction in the thermal neutron flux of a reactor was demonstrated. The subsequent decay of 47Ca to 47Sc creates a “pseudo-generator” system, which enables the repeated separation of the 47Sc daughter nuclide from the 47Ca parent nuclide. Together with the high radionuclidic purity and the superior yield of the isolated 47Sc activity, the 46Ca production route bears significant advantages over the 47Ti production route with fast neutrons. Even though the high price of enriched 46Ca represents a drawback, implementation of a suitable recovery method will limit the expenses. Based on the results obtained from this proof-of-concept study, 47Sc has the potential to be produced in a suitable quality for clinical applications, however, the quantity of radioactivity still needs to be expanded to meet the requirements for radionuclide therapy.
We thank Raffaella Schmid, Renata Farkas, Walter Hirzel and Muhamet Djelili for technical assistance.
The research was funded by the Swiss National Science Foundation (CR23I2_156852).
KAD developed the production and separation process, performed the separation experiments of 47Sc, did the radiolabeling and the stability experiments, analyzed the data and drafted the manuscript. CM was responsible for the performance of the in vitro and in vivo studies and revised the manuscript. MB supported the 47Sc separation process and reviewed the manuscript. SH performed the in vivo studies. UK and BP were responsible for the irradiation of 46Ca targets and 47Ti targets at ILL and SCK.CEN, respectively. AT and RD assisted with the yield and irradiation calculations, while AT also reviewed the manuscript. RS reviewed the manuscript. NvdM was responsible for the development of the production and separation process of 47Sc, supervised the whole study and finalized the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
This article does not contain any studies with human participants performed by any of the authors. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
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