How to generate scandium-44

Abstract

The present invention provides a method for producing a target solution 44 A method for generating Sc, comprising: (a) precipitation of a target solution containing metal species with fluoride ions, said target solution comprising at least 44 Sc, 44 Ti, and 46 Contains Sc and other metal impurities, 46 A solution containing a precipitate consisting essentially of Sc is obtained, precipitation, (b) filtering the resulting solution and 44 Sc and 44 Recovery of filtrate containing Ti, a solid-liquid extraction step comprising: (c) loading the filtrate from the previous step onto a preconditioned hydroxamate column; (d) Elution of the hydrochloric acid solution through a preconditioned hydroxamate column; a solid phase extraction chromatography step comprising: From the eluate from the previous step 44 a step of recovering Sc; The present invention relates to a method comprising:

Description

Technical Field

[0001] The present invention relates to 44 a method for generating Sc having a high radionuclide purity from Ti. 44 It relates to a method for generating Sc.

Background Art

[0002] Scandium has two radionuclides that emit β + rays ([Sc or 44 Sc), which, due to their half-life of about 4 hours and decay to non-toxic Ca, are suitable candidates for PET / CT diagnostics. For both radionuclides, the half-life is compatible with the pharmacokinetics of a wide range of targeting vectors (such as peptides, antibody fragments, and oligonucleotides). In 201, 43 the Sc radionuclide was proposed by Rosch as a potential alternative to Ga in clinical PET diagnostics (Pruszyski M, Loktionova N, Filosofov D, Roesch F. Post-elution processing of 44 Ti / 68 Sc generator derived 44 Ti / 44 Sc for clinical application. Appl Radiat Isot; 68:1636 (2010) and Rosch F. Scandium-44: benefits of a long-lived PET radionuclide available from the 44 Ti / 44 Ti / 44 Sc generator system. Curr Radiopharm; 5:187 (2012)). Many different extraction and separation methods have been described in the literature. From the initial Rosch papers to the most recent ones, scandium chemistry has been 44 Ti / 44 from a Ti / Sc generator, from neutron-irradiated Ti, cyclotron-produced 44m Sc / 44 Sc, nat Sc,46 Sc, or 47 This highlights the growing interest in scandium in Sc, accompanied by an increasing number of available documents.

[0003] With an ideal average positron energy of 0.6 MeV for a PET camera, 44 Sc has a half-life that would reach hospitals located very far from the production sites of radiopharmaceuticals. 44 This makes it very attractive for clinical PET applications as it enables the transport of Sc-labeled radiopharmaceuticals. However, 89 The simultaneous emission of high-energy gamma rays similar to those emitted by Zr must be considered. If not controlled, this could increase radiation doses to patients and staff. 44 Many different methods have been explored for generating Sc, but most involve using a cyclotron or generator.

[0004] 44 One of the Sc sources is a long-lived parent nuclide. 44 Ti(T 1 / 2 It goes through 60 years, so 44 Ti / 44Radchenko V., Engle JW, Medvedev D., Maasen JM Naranjo CM, Unc GA, Meyer CAL, Mastren T., Brugh M., Mausner L., Cutler CS, Birnbaum ER, John KD, Nortier M, Fassenberg ME Nucl.Med. Biol. 50, 25 (2017)). Titanium-44 is 45 Sc(p,2n) 44 Proton irradiation via Ti reaction (Lange R., D'Auria J., Giesen U., Vincent J., Ruth T. Preparation of a radioactive 44 Ti target. Nucl Instrum Methods Phys Res A, 423, 247 (1999)) or nat Fe or nat It is generated by fragmentation on Cu. This, in contrast to other production pathways, is not routinely radiochemically pure. 44 Obtain Sc (that is, 44m It is believed to possess the capability (Sc does not obtain). The dedicated production process requires a large beam current and a long irradiation time in order to produce sufficient effect. 23For example, it has been shown that 150 MBq can be produced by irradiation at 220 μA for 9 days, which allows for elution up to 60 MBq every 4 hours (i.e., the effect required for one imaging dose). This leads to high manufacturing costs and the need for constant and efficient use of generators over long periods. Even though some progress has been made in this field in recent years, the process from scandium target materials remains challenging. 44 Ti isolation is not very impressive. Finally, the generator system is 44 High Sc elution yield, parent nucleus 44 The Ti breakthrough suggests the development of minimally efficient separation. In addition, long lifetime 44 Ti(T 1 / 2 (1960) is thought to make the management of these generators in nuclear medical services difficult, and centralized pharmacies may be better suited to managing such generators.

[0005] Several separation methods were tested using DGA® resin or ZR® resin. Radchenko et al. separated residual scandium from the target material. 44 The potential use of DGA resin for trace separation of Ti / Sc in the context of sophisticated Ti purification was highlighted (Lange R., D'Auria J., Giesen U., Vincent J., Ruth T. Preparation of a radioactive 44Ti target. Ncl Instrum Methods Phys Res A, 423, 247 (1999)). On the other hand, ZR® resin showed high sorption affinity for titanium, while scandium could be eluted in HCl solution. Nevertheless, this generator had several drawbacks, and after several stationary bed elutions... 44Some breakthroughs have been observed with Ti. This is particularly important in generators where such long lifespans are expected. Filosofov et al. (Mausner L, Kolsky K, Joshi V, Srivastava S. Radionuclide development at BNL for nuclear medicine therapy. App Rad Isot; 49:285 (1998)) proposed circumventing this problem by passing the eluate through the column and allowing it to backflow. By using ZR® resin, Radchenko et al. demonstrated fewer breakthroughs, leading these authors to envision long-term use of this generator. Nevertheless, the more load these columns place on the material, the more likely it is that the elution or sorption performance of the extractant molecules will deteriorate over time. These effects can limit the lifespan of the generator and therefore must be carefully tested. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Pruszyski M, Loktionova N, Filosofov D, Roesch F. Post-elution processing of 44Ti / 44Sc generator derived 44Sc for clinical application. Appl Radiat Isot; 68:1636 (2010) [Non-Patent Document 2] Rosch F. Scandium-44: benefits of a long-lived PET radionuclide available from the 44Ti / 44Sc generator system. Curr Radiopharm; 5:187 (2012) [Non-Patent Document 3] Rotsch DA、Brown MA、Nolen JA、Brossard T.、Henning WH、Chemerisov SD、Gromov RG、Greene J. Electron linear accelerator production and purification of scandium-47 from titanium dioxide targets、Applied Radiation and Isotopes 131、77 (2018)

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[0007] Therefore, the object of the present invention is 44 The elution yield of Sc is high, and the parent nucleus 44 Ti breakthroughs are minimal and efficient 44 Ti / 44 The objective is to provide an Sc generator system.

[0008] The object of the present invention is also to provide efficient methods that result in high chemical and radionuclide purity. 44 Ti / 44 It also involves providing an Sc generator system.

[0009] Another objective of the present invention is to provide a generator that produces short-lived radioisotopes that can be used locally and sustainably, enabling PET imaging, having a long lifetime with ease of use and reliability, meeting high specifications for contaminants, and avoiding all breakthroughs. [Means for solving the problem]

[0010] Therefore, the present invention relates to the target solution 44 A method for generating Sc, (a) A precipitate of a target solution containing a metal species having fluoride ions, wherein the target solution is at least 44 Sc, 44 Ti, and 46 It contains Sc and other metal impurities, the amount of Sc being 10,000 to 15,000 ppm relative to the total mass of the target solution, the amount of Ti being 5 to 10 ppm relative to the total mass of the target solution, and the amount of each metal impurity being 200 to 300 ppm relative to the total volume of the target solution, thereby 46 A solution containing a precipitate essentially consisting of Sc is obtained, precipitate, (b) Filtration of the resulting solution, and the resulting, essentially 44 Sc and 44 Recovery of filtrate containing Ti, A solid-liquid extraction process including, (c) Adding the filtrate obtained in the previous step onto a pre-conditioned hydroxamate column, wherein the pre-conditioned hydroxamate column is obtained from treatment of the hydroxamate column with a strong acid and washing with water, (d) Elution of hydrochloric acid solution passed through a pre-conditioned hydroxamate column, thereby 44 Ti is adsorbed onto the column, elution, The solid-phase extraction chromatography process includes, From the eluted material in the previous process 44 The process of recovering Sc, Regarding methods including [Brief explanation of the drawing]

[0011] [Figure 1] The elution profiles of Ti-44 and Sc-44 from ZR resin are shown. [Modes for carrying out the invention]

[0012] Therefore, the method according to the present invention for generating scandium-44 is based on a combination of solid-liquid extraction and solid-phase extraction chromatography.

[0013] The starting product is a target solution containing metallic species, particularly scandium and titanium, as well as metallic impurities. This solution may also contain other radionuclides.

[0014] In particular, this target solution may contain Fe, Si, Mo, Pb, Al, Zn, and Ca.

[0015] According to one embodiment, the target solution is prepared in advance from a scandium disk. After irradiation, the irradiated disk is cooled and then dissolved in a hydrochloric acid solution.

[0016] According to one embodiment, the target solution is prepared from a scandium disk that has been pre-irradiated with an average current of over 130 μA for about 10 days to impart energy of 25 to 26 MeV to the Sc disk.

[0017] The method according to the present invention involves precipitation of a target solution containing fluoride ions.

[0018] Therefore, the precipitation process makes it possible to separate various metal species from the solution according to their solubility.

[0019] According to a preferred embodiment, the precipitation step (a) is carried out with an acid having a pH of less than 6.

[0020] This acidic pH is advantageous in that it avoids the formation of hydroxo species of scandium and any other metal impurities present in the batch obtained from the dissolution of the target.

[0021] In a preferred embodiment, with respect to the precipitation step (a), the ratio of the concentration of all metal species to the concentration of fluoride ions is 1:5 to 1:20, preferably 1:15 to 1:20.

[0022] More preferably, the ratio of the total metal concentration to the fluoride ion concentration is 1:17.

[0023] The ratio described above is preferable for optimal precipitation. In particular, if this ratio is too low, no precipitate will be obtained, and if this ratio is too high, too much solid material will be obtained.

[0024] According to a preferred embodiment, the precipitation step (a) is carried out at room temperature for at least 24 hours.

[0025] According to a preferred embodiment, the precipitation step (a) is carried out using a NaF solution.

[0026] After this precipitation process, essentially 46 A solution containing a precipitate composed of Sc is obtained.

[0027] As explained above, the precipitation process is followed by a filtration process. This filtration process is particularly useful for recovering the filtrate, while the aforementioned precipitate is discarded.

[0028] The initial solution is yellowish and acidic, while the resulting solution is a white, gel-like solution.

[0029] The recovered filtrate is essentially 44 Sc and 44 Contains Ti.

[0030] Following the solid-liquid extraction process, there is a solid-phase extraction chromatography process.

[0031] These steps include conditioning the hydroxamate column. This conditioning step is essential for the efficiency of the method according to the present invention.

[0032] This optimizes the functional groups on the resin surface to promote ion exchange, thereby enabling maximum ion exchange capacity. The resin is preferably conditioned in the first working medium to equilibrium with the solution. This, in turn, avoids unwanted reactions (such as changes in acidity or chlorine concentration).

[0033] According to the present invention, a column having a hydroxymate group is prepared.

[0034] According to the present invention, for conditioning, the hydroxylate column is treated with a strong acid such as hydrochloric acid and then rinsed with water.

[0035] According to the present invention, a strong acid has a pK of less than about -2. a The strong acid is an acid having a specific value. Preferably, the strong acid is selected from the group consisting of nitric acid, sulfuric acid, hydrochloric acid, and mixtures thereof, and is preferably hydrochloric acid.

[0036] According to a preferred embodiment, the mass of the pre-conditioned hydroxamate column is between 200 mg and 2 g.

[0037] According to a preferred embodiment, a pre-conditioned hydroxamate column is obtained by eluting the hydroxamate column with a hydrochloric acid solution of 1 M to 10 M concentration, rinsing with water, preferably pure water, and further eluting with a hydrochloric acid solution of 0.1 M to 3 M concentration in a volume V1 of 20 mL to 100 mL.

[0038] According to a preferred embodiment, a pre-conditioned hydroxamate column is obtained by eluting the hydroxamate column with 2 M HCl and rinsing with pure water. Then, preferably, 20 mL of 0.1 mol. L of HCl is added. -1 This process involves elution to remove all potential metal impurities.

[0039] According to the present invention, pure water is water that has been mechanically filtered or treated to remove impurities and make it suitable for use. Distilled water may be cited as a form of pure water, but water purified by other processes including capacitive deionization, reverse osmosis, carbon filtering, microfiltration, ultrafiltration, ultraviolet oxidation, or electrodeionization may also be cited.

[0040] Following the preparation of a pre-conditioned hydroxamate column, the filtrate (essentially) 44 Sc and 44 By placing a substance (containing Ti) onto the column and eluting it by passing a hydrochloric acid solution through the column, 44 Ti is adsorbed onto the column.

[0041] At the end of this elution, 44 Retrieve Sc.

[0042] According to a preferred embodiment, the elution step (d) is carried out using a hydrochloric acid solution with a volume V2 of 2 mL to 25 mL and a concentration of 1 M to 5 M.

[0043] More preferably, the hydrochloric acid solution for the elution step (d) has a concentration of 2 M.

[0044] More preferably, the volume V2 for the elution step (d) is 3 mL to 15 mL.

[0045] The resulting solution is radionuclideally and chemically pure for further radiolabeling, thus leading to high molar activity and high specific activity. These criteria are essential for the further use of the solution as a radiopharmaceutical generator.

[0046] This invention relates to solid-liquid separation after precipitation with fluoride ions, from a larger scandium mass. 44 Regarding methods for separating Ti, compared to Radchenko et al. mentioned above, 44 The sorption / retention of Ti does not need to be considered because, in this case, the separation is based on the difference in the solubility product between Ti and Sc, which contains fluoride ions.

[0047] This method is based on the direct addition of Ti after solid-liquid separation. 44 The purity of Sc was monitored using the ICP-OES method described later. 44 Ti / 44 The feasibility of the Sc generator was evaluated by conducting radiolabeling studies. For this purpose, DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) was used as a chelating agent, and a thermodynamically very stable complex was formed fairly rapidly and kinetically inert (Huclier-Markai S., Alliot C., Sebti J., Brunel B., Aupiais J. A comparative thermodynamic study of the formation of Scandium Complexes with DTPA and DOTA, RSC Adv 5, 99606 (2015)). In addition, it was shown that radioactive scandium from each source generally differs in the molar activity and / or cold metal ion impurity content obtained. 44m / 44 The molar activity of Sc was consistently above 20 MBq / nmol (4 hours after luminescence). However, the generator 44 Ti / 44In Sc, the molar activity was estimated to be a maximum of approximately 0.2 MBq / nmol (for DOTA; 4 hours after elution) (Pniok M., Kubicek V., Havlickova J., Koatek J., Sabatie A., Plutnar J., Huclier-Markai S., Hermann P. Thermodynamic and kinetic study of scandium(III) complexes of DTPA and DOTA: A step toward scandium radiopharmaceuticals. Chem. Eur. J. 20, 2 (2014)). Therefore, the method of the present invention achieved a higher molar activity on DOTA (i.e., 2 MBq / nmol). [Examples]

[0048] Materials and methods Chemical reagents Nitric acid and hydrochloric acid were received as ultra-high purity solutions (SCP Science). Citric acid was purchased from Sigma Aldrich (Saint-Louis, USA). All diluents were prepared in ultrapure water (Millipore, 18.2 MΩ.cm). NaF was purchased from Baker Chemical Co. (99.7% purity, Phillipsburg, NJ, USA) and diluted in 6 M HCl. Polypropylene (PP) Whatman syringe filters (0.2 μm cutoff) were connected to the corresponding 1 mL syringes and used as is.

[0049] First, the ZR® resin (hydroxamate group) supplied by Trischem (France) was eluted with 2M HCl and rinsed with pure water. Then, it was dissolved in 20 mL of 0.1 mol.L HCl. -1The resin was eluted to remove all potential metal impurities. The resin was loaded onto a 5 mL Pierce Centrifuge column manufactured by ThermoFisher (USA). Commercially available 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA, Macrocyclics Inc.) was used as is.

[0050] Target design, irradiation, and dissolution A scandium sputtering target disk (d×h=2.375×0.196 inches, i.e., 6.0325 cm×4.9784 mm, m=43.3 g) was purchased from American Elements, Inc. (Los Angeles, CA, USA). For irradiation, the disk was isolated in an Inconel can with a 0.012-inch (0.3048 mm) window, laser-welded under a helium atmosphere. The target was irradiated at the BLIP facility at Brookhaven National Laboratory for 10.4 days at an average current of 131.5 μA. The energy on the Sc disk was calculated to be 25–26 MeV.

[0051] After irradiation, the target was allowed to cool for at least 40 days and then transferred to a hot cell for chemical treatment. The target was opened by cutting out a window, and the scandium disc was removed from the can. The Sc disc was dissolved in an 800 mL glass beaker by adding 50 mL fractions of HCl of various concentrations (4 N, 6 N, 12 N), starting with 4 N HCl. The total amount of acid added was 3.24 moles, resulting in a total volume of the resulting solution close to 400 mL. The solution was left undisturbed overnight. The following day, a small amount of fluffy residue was observed at the bottom of the beaker.

[0052] The Sc target solution was decanted into a plastic bottle. The remaining residual suspension was passed through an empty Biorad column, washed with 1N HCl, and collected. All the washing fraction was added to the Sc target solution and transferred to a glass beaker. The volume of the solution was reduced to 250-300 mL by evaporation. A total of 100 mL of 2N HCl was added to the solution to return the volume to 400 mL.

[0053] The solution was divided into two parts (200 mL and 190 mL) using a graduated plastic bottle. The solution was weighed. Aliquots were taken for gamma-ray spectrometry analysis. The two parts were processed separately.

[0054] 200 mL of material passed through a 5 mL (1.424 g) fixed-bed volume of ZR® resin (Triskem, France) pre-treated with several column volumes of 2N HCl. The input material was collected in 30-40 mL fractions. The column was washed with 30 mL of 2N HCl. The column was eluted with a 2.5 H2O2-2N HCl solution to obtain three fractions of 40 mL, 45 mL, and 20 mL. All fractions that were input, eluted, and washed were analyzed using gamma-ray spectroscopy by taking precise aliquots of the fractions.

[0055] 190.4 mL was processed similarly, except that a 7 mL fixed-layer column was used and the elution fraction size was adjusted based on the results of processing the first 200 mL fraction.

[0056] The eluates from both processes were combined and evaporated until dry. The residue was resuspended in 6N HCl to a total volume of 56.7 mL. The total activity was approximately 873 μCi. Three aliquots were taken from this solution. The first aliquot (100 μL) was taken for initial ICP-OES analysis and gamma-ray spectrometry analysis. The other two aliquots (1 mL each, corresponding to 15.4 μCi) were taken to evaluate direct addition to the ZR® resin after precipitation.

[0057] Gamma-ray spectrometry Gamma-ray spectrometry was performed using an ORTEC (Oak Ridge, TN, USA) HPGe detector GEM 13180-P10 with a relative efficiency of 10% at 1333 keV. Detector response function determination was attributed to NIST and supplied by Eckert and Ziegler (Atlanta, GA, USA). 241 Am,109 CD, 57 Co, 139 Ce, 203 Hg, 113 Sn, 137 Cs, 88 Y and 60 The procedure was performed using standards of radionuclides containing a mixture of Co.

[0058] Titanium-44 was measured using its gamma rays at 68 keV and 78 keV, while scandium-44 was analyzed using its gamma rays at 1157 keV. Both elements were monitored through these gamma rays throughout the entire separation process.

[0059] ICP-OES Stable contaminants were determined by inductively coupled plasma atomic emission spectroscopy (ICP-AES) using a Perkin Elmer instrument. Single-element and multi-element standards (approximately 10 ppm, SCP Science) were used for ICP-AES calibration. The analysis was repeated three times based on a 50-second sample exposure time. Data were analyzed using WinSpec software. The following elements were monitored: Al, As, Ca, Co, Cr, Cu, Cd, Fe, Mg, Mn, Mo, Na, Ni, Pb, Sb, Sc, Si, Sn, Ta, Ti, V, and Zn.

[0060] Sedimentation and solid-liquid separation To discard macro amounts of scandium present in the target solution batch derived from trace amounts of titanium-44, a 4.7 M NaF solution was added to the target solution batch. The initial batch dilution factor was 1 / 3, which was sufficient to induce the scandium precipitation reaction. 44 Ti / 44 It was shown that the volume of the Sc generator should not be too large in order to further facilitate its introduction onto the resin column. Under these conditions, the opportunity for TiF4 precipitate formation is extremely low, because the TiF4 precipitate can only form under thorough conditions (T°>400°C + high pressure under HF gas).

[0061] [Number]

[0062] At equilibrium at 20 °C, K s = [Sc 3+ eq [F - eq = 5.81×10 -24 Equation 2 At any time t of the reaction under given experimental conditions, Q sp = [Sc 3+ t × [F - t 3 Equation 3 To cause precipitation, Q sp > K sp (from Equations 2 and 3).

[0063] The solution was allowed to reach equilibrium for 24 hours and then solid-liquid separation was carried out by filtering the resulting suspension through a centrisart filter. The filtrate was then used for dynamic separation on a resin column. The filter was rinsed with concentrated HCl and then this wash solution was analyzed by gamma spectrometry. A 1 mL aliquot of this wash solution was taken and placed in 10 mL of HNO3 (2% w / v) for ICP-OES analysis

[0064] Dynamic column separation This method has been carefully investigated for the direct loading of Ti solutions onto ZR (registered trademark) resin after solid-liquid separation.

[0065] This method was tested and optimized with a low activity batch (about 3 μCi). After each step, the fractions were analyzed by gamma spectrometry to evaluate the activity and radionuclide purity. A 100 μL aliquot of each fraction was taken and analyzed by ICP-OES to determine the chemical purity of the eluted fractions.

[0066] One-step procedure: ​​​​220 mg of ZR(registered trademark) resin was weighed and conditioned as described above. The filtrate from the precipitate was added to a ZR column in 6 M HCl. Elution was performed with 10 mL of 2 M HCl. The fractions were collected in mL units and analyzed by gamma-ray spectrometry to evaluate the purity of the active radionuclides. 100 μL aliquots of each fraction were taken and analyzed by ICP-OES to determine the chemical purity of the eluted fraction.

[0067] Application of the protocol to a 10μCi generator A 9.7 μCi aliquot of the initial solution was evaporated until dry and then redissolved in 1 mL of 2 M HCl. The resulting solution was then directly placed onto a ZR® column corresponding to the 1.6 g of pre-conditioned ZR® resin described above. Elution was performed with 10 mL of 2 M HCl. The fractions were collected in mL units and analyzed by gamma-ray spectrometry to evaluate the purity of the active radionuclides. 100 μL aliquots of each fraction were analyzed by ICP-OES to determine the chemical purity of the eluted fractions.

[0068] Radiolabeling research Add 50 μL (i.e., 2 nmol) of DOTA solution (i.e., 10 nmol, Macrocyclics Inc.) to 450 μL of DOTA solution. 44 Sc was added and mixed in a 2 mL screw-cap Wheaton V-bottom vial. The solution was placed in a 90°C boiling water bath for 20 minutes and then cooled to room temperature. To test the radiolabeling yield, 2 μL was dropped onto a TLC Flex Plate (silica gel 60A, F-254, 200 μm, Selectro Scientific) and 0.04 mol.L was measured. -1 Radio-TLC was performed by elution with an aqueous NH4OAc / methanol 50 / 50 (v / v) developing solution. The activity distribution on the plate was evaluated by counting for 20 minutes on a BIOSCAN AR 2000 (BIOSCAN).

[0069] Results and Discussion Sedimentation and solid-liquid separation In recent years, as has been emphasized by Radchenko et al., from irradiated scandium 44 The radiochemical separation of Ti is 44 Because Ti has a long half-life (T 1 / 2 =60.0a), does not require rapid chemistry. On the other hand, any efficient separation strategy is useful 44 Ti loss should be reduced. Based on these two principles, a method based on cation exchange resins was developed. However, it was concluded that both branched DGA (BDGA) and ZR (hydroxamate) resins could be expected to provide efficient and rapid Ti / Sc separation. BDGA strongly adsorbs scandium, and is therefore preferred under conditions where a large amount of scandium is not present. 44 It should be used for the precise purification of Ti. On the other hand, ZR hydroxamates are used from bulk scandium substrates without carrier addition. 44 It has proven to be very suitable for Ti recovery. However, after 40 column-stationary-bed volume elutions by direct elution, this generator concept yields approximately 20 Bq to approximately 80 Bq. 44 This indicates an increase in the Ti breakthrough level (a fourfold increase). 21 . Optimal 44 The arrangement of the Ti input action may tend to result in even lower breakthrough levels. The long-term performance of this prototype system remains unaddressed.

[0070] According to the present invention, a different sequence was used, similar to that of Radchenko et al., based on precipitation first, then solid-liquid extraction, and finally cation exchange.

[0071] Prior to any further processing, it was necessary to identify and quantify the metallic impurities present in the initial batch derived from the target dissolve. ICP-OES analysis revealed a Sc concentration of approximately 13345 ppm and a Ti concentration of approximately 7 ppm. Other metallic impurities present in the batch, along with their corresponding concentrations, are listed in Table 1.

[0072] [Table 1]

[0073] In addition, gamma-ray spectrometry analysis was performed to determine the activation products, i.e. 46 Sc, 88 Y, or 88 It was shown that V was present during the initial batch. 46 Except for Sc, 88 Y and 88 The effect measured at V was, 44 It was very low compared to the overall effect of Ti. 51 Cr, 54 Mn and 57 Co was detected, but below the limit of quantification. Based on these results, and because the chemical and radionuclide purity did not meet the requirements, further improvements to the purification process were necessary. The main goal was to reduce the macroscopic amount of Co. 46 When it leaves Sc, low concentrations 44 The goal was to recover Ti. According to the literature (Gile, JD, Garrison, WM, and Hamilton JG, Carrier-free Radioisotopes from Cyclotron Targets XIII. Preparation and Isolation of Sc 44, 46, 47, 48 from titanium. The Journal of Chemical Physics 18, 1685 (1950) and Walter RI, Preparation of carrier-free scandium and vanadium activities from titanium cyclotron targets. J. Inorg. Nucl. Chem. 6, 63-66 (1958)), the formed Sc radiocolloids were filtered from titanium to remove carrier-free components. 46Sc was separated in high yield. In these papers, Sc colloids were formed by adding ammonia to a solution of titanium peroxide complex. More recently, Bokhari et al. (Bokhari TH, Mushtaq A., Khan IU, Separation of no-carrier-added radioactive scandium from neutron irradiated titanium. J. Radioanal. Nucl. Chem, 283, 389~393 (2010)) prepared radioactive scandium by irradiating titanium targets, dissolving these targets in HF, and then separating radioactive scandium from titanium fluoride on silica gel. In a very recent assessment by Pyrzynska et al., scandium can be exfoliated by high concentrations of strong mineral acids, basic solutions, or fluoride salts by forming ScF3 precipitates. Based on all this data, the separation / purification process according to the present invention is based on differences in the solubility of the product. This step was not implemented in the procedure described by Radchenko et al. in recent years. The precipitation reaction was carried out on the initial batch by adding NaF solution. According to the Handbook of Chemistry, the solubility of NaF is approximately 0.962 M at 20°C, but a supersaturated solution may be prepared. Therefore, a 4.7 M NaF solution was prepared. The desired volume of this solution was then added. 44 Ti / 44 It was added to the initial batch of Sc. The total volume added corresponded to up to half of the initial batch volume in order to limit the dilution to 1 / 3. In addition to this, HF / F - Since the pKa value is 3.2 and the initial batch is within the acidic pH range (<2), F -It is assumed that only the species exists in the solution. In the case of the Ti species, especially when considering the TiF4 precipitate, thorough conditions are required for its formation (i.e., T°>400°C under high pressure in a flow of HF gas). The opportunity to form this complex under selected experimental conditions (i.e., room temperature and atmospheric pressure) is very low because these thorough conditions cannot be achieved under the experimental conditions of this work. Under these conditions, Ti and Sc are always distinguishable. Preliminary experiments have shown that the optimal conditions for the precipitation reaction are F relative to the metal. - It was shown that this was achieved under a ratio >10:1 (the best conditions obtained with a 12:1 ratio) and acidic conditions (pH < 2). While NH4OH may be added to produce a larger amount of precipitate, it should be noted that this is likely to correspond mostly to the TiO2 type rather than Ti(III). The solution was allowed to stand at room temperature for 24 hours to reach equilibrium. This time was shown to be sufficient to reach equilibrium. As a result, the equilibrium solution was filtered through a 0.2 μm PP Whatman filter. A 100 μL aliquot of the filtrate was diluted to 1 mL with 1% HNO3 and analyzed by gamma-ray spectrometry. 44 Ti and 44 It was shown that only Sc was present in the solution (due to decay). The filter itself was also analyzed by gamma-ray spectrometry, even though its shape had not been calibrated on the gamma-ray spectrometer. This measurement provided qualitative information, and in particular, regarding other radionuclides, the filter was... 46 Sc and 44 It only contained Sc (that is, 44 (Ti was not detected). The same sample was prepared in 5 mL with an additional 1% HNO3 and analyzed by ICP-OES to determine the stable metallic impurities present in the solution. Fe, Zn, Ca, and Ta were shown to be the main impurities remaining in the filtrate after precipitation / filtration.

[0074] To achieve high volume and high molar activity, in order to meet the requirements for using radiopharmaceuticals, the method of the present invention was envisioned for precise purification of the filtrate and input into the generator.

[0075] Dynamic column isolation 1. Determining the most suitable protocol Method #1: Two-step procedure: i) Purification on a DGA® column and ii) Loading on a ZR® column In the procedures described herein, 44 Before introducing Ti, it was decided to first further purify the sample and create a generator. This purification was performed using a cyclotron. 44 The procedure for generating Sc was based on the method described by Alliot et al. (Huclier-Markai S, Sabatie A, Ribet S, Kubicek V, Paris M, Vidaud C, Chemical and biological evaluation of scandium(III)-polyaminocarboxylate complexes as potential PET agents and radiopharmaceuticals. Radiochim Acta; 99:653 (2011)). DGA was used in several operations of the scandium isotope purification process. For this purpose, a DGA column was set up. Note that 200 mg of DGA® resin (Triskem) was weighed, pre-conditioned with 1 M NaOH, rinsed with water, and finally re-conditioned with 2 M HCl. 44 Ti / 44 The Sc filtrate was passed through a column for elution. Fractions were collected in mL units by first eluting with a 10 M HCl solution (maximum 17 mL), and then with a 2 M HCl solution. Gamma-ray spectrometry analysis was performed on each collected fraction (mL) to monitor the purity of radionuclides. After confirming the absence of radionuclides, the first 2 mL was discarded. Using a 10 M HCl solution, fractions 3 to 17 were eluted. 44 Ti was completely recovered. Gamma-ray spectrometry analysis was performed. 46 This showed that neither Sc nor other radioactive nuclide impurities were present in these elution fractions. 44Only Ti was present, or depending on the analysis time, its decay products were also present. 44 Sc was also present. To monitor chemical purity, fractions 1, 2, and 17 were analyzed by ICP-OES. Only Na was found, and all other metallic impurities were below detection levels. Subsequently, following the example of Horwitz et al. (Dr. E. Philip Horwitz, Daniel R. McAlister & Anil H. Thankkar (2008) Synergistic Enhancement of the Extraction of Trivalent Lanthanides and Actinides by Tetra-(n-Octyl)Diglycolamide from Chloride Media, Solvent Extraction and Ion Exchange, 26:1, 12~24, DOI:10.1080 / 07366290701779423), the elution of other chemical impurities (i.e., Al, Fe, etc.) may be carried out using 2M HCl while leaving Ti in the column. Elution was carried out under these conditions up to a maximum of 50 mL. The fraction was analyzed by gamma-ray spectrometry and showed that no radionuclides were present. Chemical analysis also showed no presence of stable metal impurities. Therefore, the overall chemical purity after DGA column treatment was excellent.

[0076] First Rosch (Pruszyski M, Loktionova N, Filosofov D, Roesch F. Post-elution processing of 44 Ti / 44 Sc Generator Generated 44 As described in Sc for clinical application. Appl Radiat Isot;68:1636 (2010), 44 Ti / 44 To make an Sc generator, 44Ti must be adsorbed onto the resin. In the original process, the cation exchanger AG50WX8 resin was used. Radchenko et al. developed the same idea, but these authors used an alternative method with a hydroxamate-based ZR resin (registered trademark). Since the equilibrium partition coefficients of Ti and Sc were described in these documents, the same method was used in the second step of this process.

[0077] A fraction of 3.1 μCi was taken from the DGA elution and placed on 220 mg of ZR resin, and pre-conditioned with 2 M HCl. Then, 44 Sc elution was performed using a 2M HCl solution. After confirming that these fractions did not contain radionuclides, the first 2 mL was discarded. Elution was continued using another 10 mL of 2M HCl, and fractions were collected in mL units. The fractions were analyzed by gamma-ray spectrometry. 44 No Ti breakthrough was observed.

[0078] 100% of the input activity ( 44 When measured with Sc, the elution was recovered immediately after the initial elution and remained so even after 24 hours. After 24 hours, no additional metal or radionuclide impurities were detected in the eluted fraction. The resulting molar activity was estimated to be 0.15 μCi / nmol = 5.3 kBq / nmol. This was attributed to the small amount of radioactivity loaded onto the column. This, in turn, led the inventors to consider Method #2 (corresponding to the method of the present invention).

[0079] Method #2: One-step procedure: Direct loading onto the ZR(registered trademark) column. After precipitation / filtration, based on the results of Method #1, 3.5 μCi aliquots were directly added onto pre-conditioned ZR resin. The radionuclide purity of these aliquots was very good. 44 Ti, 44 Sc and trace amounts 88 V and 88It contained Y. ICP-OES analysis of the filtrate before input showed that the main impurities were Fe, Mo, Si, (Zr), and Ta, while Al, Ca, Cu, Ni, and Zn were present at lower concentrations. Elution was then performed with 2M HCl. Some 44 Ti was eluted in the first 2 mL, representing 2.8% of the loaded initial activity, but after 24 hours, no further activity was observed. 44 Ti was not released from the column. 44 Sc eluted in 10 mL of 2 M HCl, and this 44 This represents 97% of the initial activity loaded in Ti. After 24 hours, another elution was performed, showing the same percentage of elution, and in both fractions... 44 Ti was not present. Nevertheless, it should be noted that 75% of the loaded initial activity was recovered in 4 mL (approximately 2.6 μCi). The obtained volumetric activity was 0.64 μCi / mL. In the eluted fraction, no other metal impurities were found in the eluate (at concentrations below the detection limit). The obtained molar activity will be estimated by radiolabeling studies.

[0080] 2. Application to 10μCi generators Therefore, it was decided to collect fractions 3-17 on a DGA column by elution with 10M HCl to obtain approximately 10 μCi. These fractions were evaporated using an epiradiator and redissolved in 500 μL of 1M HCl. The total activity was 9.7 μCi. These 9.7 μCi were loaded onto 1.5 g of ZR resin and preconditioned with 2M HCl. Then, using a 2M HCl solution, 44 Sc elution was performed. The first 3 mL was discarded after confirming that these fractions did not contain any radioactive materials. Elution was further performed with 12 mL of 2 M HCl, and the fractions were collected in mL units. The fractions were analyzed by gamma-ray spectrometry. Of the accumulated total fractions, 44 The Ti breakthrough accounted for approximately 0.2% of the total activity.

[0081] 65% of the loaded activity ( 44When measured by Sc, it was recovered immediately after the first elution and showed to be over 95% after 24 hours.

[0082] Fe, Al, and Zn metal impurities were directly eluted in the first elution from the generator loaded with ZR resin. No additional metal impurities or radioactive nuclide impurities were detected in the eluted fraction after 24 hours. The resulting molar activity was estimated to be 75.2 μCi / nmol = 2.8 MBq / nmol.

[0083] Radiolabeling research Loaded on the ZR resin according to the present invention 44 Ti / 44 We set up a Sc generator and enabled direct radiolabeling using the DOTA ligand. The chelate ligand DOTA binds to transition and rare-earth metal ions with high stability under physiological conditions, leading to its use in vivo. The total percentage of radiolabeled DOTA was found to be 90% with a 1:1 Sc:L molar ratio, compared to 98% with a 1:2 Sc:L molar ratio. Even though these data are very well known, it is important to utilize the specific activity of the resulting loaded generator. From a 9.7 μCi generator, this specific activity was calculated to be 54 μCi / nmol = 2 MBq / nmol. This specific activity was calculated by Roesch. 44 Ti / 44 It was higher than what was determined by the Sc generator (estimated to be approximately 0.2 MBq / nmol). 44 Compared to Sc sources, particularly those from cyclotron generation, this specific activity is, 44m / 44 It was lower than what was determined on Sc (which showed a specific activity of 37 MBq / nmol).

[0084] In conclusion, the present invention relates to the substantial amount of proton irradiation of scandium targets at the BNL proton accelerator plant. 44 Ti generation and 44 Ti / 44 Regarding the fabrication of a Sc generator. PET imaging isotopes. 44 Sc is 44 Ti / 44 It can be supplied routinely by a Sc generator. Uncarrier-free Ti is recovered from 13 g of Sc by performing an efficient and easy method. This procedure involves three steps: firstly, by precipitation with fluoride 44 In addition to the precise separation of Ti, secondly, from residual Sc and other residual metal contaminants... 44 A cation exchange step in an HCl medium for the precision purification of Ti, thirdly, cation exchange for loading the generator. In summary, this method achieves a recovery rate of 90%. 44 Ti was obtained. The molar activity obtained on the DOTA ligand is different from other 44 Ti / 44 The molar activity was shown to be higher than that estimated by the Sc generator (i.e., 2 MBq / nmol compared to 0.2 MBq / nmol). This molar activity increases due to the increased activity, as the chemical and radioactive nuclide purity achieved by this method was good.

[0085] Comparative example: The effect of conditioning resins The ZR resin described above was tested with NaOH, then rinsed with water, and reconditioned with 2M HCl.

[0086] However, three issues were highlighted:

[0087] Problem 1: A large amount of Si (>12 ppm) leached from the resin (colloid in the lungs and liver).

[0088] Problem 2: When the generator is loaded, the resin turns brown. This is likely due to the decomposition of functional groups on the surface of the resin. This can also be explained by the high concentration (excessively high, 10M) of acid used to load the column.

[0089] Problem 3: Elute Ti and Sc together (see Figure 1). Therefore, the column is: 44 It appears completely inefficient because it does not retain Ti (and therefore cannot be used as a generator).

Claims

1. From the target solution ４４ A method for generating Sc, (a) A precipitate of a target solution containing a metal species having fluoride ions, wherein the target solution is at least ４４ Sc, ４４ Ti, and ４６ It contains Sc and other metal impurities, wherein the amount of Sc is 10,000 to 15,000 ppm relative to the total mass of the target solution, the amount of Ti is 5 to 10 ppm relative to the total mass of the target solution, and the amount of each metal impurity is 200 to 300 ppm relative to the total volume of the target solution, thereby ４６ A solution containing a precipitate essentially composed of Sc is obtained, precipitate, (b) Filtration of the resulting solution, and the resulting ４４ Sc and ４４ Recovery of filtrate essentially containing Ti, A solid-liquid extraction process including, (c) Adding the filtrate obtained in the previous step onto a pre-conditioned hydroxamate column, wherein the pre-conditioned hydroxamate column is obtained from treatment of the hydroxamate column with a strong acid and washing with water, (d) Elution of the hydrochloric acid solution passed through the preconditioned hydroxamate column, thereby ４４ Ti is adsorbed onto the column, elution, The solid-phase extraction chromatography process includes, From the eluate of the previous step ４４ A step of recovering Sc, and A method that includes this.

2. The method according to claim 1, wherein the precipitation step (a) is carried out with an acid having a pH of less than 6.

3. The method according to claim 1 or 2, wherein in the precipitation step (a), the ratio of the concentration of all metal species to the concentration of fluoride ions is 1:5 to 1:

20.

4. The method according to any one of claims 1 to 3, wherein the precipitation step (a) is carried out at room temperature for at least 24 hours.

5. The method according to any one of claims 1 to 4, wherein the precipitation step (a) is carried out using a NaF solution.

6. The method according to any one of claims 1 to 5, wherein the mass of the preconditioned hydroxamate column is 200 mg to 2 g.

7. The method according to any one of claims 1 to 6, wherein the pre-conditioned hydroxamate column is obtained by eluting the hydroxamate column with a hydrochloric acid solution of 1 M to 10 M concentration, rinsing with water, and further eluting with a hydrochloric acid solution of 0.1 M to 3 M concentration in a volume V1 of 20 mL to 100 mL.

8. The method according to any one of claims 1 to 7, wherein the elution step (d) is carried out using a hydrochloric acid solution of a concentration of 1 M to 5 M in a volume V2 of 2 mL to 25 mL.

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