Separation of 44Sc from 44Ti in the Context of A Generator System for Radiopharmaceutical Purposes with the Example of [44Sc]Sc-PSMA-617 and [44Sc]Sc-PSMA-I&T Synthesis.

Today, 44Sc is an attractive radionuclide for molecular imaging with PET. In this work, we evaluated a 44Ti/44Sc radionuclide generator based on TEVA resin as a source of 44Sc. The generator prototype (5 MBq) exhibits high 44Ti retention and stable yield of 44Sc (91 ± 6 %) in 1 mL of eluate (20 bed volumes, eluent-0.1 M oxalic acid/0.2 M HCl) during one year of monitoring (more than 120 elutions). The breakthrough of 44Ti did not exceed 1.5 × 10-5% (average value was 6.5 × 10-6%). Post-processing of the eluate for further use in radiopharmaceutical synthesis was proposed. The post-processing procedure using a combination of Presep® PolyChelate and TK221 resins made it possible to obtain 44Sc-radioconjugates with high labeling yield (≥95%) while using small precursor amounts (5 nmol). The proposed method takes no more than 15 min and provides ≥90% yield relative to the 44Sc activity eluted from the generator. The labeling efficiency was demonstrated on the example of [44Sc]Sc-PSMA-617 and [44Sc]Sc-PSMA-I&T synthesis. Some superiority of PSMA-I&T over PSMA-617 in terms of 44Sc labeling efficiency was demonstrated (likely due to presence of DOTAGA chelator in the precursor structure). It was also shown that microwave heating of the reaction mixture considerably shortened the reaction time and improved radiolabeling yield and reproducibility of [44Sc]Sc-PSMA-617 and [44Sc]Sc-PSMA-I&T synthesis.

Cyclotron Production and Separation of Scandium Radionuclides from Natural Titanium Metal and Titanium Dioxide Targets.

Theranostic strategies involve select radionuclides that allow diagnostic imaging and tailored radionuclide therapy in the same patient. An example of a Food and Drug Administration-approved theranostic pair is the 68Ga- and 177Lu-labeled DOTATATE peptides, which are used to image neuroendocrine tumors, predict treatment response, and treat disease. However, when using radionuclides of 2 different elements, differences in the pharmacokinetic and pharmacodynamic profile of the agent can occur. Theranostic agents that incorporate the matched-pair radionuclides of scandium-43Sc/47Sc or 44Sc/47Sc-would guarantee identical chemistries and pharmacologic profiles. The aim of this study was to investigate production of 43,44,47Sc via proton-induced nuclear reactions on titanium nuclei using a 24-MeV cyclotron. Methods: Aluminum, niobium, and tantalum target holders were used with titanium foils and pressed TiO2 to produce scandium radionuclides with proton energies of up to 24 MeV. Irradiated targets were digested using NH4HF2 and HCl in a closed perfluoroalkoxy alkane vessel in 90 min. Scandium radionuclides were purified via ion-exchange chromatography using branched N,N,N',N'-tetra-2-ethylhexyldiglycolamide. The titanium target material was recovered via alkali precipitation with ammonia solution. Results: Titanium foil and TiO2 were digested with an average efficiency of 98% ± 3% and 95% ± 1%, respectively. The typical digestion time was 45 min for titanium foil and 75 min for TiO2 The average scandium recovery was 94% ± 3%, and the average titanium recoveries from digested titanium foil and TiO2 after precipitation as TiO2 were 108% ± 8% and 104% ± 5% of initial mass, respectively. Conclusion: This work demonstrated a robust method for the cyclotron production of scandium radionuclides that could be used with natural or enriched TiO2 target material.

Biosynthetic new composite material containing CuO nanoparticles produced by Aspergillus terreus for 47Sc separation of cancer theranostics application from irradiated Ca target.

Copper oxide nanoparticles (CuO NPs) are needed in various fields, especially in the biomedical field. CuO NPs was obtained from Aspergillus terreus filtrate. CuO NPs structure was confirmed by UV-Vis spectrophotometry, as well as Fourier transform infrared (FT-IR), X-ray diffraction (XRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). XRD offers the nanoparticles purity of CuO biosynthesis. CuO NPs are spherical when examined with TEM. The average size of CuO NPs from TEM was 15.75 ± 3.95 nm. New composite of P (AA-AN)-NPs CuO was synthesized by biotechnology and the induced γ-radiation. The distribution coefficient value (Kd) of 47Sc(III) as well as 47Ca(II) ions for the synthetic new composite was determined by batch technique. Radiochemical separation of 47Sc(III) from irradiated calcium target was studied using chromatographic column packed with the new composite material. The recovery yield of 78 ± 1.2% for 47Sc(III) was obtained using 1 M HCl. The quality control tests (chemical, radionuclide and radiochemical purities) of the eluted 47Sc confirmed that it's adequate for nuclear medicine applications.

Synthesis of chitosan-acrylic acid/multiwalled carbon nanotubes composite for theranostic 47Sc separation from neutron irradiated titanium target.

A simple and efficient separation method of carrier-free 47Sc from neutron irradiated titanium target using a novel chitosan-acrylic acid/multiwalled carbon nanotubes (CS-AA/MWCNTs) composite was established. The synthesis of the CS-AA/MWCNTs composite was achieved using gamma radiation-induced template polymerization. The grafting efficiency (GE%) of AA on CS onto the surface of f-MWCNTs reached a maximum of~84% under the optimized conditions (30 wt% CS, 1.0 wt% AA, 0.15 wt% f-MWCNTs, >0.2 wt% N,N'-Methylenebisacrylamide (NMBA), and irradiation dose ~25 kGy). Different analyses (FT-IR, SEM, TGA and DTA) were examined for confirming the structural morphology and mechanical properties of the new synthesized composite. Interestingly, the CS-AA/MWCNTs composite depicted a selective adsorption of Sc(III) rather than Ti(IV) ions at pH 5 with adsorption efficiency of ~93.93%. The ionic exchange separation of no-carrier-added (NCA)47Sc(III) from irradiated TiO2 target on CS-AA/MWCNTs composite packed column efficiently eluted 47Sc(III) by 91 ± 0.8% using 1 M HCl solution. The quality control tests (radionuclidic, radiochemical, and chemical purities) for the eluted 47Sc(III) clarified its high purity and validity for cancer theranostics.

Improved procedures of Sc(OH)3 precipitation and UTEVA extraction for 44Sc separation.

BACKGROUND: 44Sc is becoming attractive as a PET radionuclide due to its decay characteristics. It can be produced from 44Ca present in natural calcium with 2.08% abundance. MATERIALS AND METHODS: The targets were mostly prepared from natural CaCO3 or metallic calcium in the form of pellets. After irradiation they were dissolved in 3 M hydrochloric acid and 44Sc was separated from excess of calcium by precipitation of scandium hydroxide using ammonia. Alternatively, targets were dissolved in 11 M hydrochloric acid and 44Sc was separated by extraction chromatography on UTEVA resin. As the next step, in both processes 44Sc was further purified on a cation exchange resin. Initially, the separation procedures were developed with 46Sc as a tracer. Gamma spectrometry with a high purity germanium detector was used to determine the separation efficiency. Finally, the CaCO3 pellet with 99.2% enrichment in 44Ca was activated with protons via 44Ca(p,n)44Sc nuclear reaction. RESULTS: Altogether twenty two irradiations and separations were performed. The working procedures were developed and the quality of separated 44Sc solution was confirmed by radiolabeling of DOTATATE. The chemical purity of the product was sufficient for preclinical experiments. At the end of around 1 hour proton beam irradiation of CaCO3 pellet with 99.2% enrichment in 44Ca the obtained radioactivity of 44Sc was more than 4.8 GBq. CONCLUSION: 44Sc can be produced inexpensively with adequate yields and radionuclidic purity via 44Ca(p,n)44Sc nuclear reaction in small cyclotrons. The recovery yield in both investigated separation methods was comparable and amounted above 90%. The obtained 44Sc was pure in terms of radionuclide and chemical purity, as shown by the results of peptide radiolabeling.

Measurement of the 43Sc production cross-section with a deuteron beam.

43,44Sc/47Sc is one of the most promising theranostic pairs in nuclear medicine. The co-emission of 1157 keV γ-rays with 99.9% branching ratio by 44Sc and the presence of its metastable state 44 mSc push to favour the adoption of 43Sc for Positron Emission Tomography (PET) diagnostic procedures to lighten the dose to the patient and to the personnel. The ß+ emitter 43Sc can be produced at a medical cyclotron by proton bombardment of an enriched 43Ca or 46Ti oxide target. 43Sc can be also produced by deuteron bombardment of an enriched 42Ca oxide target. Only a few medical cyclotrons currently in operation offer deuteron beams. Some can be adapted to operate both a proton or a deuteron source. To compare these three production routes, an accurate knowledge of the cross-sections is essential. In this paper, we report on the cross-section measurement of the reaction 42Ca(d,n)43Sc performed at the 6 MV HVEC EN-Tandem of the Ion Beam Physics group at ETH in Zürich. A study of the production yield by using commercially available enriched target materials is also presented.

Production of Sc medical radioisotopes with proton and deuteron beams.

Proton and deuteron beams (15.3 and 6.8 MeV, respectively) extracted from the PETtrace medical cyclotron at the Radiopharmaceuticals Production and Research Centre in the University of Warsaw, Heavy Ion Laboratory, 28 MeV protons from the C30 cyclotron at the National Centre for Nuclear Research, Swierk, near Warsaw and 33 MeV protons from the ARRONAX accelerator, Nantes were used to produce and investigate the medically interesting Sc radioisotopes. Both natural and isotopically enriched CaCO3 and TiO2 targets were used (42Ca, 43Ca, 44Ca, 48Ca, 48Ti). The production efficiency and isotopic purity were determined and are reported here for the highest commercially available enrichments of the target material. The Thick Target Yield, Activities at the End of Bombardment (EOB) and the relative activities of produced impurities at EOB are reported for 43Sc, 44gSc, 44mSc and 47Sc produced with particle energies below 33 MeV.

Selective recovery of vanadium and scandium by ion exchange with D201 and solvent extraction using P507 from hydrochloric acid leaching solution of red mud.

D201 resin and P507 extractant diluted with sulfonated kerosene were used to respectively separate vanadium and scandium, and impurity ions from hydrochloric acid leaching solution of red mud. More than 99% of vanadium was selectively adsorbed from the hydrochloric acid leaching solution under the conditions of pH value of 1.8, volume ratio of leaching solution to resin of 10, and flow rate of 3.33 mL/min. Maximum extraction and separation of scandium was observed from the acid leaching solution at an aqueous pH value of 0.2. More than 99% of scandium can be selectively extracted using 15% P507, 5% TBP at the aqueous solution/organic phase (A/O) ratio of 10:1 for 6 min. The loaded organic phase was washed with 0.3 mol/L sulfuric acid, wherein most impurities were removed. After the process of desorption or stripping, precipitation, and roasting, high-purity V2O5 and Sc2O3 were obtained. Finally, a conceptual flow sheet was established to separate and recover vanadium and scandium from red mud hydrochloric acid leaching solution.

Production and purification of Scandium-47: A potential radioisotope for cancer theranostics.

In this study, production of 47Sc radionuclide by irradiating the natural titanium dioxide powder (TiO2) in the fast neutron flux (~3*1013ncm-2s-1) for 4 days in Tehran Research Reactor (TRR, Iran) and separation from titanium target was investigated. The study showed the feasibility of production 47Sc by TRR. The separation efficiency and radiochemical purity (ScCl3) of radio-scandium, 47Sc radionuclide purity were obtained 98%, 99% and 88% respectively.

[Leaching of Rare Earth Elements from Coal Ashes Using Acidophilic Chemolithotrophic Microbial Communities].

A method for leaching rare earth elements from coal ash in the presence of elemental sulfur using communities of acidophilic chemolithotrophic microorganisms was proposed. The optimal parameters determined for rare element leaching in reactors were as follows: temperature, 45 degrees C; initial pH, 2.0; pulp density, 10%; and the coal ash to elemental sulfur ratio, 10 : 1. After ten days of leaching, 52.0, 52.6, and 59.5% of scandium, yttrium, and lanthanum, respectively, were recovered.

Scandium-44: benefits of a long-lived PET radionuclide available from the (44)Ti/(44)Sc generator system.

(44)Ti/(44)Sc radionuclide generators are of interest for molecular imaging. The 3.97 hours half-life of (44)Sc and its high positron branching of 94.27% may stimulate the application of (44)Sc-labeled PET radiopharmaceuticals. This review describes the current status of (44)Ti production, (44)Ti/(44)Sc radionuclide generator development, post-processing of generator eluates towards medical application, identification of ligands adequate to Sc(III) co-ordination chemistry, proof-of-principle labeling of (44)Sc-DOTA-octreotides, investigation of in vitro and in vivo parameters, and initial applications for molecular imaging - both in small animals and humans.

Radiolabeling of DOTATOC with the long-lived positron emitter 44Sc.

The positron-emitting radionuclide (44)Sc with a half-life of 3.97 h and a ß(+) branching of 94.3% is of potential interest for clinical PET. As so far it is available from a (44)Ti/(44)Sc generator in Mainz, where long-lived (44)Ti decays to no-carrier-added (nca) (44)Sc. The (44)Sc is a trivalent metal cation and should be suitable for complexation with many well established bifunctional chelators conjugated to peptides or other molecular targeting vectors. Thus, the aim of this work was to investigate the potential of (44)Sc for labeling of DOTA-conjugated peptides. DOTA-D-Phe(1)-Tyr(3)-octreotide (DOTATOC) was used as a model molecule to study and optimize labeling procedure. Reaction parameters such as buffer conditions, concentration of peptide, pH range, reaction temperature and time were optimized. Addition of 21 nmol of DOTATOC to (44)Sc in ammonium acetate buffer pH 4.0 provided labeling yields >98% within 25 min of heating in an oil-bath at 95°C. This time can be reduced to 3 min only by applying microwave supported heating. (44)Sc-DOTATOC was found to be stable in 0.9% NaCl, PBS pH 7.4, fetal calf and human serums, and also in the presence of competing metal cations (Fe(3+), Ca(2+), Cu(2+), Mg(2+)), as well as other ligand competitors, like EDTA and DTPA, even after almost 25 h incubation at 37°C. Present study shows that nca (44)Sc forms stable complexes with the macrocyclic ligand DOTA and that (44)Sc-DOTATOC and analog targeting vectors may be synthesized for further preclinical and clinical investigations.

Synthesis, isolation, and addition patterns of trifluoromethylated D5h and I(h) isomers of Sc3N@C80: Sc3N@D5h-C80(CF3)18 and Sc3N@I(h)-C80(CF3)14.

Sc(3)N@D(5h)-C(80) and Sc(3)N@I(h)-C(80) were trifluoromethylated with CF(3)I at 400 °C, affording mixtures of CF(3) derivatives. After separation with HPLC, the first multi-CF(3) derivative of Sc(3)N@D(5h)-C(80), Sc(3)N@D(5h)-C(80)(CF(3))(18), and three new isomers of Sc(3)N@I(h)-C(80)(CF(3))(14) were investigated by X-ray crystallography. The Sc(3)N@D(5h)-C(80)(CF(3))(18) molecule is characterized by a large number of double C-C bonds and benzenoid rings within the D(5h)-C(80) cage and a fully different position of the Sc(3)N unit compared to that in the pristine Sc(3)N@D(5h)-C(80). A detailed comparison of five Sc(3)N@I(h)-C(80)(CF(3))(14) isomers reveals a strong influence of the exohedral additions on the behavior of the Sc(3)N cluster inside the I(h)-C(80) cage.

Post-elution processing of (44)Ti/(44)Sc generator-derived (44)Sc for clinical application.

The (44)Ti/(44)Sc (T(1/2)(44)Ti=60a) generator provides cyclotron-independent access to positron-emitting (44)Sc (T(1/2)=3.97d) for PET imaging. This work aims to post-elution processing of initial (44)Sc generator eluates in order to reduce its volume, HCl concentration and remove the oxalate anions. The on-line adsorption of (44)Sc on cationic resin AG 50W-X8 (200-400 mesh, H(+)-form) is achieved with >98% efficacy. Subsequently, the purified (44)Sc is desorbed by using 3ml of 0.25M ammonium acetate (pH=4.0). The post-processing takes 10min. The overall yield of the post-processing reached 90%, which is referred to the (44)Sc obtained from the (44)Ti/(44)Sc generator. In addition to the chemical purification, the content of (44)Ti breakthrough was further reduced by one order of magnitude. The 185MBq generator finally provides 150MBq of (44)Sc containing <10Bq of (44)Ti ready for labeling.

Speciation of scandium and gallium in soil.

A method for the speciation of scandium and gallium in soil has been developed. The sequential extraction scheme of Tessier et al. for heavy metals was examined for the scandium and gallium separation. The regents proposed by Tessier were used for the extraction, and only for the residual fraction the HClO4 was replaced with H2SO4. The optimum conditions for leaching scandium and gallium from the soil were chosen for each fraction. Very sensitive, spectrophotometric methods based on the mixed complexes of Sc(III) and Ga(III) with Chrome Azurol S and benzyldodecyldimethylammonium bromide were applied for the scandium and gallium determination after their separation by solvent extraction. 100% mesityl oxide and a 0.5M solution of 2-thenoyltrifluoroacetone in xylene were chosen for the extraction of scandium and butyl acetate was selected for gallium. Soil samples from two different regions of Poland were the object of this research. The content of scandium and gallium found in the individual fractions of Upper Silesia soil (industrial region) was [in microgg(-1)] Sc: I, 1.52; II, 0.53; III, 7.78; IV, 1.79; V, 0.20; Ga: I, 24.7; III, 29.2; IV, 35.4; V, 6.9. In Podlasie soil (agricultural region), the content of both elements was clearly lower. The total content of scandium and gallium in the five soil fractions was in good correlation with the total content of these elements in the soils found after HF-H2SO4 digestion. Analysis using the ICP-OES method gave comparable results.

Preparation and structure of CeSc2N@C80: an icosahedral carbon cage enclosing an acentric CeSc2N unit with buried f electron spin.

Herein, we report the preparation, purification, and characterization of a mixed trimetallic nitride endohedral metallofullerene, CeSc(2)N@C(80). Single-crystal X-ray diffraction shows that CeSc(2)N@C(80) consists of a four-atom asymmetric top (CeSc(2)N) inside a C(80) (I(h)()) carbon cage. Unlike the situation in most endohedrals of the M(3)N@C(2)(n)() type, the nitride ion is not located at the center of the carbon cage but is offset by 0.36 A in order to accommodate the large Ce(III) ion. The cage carbon atoms near the endohedral Ce and Sc atoms exhibit significantly larger pyramidal angles than the other carbon atoms on the C(80) cage. Surprisingly, at ambient temperature, the (13)C NMR spectrum exhibits isotropic motional averaging yielding only two signals (3 to 1 intensity ratio) for the icosahedral C(80) cage carbons. At the same temperature, the (45)Sc NMR exhibits a relatively narrow, symmetric signal (2700 Hz) with a small temperature-dependent Curie shift. A rotation energy barrier (E(a) = 79 meV) was derived from the (45)Sc NMR line-width analysis. Finally, the XPS spectrum for CeSc(2)N@C(80) confirms a +3 oxidation state for cerium, Ce(3+)(4f(1)5d(0)). This oxidation state and the Curie shift are consistent with a weakly paramagnetic system with a single buried f electron spin.

Radiochemical purification of no-carrier-added scandium-47 for radioimmunotherapy.

A procedure, adaptable to large-scale remote operation, was developed to purify no-carrier-added (NCA) 47Sc from irradiated Ti targets. Methods based on extraction chromatography and cation-exchange chromatography were compared. Results of this comparison led to the development of an optimized procedure based on cation-exchange with Dowex AG 50W-X4 and 47Sc elution with HCl/HF. This method gave 90-97% overall 47Sc recovery, with a Ti separation factor greater than 2.4 x 10(-5), and specific activities > or = 0.9 GBq microgram-1. Use of the 47Sc product, for labeling monoclonal antibodies, resulted in consistent labeling yields of > or = 90%.