WO2024003344A1 - Production of the radionuclide lanthanum-135 - Google Patents

Production of the radionuclide lanthanum-135 Download PDF

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Publication number
WO2024003344A1
WO2024003344A1 PCT/EP2023/067985 EP2023067985W WO2024003344A1 WO 2024003344 A1 WO2024003344 A1 WO 2024003344A1 EP 2023067985 W EP2023067985 W EP 2023067985W WO 2024003344 A1 WO2024003344 A1 WO 2024003344A1
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powder
target
hci
barium
equal
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PCT/EP2023/067985
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French (fr)
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Mikael Jensen
Kristina PEDERSEN
Claire DEVILLE
Andreas Ingemann JENSEN
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Danmarks Tekniske Universitet
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Publication of WO2024003344A1 publication Critical patent/WO2024003344A1/en

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    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01F—COMPOUNDS OF THE METALS BERYLLIUM, MAGNESIUM, ALUMINIUM, CALCIUM, STRONTIUM, BARIUM, RADIUM, THORIUM, OR OF THE RARE-EARTH METALS
    • C01F11/00—Compounds of calcium, strontium, or barium
    • C01F11/18—Carbonates
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01F—COMPOUNDS OF THE METALS BERYLLIUM, MAGNESIUM, ALUMINIUM, CALCIUM, STRONTIUM, BARIUM, RADIUM, THORIUM, OR OF THE RARE-EARTH METALS
    • C01F11/00—Compounds of calcium, strontium, or barium
    • C01F11/20—Halides
    • C01F11/24—Chlorides
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01F—COMPOUNDS OF THE METALS BERYLLIUM, MAGNESIUM, ALUMINIUM, CALCIUM, STRONTIUM, BARIUM, RADIUM, THORIUM, OR OF THE RARE-EARTH METALS
    • C01F17/00—Compounds of rare earth metals
    • C01F17/10—Preparation or treatment, e.g. separation or purification
    • C01F17/13—Preparation or treatment, e.g. separation or purification by using ion exchange resins, e.g. chelate resins
    • G—PHYSICS
    • G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
    • G21G—CONVERSION OF CHEMICAL ELEMENTS; RADIOACTIVE SOURCES
    • G21G1/00—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes
    • G21G1/001—Recovery of specific isotopes from irradiated targets
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2006/00—Physical properties of inorganic compounds
    • C01P2006/80—Compositional purity
    • G—PHYSICS
    • G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
    • G21G—CONVERSION OF CHEMICAL ELEMENTS; RADIOACTIVE SOURCES
    • G21G1/00—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes
    • G21G1/04—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes outside nuclear reactors or particle accelerators
    • G21G1/10—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes outside nuclear reactors or particle accelerators by bombardment with electrically charged particles
    • G—PHYSICS
    • G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
    • G21G—CONVERSION OF CHEMICAL ELEMENTS; RADIOACTIVE SOURCES
    • G21G1/00—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes
    • G21G1/001—Recovery of specific isotopes from irradiated targets
    • G21G2001/0094—Other isotopes not provided for in the groups listed above

Definitions

  • the present disclosure relates to a method for extraction of Barium (Ba) and Lanthanum (La) from an irradiated target is provided. Further provided is a proton bombardment target and a method for production of a Ba-comprising proton bombardment target.
  • TRT targeted radionuclide therapy
  • cancer metastasis is a major contributor to mortality in cancer, and consequently a key area for innovative new treatments to improve prognosis.
  • targeting vectors are combined with radionuclides.
  • the targeting vectors deliver the radionuclides to cancer lesions, where the radionuclides deliver highly precise and localized ionizing radiation, thereby specifically destroying the cancer cells.
  • Auger electron radiotherapy A special type of targeted radionuclide therapy is Auger electron radiotherapy (AuRT).
  • AuRT specific radionuclides are used. These are characterized by the emission of showers of short range Auger electrons, upon radioactive decay. Once Auger electron emitting radionuclides are delivered to the nuclei of cancer cells, the emission of Auger electrons destroys the DNA and effectively kill the cancer cells.
  • Lanthanum-135 is a particular well-suited Auger electron emitter, which decays to Barium-135 primarily via electron capture and secondarily via p + decay with a half-life of the order of 18.9 hours. It has a high yield of Auger electrons, and a low yield of accompanying X-rays, which are an unwanted source of off-target damage. Further, it has the radiopharmaceutically convenient decay half-life of about 19 hours.
  • La-135 has not yet been available in adequate supply as only insufficient production means have been available. These were primarily based on metallic Barium targets, which were irradiated with protons to produce La-135 within the target as reported in Fonslet et al. 2018 Phys. Med. Biol. 63. Further, an optimized method for removing the contaminant target material (Ba) from the desired radionuclide (La-135) have been reported, wherein a diglycolamide (DGA) resin was employed, see Aluicio-Sarduy et al. Chem. Eur. J. 2020, 26, 1238-1242.
  • DGA diglycolamide
  • Ba-135 enriched Ba is primarily available as a carbonate salt, i.e. as [ 135 Ba]BaCC>3, which makes target preparation very challenging as salts are difficult to compress and the thermal conductivity of BaCCh is poor, which means that the target is easily damaged during bombardment with protons at appreciable currents. As a result of this only low currents can be applied during the bombardment, e.g. less than 10 pA.
  • the project leading to this application has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 101008571 (PRISMAP - The European medical radionuclides programme) and from The Innovation Fund Denmark under grant agreement No 1046-00027 within the InnoExplorer programme.
  • a method for extraction of Barium (Ba) and Lanthanum (La) from an irradiated target in a second aspect is provided a proton bombardment target, and in a third aspect is provided a method for production of a Ba-comprising proton bombardment target.
  • a method for extraction of Barium (Ba) and Lanthanum (La) from an irradiated target comprises the steps of: providing an irradiated target comprising Ba and La, dissolving the irradiated target in hydrochloric acid (HCI) so as to produce a precipitate of Barium Chloride (BaCh) and a supernatant, and extracting La from the supernatant.
  • HCI hydrochloric acid
  • the method thus presents a purification procedure for the purification of La from a sample target comprising Ba and La.
  • the irradiated target is a target that has been configured for use in targeted irradiation, such as for targeted proton irradiation, and which has been irradiated by a targeted beam.
  • the irradiated target is a target that has been irradiated by a proton beam.
  • Ba-135 and Ba-136 can undergo a charged particle reaction to make La- 135, the charged particle reaction routes being: 135 Ba(p,n) 135 La and 136 Ba(p,2n) 135 La.
  • Other light charged particle routes for making of La-135 from bombardment of a target comprising Ba are: 134 Ba(d,n) 135 La and 135 Ba(d,2n) 135 La.
  • the irradiated target is a target as provided in the second aspect or a target produced using the method provided in the third aspect.
  • the irradiated target is made of compressed powders.
  • the Ba salt is Barium carbonate (BaCCh).
  • BaCCh Barium carbonate
  • more than 50% of the Ba is comprised in a Ba salt, such as more than 60% of the Ba, such as more than 70% of the Ba, such as more than 80% of the Ba.
  • the Ba is enriched with Barium-135 and/or with Barium-136.
  • the irradiated target further comprises Aluminium (Al) powder or an Al- comprising powder.
  • the Al-comprising powder is an alloy, i.e. the powder of an alloy.
  • the irradiated target further comprises Aluminium (Al) powder having a purity equal to or above 85% trace metals basis, such as equal to or above 90% trace metals basis, such as equal to or above 95% trace metals basis, such as equal to or above 99% trace metals basis, such as equal to or above 99.5% trace metals basis.
  • Mixing the Ba-comprising powder with an Al-comprising powder may aid in diverting heat from the Ba-comprising powder during bombardment, such as during proton bombardment. Further, the mix of an Al-comprising powder, such as an analytical grade Al powder, and a Ba salt can make it possible to produce a workable target from a hard powder such as a Ba salt.
  • the irradiated target comprises BaCOs and Al in a predetermined w/w ratio, where the predetermined w/w ratio of BaCOs/AI is between 0.25 and 4, such as between 0.3 and 3, such as between 0.4 and 2, such as between 0.45 and 1.0.
  • the irradiated target comprises a predetermined ratio of X/Y, where X is the combined amount of Ba and La atoms, and where Y is the amount of Al atoms, and wherein the predetermined ratio of X/Y is between 0.034 and 0.55, such as between 0.041 and 0.41 , such as between 0.055 and 0.27, such as between 0.062 and 0.14.
  • dissolving the target in HCI comprises placing the irradiated target in a first solution of HCI having a first molarity, and using a second solution of HCI having a second molarity to produce the precipitate of BaCh, wherein the second molarity is higher than the first molarity.
  • the second solution of HCI is made by increasing the molarity of the first solution of HCI.
  • extracting La from the supernatant comprises performing a solid phase extraction (SPE) on the supernatant.
  • SPE solid phase extraction
  • the SPE comprises using a DGA resin, such as a branched DGA resin, and a TK200 resin.
  • DGA resin and TK200 resin are commercially available resins.
  • DGA resin comprises the functional group N,N,N’,N’-tetra-2-ethylhexyl diglycolamide.
  • TK200 resin comprises the functional group trioctylphosphine oxide.
  • the SPE comprises using a first resin comprising the functional group N,N,N’,N’-tetra-2-ethylhexyl diglycolamide and a second resin comprising the functional group trioctylphosphine oxide.
  • the SPE comprises the step of: passing the supernatant through first a DGA resin and then a TK200 resin. In other embodiments, the SPE comprises the step of: passing the supernatant through first a TK200 resin and then a DGA resin.
  • using a DGA resin and a TK200 resin comprises using a single cartridge comprising both DGA resin and TK200 resin with the DGA resin being on top in the cartridge, where being on top means that the DGA resin is closer to the end of the cartridge in which liquid is added. That is, in some embodiments using the first resin and the second resin comprises using a single cartridge comprising both the first resin and the second resin with the first resin being upstream in the cartridge.
  • the SPE comprises the steps of: washing the cartridge with a third solution of HCI having a third molarity, the third solution of HCI being configured to wash out Ba 2+ , and eluting the cartridge with a fourth solution of HCI having a fourth molarity, the fourth solution of HCI being configured to elute La 3+ .
  • the third solution of HCI is further configured to wash out Al 3+ .
  • a proton bombardment target comprises a plurality of powders pressed into a pellet, the plurality of pressed powders comprising a first powder and a second powder, the first powder comprising Barium (Ba), the first powder and the second powder being present in the target in a predetermined ratio, wherein the second powder comprises Aluminium (Al).
  • the first powder comprises a Barium (Ba) salt.
  • the first powder comprises Barium carbonate (BaCCh).
  • the first powder is enriched with Barium-135 and/or with Barium-136.
  • the first powder comprises [ 135 Ba]BaCC>3 and/or [ 136 Ba]BaCC>3.
  • the second powder comprises Aluminium (Al) powder having a purity equal to or above 85% trace metals basis, such as equal to or above 90% trace metals basis, such as equal to or above 95% trace metals basis, such as equal to or above 99% trace metals basis, such as equal to or above 99.5% trace metals basis.
  • Al Aluminium
  • the predetermined ratio is a ratio of X/Y, where X is the combined amount of Ba and La atoms and Y is the amount of Al atoms and wherein the predetermined ratio of X/Y is between 0.034 and 0.55, such as between 0.041 and 0.41 , such as between 0.055 and 0.27, such as between 0.062 and 0.14.
  • a method for production of a Ba-comprising proton bombardment target comprises: providing a first powder, the first powder comprising Barium (Ba), providing a second powder, mixing the first powder and the second powder in a predetermined ratio to produce a mixed powder, pressing a pellet comprising the mixed powder, the pellet being configured for use as a proton bombardment target, wherein the second powder comprises Aluminium (Al).
  • the first powder comprises a Barium (Ba) salt.
  • the first powder comprises Barium carbonate (BaCOs).
  • the first powder is enriched with Barium-135 and/or with Barium-136.
  • the first powder comprises [ 135 Ba]BaCC>3 and/or [ 136 Ba]BaCC>3.
  • the second powder comprises Aluminium (Al) powder having a purity equal to or above 85% trace metals basis, such as equal to or above 90% trace metals basis, such as equal to or above 95% trace metals basis, such as equal to or above 99% trace metals basis, such as equal to or above 99.5% trace metals basis.
  • Al Aluminium
  • the predetermined ratio is a ratio of X/Y, where X is the combined amount of Ba and La atoms and Y is the amount of Al atoms and wherein the predetermined ratio of X/Y is between 0.034 and 0.55, such as between 0.041 and 0.41 , such as between 0.055 and 0.27, such as between 0.062 and 0.14.
  • FIG. 1 shows a flow diagram of a method for extraction of Barium (Ba) and Lanthanum (La) from an irradiated target according to some embodiments
  • FIG. 2 shows a flow diagram of a method for extraction of Barium (Ba) and Lanthanum (La) from an irradiated target according to some embodiments
  • FIG. 3 shows a flow diagram of part of a method for extraction of Barium (Ba) and Lanthanum (La) from an irradiated target according to some embodiments
  • FIG. 4A illustrates a proton bombardment target according to some embodiments
  • FIG. 4B shows a photograph of a produced proton bombardment target according to some embodiments.
  • FIG. 1 shows a flow diagram of a method for extraction of Barium (Ba) and Lanthanum (La) from an irradiated target according to some embodiments.
  • step 103 an irradiated target comprising Ba and Al is dissolved and during separation step 109 BaCh is precipitated.
  • An extraction procedure is performed in step 125 to extract La from the supernatant.
  • the extraction procedure could be a Solid Phase Extraction (SPE) during which La ions are eluted.
  • SPE Solid Phase Extraction
  • the Ba can be reused in a new target.
  • Making the Barium used in the target as least partially recyclable is advantageous, especially so as the Barium used in the target will usually be enriched Ba-135, which is expensive.
  • FIG. 2 shows a flow diagram of a method for extraction of Barium (Ba) and Lanthanum (La) from an irradiated target according to some embodiments.
  • step 103 an irradiated target comprising BaCCh and Al is dissolved in a first solution of HCI having a first molarity.
  • the first molarity may be 3 M.
  • step 105 the dissolved target is evaporated to dryness, and then, in step 107, the solid is taken up in a small amount of HCI solution, for example a few mL of HCI 0.01 M.
  • a separation step 109 the solid is placed in a second solution of HCI having a higher molarity than the first solution of HCI, where the molarity of the second solution is configured to form a precipitate of BaCh.
  • the second molarity may be 8 M.
  • BaCh is precipitated.
  • the precipitate is then further separated by centrifugation in step 113.
  • the centrifugation produces a pellet of BaCh allowing for easy removal of BaCh leaving a supernatant comprising metal ions: La-135, Al and impurities, such as e.g. Zn, Fe, and leftover Ba, dissolved in HCI.
  • the pellet of BaCh and the supernatant can now easily be further treated separately.
  • the Ba can be added to a new target as BaCCh.
  • the Ba in the form of BaCh allows for easy recycling and conversion to BaCCh by dissolution of the BaCh in a small amount of water, step 117, and addition of (NH ⁇ CCh, step 119.
  • BaCCh is recovered in step 121 and can be reused.
  • Making the Barium used in the target as least partially recyclable is advantageous, especially so as the Barium used in the target will usually be enriched with Ba-135, which is expensive.
  • a Solid Phase Extraction is performed in step 125, wherein resins having suitable functional groups are used to bind various metal ions. Depending on the HCI concentration the metal ions will form various species making it possible to load/elute them from the column(s) during the Solid Phase Extraction procedure.
  • a combined column comprising both DGA resin and TK200 resin, i.e. in a single cartridge, with the DGA resin being on top can be used.
  • a column comprising DGA resin and a separate column comprising TK200 resin may be used, see FIG. 3 and its description.
  • the supernatant is loaded on the combined column, where the DGA resin retains the La 3+ ions and lets the Al 3+ ions pass through when a suitable concentration of HCI is used as eluent.
  • the DGA resin is, however, not optimal for removing impurities such as Fe 3+ ions and Zn 2+ ions, which tend to at least partially follow the La 3+ during a later elution step. Therefore, a TK200 resin is arranged below the DGA resin, and the TK200 resin is able to retain Fe and Zn ions when a suitable concentration of HCI is used as eluent.
  • the radionuclide La-135 will be bonded to a chelator molecule and Fe and Zn may be able to bond to the chelator as well.
  • Fe and Zn may be able to bond to the chelator as well.
  • Trace amounts of Al is less critical as the chelators used for La often have less affinity to bind Al.
  • the combined column is then washed with a third solution of HCI having a third molarity, where the third solution of HCI is configured to wash out Ba 2+ .
  • the combined column is eluted with a fourth solution of HCI having a fourth molarity, the fourth solution of HCI being configured to elute La 3+ .
  • step 129 the eluted fraction is evaporated to dryness and, in step 131 , taken up in HCI, now ready for labelling.
  • FIG. 3 shows a flow diagram of part of a method for extraction of Barium (Ba) and Lanthanum (La) from an irradiated target according to some embodiments.
  • the method may comprise using a column comprising DGA resin and a separate column comprising TK200 resin.
  • An example of this according to some embodiments is shown in fig. 3, wherein the Solid Phase Extraction (SPE) in step 125 comprises first loading the supernatant on a column containing DGA resin. The column comprising DGA resin is then washed with a third solution of HCI having a third molarity, where the third solution of HCI is configured to wash out Ba 2+ , e.g. with 8 M HCI.
  • SPE Solid Phase Extraction
  • the column comprising DGA resin is eluted with a fourth solution of HCI having a fourth molarity, the fourth solution of HCI being configured to elute La 3+ , e.g. with 3 M HCI.
  • This will provide an eluate comprising La and impurities such as e.g. Zn and Fe.
  • FIG. 4A illustrates a bombardment target pellet according to some embodiments.
  • the Ba-comprising proton bombardment target may be prepared as a pellet 1 held within a holder 3.
  • the pellet 1 is made using a plurality of powders, which are pressed into the shape of the pellet 1.
  • An Aluminium-comprising powder is mixed with a Barium-comprising powder, which has the possible advantages that the Al- comprising powder may aid in the packing of the Ba-comprising powder, and that the Al- comprising powder may aid in diverting heat from the Ba-comprising powder during bombardment, such as during proton bombardment.
  • the holder for the target pellet 1 may comprise or be made almost entirely of Silver (Ag) in the form of a disc having an indentation in which the pellet may be pressed.
  • Ag Silver
  • FIG. 4B shows a photograph of a prepared proton bombardment target according to some embodiments.
  • the proton bombardment target shown comprises a 1 :2 nat BaCO3:AI w/w pellet 1 having a diameter of 9 mm.
  • the target pellet was pressed in a Silver (Ag) disc 3 having a circular centre indentation. See details for the preparation in the section describing Experiment 2.
  • La-135 was extracted from a 150-200 mg 1 :2 BaCO3:AI w/w target.
  • the proton bombardment target used in the experiment comprised natural Ba; The reason for this being that enriching the Ba with Ba-135 is expensive and the experiment was done to demonstrate the efficacy of the purification method.
  • the target was first dissolved at 60°C in HCI 3 M. After evaporation of the dissolved target to dryness, the solid was taken up in a few mL of HCI 0.01 M. Addition of concentrated HCI (30% w/w) in order to reach an HCI concentration around 8 M, led to the precipitation of most of the Barium in the form of BaCh. The precipitate was removed by centrifugation and stored separately. This removed most of the radiochemical impurity Ba-135m.
  • the TK200 resin is able to retain Fe and Zn when HCI 3 M is used as eluent. As La can be eluted with HCI concentrations of 3 M and below the combination of both resins creates a suitable column that lets the Al be washed out first, while the trace impurities are retained during the La elution with HCI 3 M.
  • the supernatant was loaded on the combined column previously washed with HCI 3 M and conditioned with HCI 8 M. The column was then washed with 20 mL HCI 8 M followed by elution of the La with HCI 3 M. The eluted fraction was evaporated to dryness and taken up in HCI 0.001 M, ready for labelling.
  • the remaining impurities measured by ICP-OES analysis are essentially Al (around 1.0 pg in the whole sample) and traces of La and Ba.
  • the y spectrum of the purified sample shows the presence of three La isotopes, La-132, La-133, and La-135, as well as some Co-56, a radiochemical impurity.
  • a Silver (Ag) disc As holder for the target pellet was used a Silver (Ag) disc with a diameter of 28 mm and a thickness of 5 mm. The disc had a circular centre indentation with a diameter 9 mm and a depth of 3 mm. A homogeneous nat BaCO3:AI powder mixture (1 :2, w/w, 150 mg) was pressed into the centre indentation using a hydraulic press providing 0.5-1 t pressure. A photograph of the prepared target before irradiation is shown in fig. 4B.
  • BaCOs is a stable compound, but on its own it is difficult to press into a workable target on an Ag disc. Mixing the BaCOs with Al powder, however, facilitates the pressing of a target pellet. Further, the Al helps with heat dissipation. Experimentally, the mixing of Al powder with the BaCOs has shown that 20 pA of current could be used compared to only 10 pA of current when using a target made of pure BaCOs. Al is also a light material, which means it only provides little stopping of a proton beam. Lastly, the reaction product from a proton bombardment of Al is Si-27, which has a very short half-life (about 4 seconds), which means the reaction product will have decayed shortly after its production.
  • the Ag disc was mounted on a target holder with direct water cooling being supplied to the backside of the Ag disc.
  • a 50 pm thick Niobium (Nb) foil was placed in front of the target.
  • the target was irradiated with a 16.5 MeV proton beam at 10-20 A for 30-120 min and left overnight on the cyclotron before handling to allow for short-lived isotopes to decay.
  • a Silver (Ag) disc As holder for the target pellet was used a Silver (Ag) disc with a diameter of 28 mm and a thickness of 5 mm. The disc had a circular centre indentation with a diameter 14 mm and a depth of 3 mm. A homogeneous nat BaCO3:AI powder mixture (1 :2, w/w, 361 mg) was pressed into the centre indentation using a hydraulic press providing 2.5 t pressure. The Ag disc was mounted on a target holder with direct water cooling being supplied to the backside of the Ag disc. A 50 pm thick Nb foil was placed in front of the target.
  • the target was irradiated with a 16.5 MeV proton beam at 20 pA for 1 h and left overnight on the cyclotron before handling to allow for short-lived isotopes to decay. Unfortunately, after opening it, it was clear that the target did not withstand the heat due to its larger diameter, which reduced the thermal conductivity of the silver disc. The target material presented as black and crumbly, and the Nb foil was strongly deformed. The La-135 activity produced at end of bombardment reached 65 MBq.
  • a Silver (Ag) disc As holder for the target pellet was used a Silver (Ag) disc with a diameter of 28 mm and a thickness of 5 mm. The disc had a circular centre indentation with a diameter 9 mm and a depth of 3 mm. A homogeneous nat BaCO3:AI powder mixture (1 :1 , w/w, 152 mg) was pressed into the centre indentation using a hydraulic press providing 0.5-1 t pressure. The Ag disc was mounted on a target holder with direct water cooling being supplied to the backside of the Ag disc. A 50 pm thick Nb foil was placed in front of the target.
  • the target was irradiated with a 16.5 MeV proton beam at 20 pA for 1 h and left overnight on the cyclotron before handling to allow for short-lived isotopes to decay. Unfortunately, after opening it, it was clear that the target did not withstand the heat due to its larger amount of BaCOs, which reduced the thermal conductivity of the target material. The target material presented as black and crumbly. The La-135 activity produced at end of bombardment reached 66 MBq.
  • the BaCC>3:AI ratio was kept at 1 :2 (w/w) as in Experiment 1.
  • One target was made to have 150 mg of the target material, while the other was made to have 200 mg of target material, and both targets were made to have a diameter of 9 mm.
  • the target was irradiated for 4 hours with a 16.5 MeV proton beam at 20 pA.
  • the formation of multiple La isotopes is reduced and the target could be handled already 30 minutes after End of Beam (EOB).
  • the only radionuclides detected besides La-135 were Ba-135m, Cd-107, Cs-132, and Co- 56.
  • the [ 135 Ba]BaCl2 can be recycled and converted back to [ 135 Ba]BaCO3 by dissolution in a few mL of water and addition of Ammonium carbonate, (NH 4 ) 2 CO3. After centrifugation and thorough drying, the precipitated [ 135 Ba]BaCO3 can be used to prepare a new target.
  • La-135 was the only La isotope detected in the final sample with Co- 56 being present as a minor impurity. As the Co- 56 comes from the Fe impurity present in the Al powder used in the target, the amount of this impurity could be significantly reduced by using an Al powder of higher purity.

Abstract

Provided is a method for extraction of Ba and La from an irradiated target, the method comprising the steps of: providing an irradiated target comprising Ba and La, dissolving the irradiated target in HCI so as to produce a precipitate of BaCl2 and a supernatant, and extracting La from the supernatant. Further provided is a proton bombardment target and a method for production of a Ba-comprising proton bombardment target.

Description

PRODUCTION OF THE RADIONUCLIDE LANTHANUM-135
The present disclosure relates to a method for extraction of Barium (Ba) and Lanthanum (La) from an irradiated target is provided. Further provided is a proton bombardment target and a method for production of a Ba-comprising proton bombardment target.
BACKGROUND OF THE INVENTION
In the field of nuclear medicine, targeted radionuclide therapy (TRT) is a rapidly emerging approach to treating metastatic cancer. Cancer metastasis is a major contributor to mortality in cancer, and consequently a key area for innovative new treatments to improve prognosis. In TRT, targeting vectors are combined with radionuclides. The targeting vectors deliver the radionuclides to cancer lesions, where the radionuclides deliver highly precise and localized ionizing radiation, thereby specifically destroying the cancer cells.
A special type of targeted radionuclide therapy is Auger electron radiotherapy (AuRT). In AuRT, specific radionuclides are used. These are characterized by the emission of showers of short range Auger electrons, upon radioactive decay. Once Auger electron emitting radionuclides are delivered to the nuclei of cancer cells, the emission of Auger electrons destroys the DNA and effectively kill the cancer cells.
Lanthanum-135 is a particular well-suited Auger electron emitter, which decays to Barium-135 primarily via electron capture and secondarily via p+ decay with a half-life of the order of 18.9 hours. It has a high yield of Auger electrons, and a low yield of accompanying X-rays, which are an unwanted source of off-target damage. Further, it has the radiopharmaceutically convenient decay half-life of about 19 hours.
However, La-135 has not yet been available in adequate supply as only insufficient production means have been available. These were primarily based on metallic Barium targets, which were irradiated with protons to produce La-135 within the target as reported in Fonslet et al. 2018 Phys. Med. Biol. 63. Further, an optimized method for removing the contaminant target material (Ba) from the desired radionuclide (La-135) have been reported, wherein a diglycolamide (DGA) resin was employed, see Aluicio-Sarduy et al. Chem. Eur. J. 2020, 26, 1238-1242.
It remains a challenge that only low amounts of La-135 can be produced in this way since metallic Ba targets are very difficult to prepare and handle due to oxidation of the Ba. By using Ba, which have been enriched with Ba-135, in the production of the irradiation target the amount of La-135 produced can be increased. However, Ba-135 enriched Ba is primarily available as a carbonate salt, i.e. as [135Ba]BaCC>3, which makes target preparation very challenging as salts are difficult to compress and the thermal conductivity of BaCCh is poor, which means that the target is easily damaged during bombardment with protons at appreciable currents. As a result of this only low currents can be applied during the bombardment, e.g. less than 10 pA.
Thus, the use of La-135 in TRT has been hindered, as a reliable and scalable La-135 production procedure was lacking.
There is thus a need for a reliable and scalable method of producing La-135.
It is an object to provide an improved method of producing the radionuclide La-135.
It is a further object to provide an improved proton bombardment target.
It is a further object to provide an improved method for production of a Ba-comprising proton bombardment target.
The project leading to this application has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 101008571 (PRISMAP - The European medical radionuclides programme) and from The Innovation Fund Denmark under grant agreement No 1046-00027 within the InnoExplorer programme.
SUMMARY OF THE INVENTION
At the DTU Hevesy Laboratory new procedures have been invented to facilitate a viable production procedure for the production of La-135 in the required amount and quality for use in TRT.
In a first aspect is provided a method for extraction of Barium (Ba) and Lanthanum (La) from an irradiated target, in a second aspect is provided a proton bombardment target, and in a third aspect is provided a method for production of a Ba-comprising proton bombardment target.
In the aspects, the terms and features relate to the terms and features having the same name in the other aspects and therefore the descriptions and explanations of terms and features given in one aspect apply to the other aspects.
In the first aspect, a method for extraction of Barium (Ba) and Lanthanum (La) from an irradiated target is provided. The method comprises the steps of: providing an irradiated target comprising Ba and La, dissolving the irradiated target in hydrochloric acid (HCI) so as to produce a precipitate of Barium Chloride (BaCh) and a supernatant, and extracting La from the supernatant. The method thus presents a purification procedure for the purification of La from a sample target comprising Ba and La.
The irradiated target is a target that has been configured for use in targeted irradiation, such as for targeted proton irradiation, and which has been irradiated by a targeted beam. In some embodiments, the irradiated target is a target that has been irradiated by a proton beam. During proton bombardment Ba-135 and Ba-136 can undergo a charged particle reaction to make La- 135, the charged particle reaction routes being: 135Ba(p,n)135La and 136Ba(p,2n)135La. Other light charged particle routes for making of La-135 from bombardment of a target comprising Ba are: 134Ba(d,n)135La and 135Ba(d,2n)135La.
In some embodiments, the irradiated target is a target as provided in the second aspect or a target produced using the method provided in the third aspect.
In some embodiments, the irradiated target is made of compressed powders.
In some embodiments, at least part of, or most of, the Ba is comprised in a Ba salt. In some embodiments, the Ba salt is Barium carbonate (BaCCh). For example, in some embodiments, more than 50% of the Ba is comprised in a Ba salt, such as more than 60% of the Ba, such as more than 70% of the Ba, such as more than 80% of the Ba. In some embodiments, the Ba is enriched with Barium-135 and/or with Barium-136.
In some embodiments, the irradiated target further comprises Aluminium (Al) powder or an Al- comprising powder. In some embodiments, the Al-comprising powder is an alloy, i.e. the powder of an alloy. In some embodiments, the irradiated target further comprises Aluminium (Al) powder having a purity equal to or above 85% trace metals basis, such as equal to or above 90% trace metals basis, such as equal to or above 95% trace metals basis, such as equal to or above 99% trace metals basis, such as equal to or above 99.5% trace metals basis. Mixing the Ba-comprising powder with an Al-comprising powder may aid in diverting heat from the Ba-comprising powder during bombardment, such as during proton bombardment. Further, the mix of an Al-comprising powder, such as an analytical grade Al powder, and a Ba salt can make it possible to produce a workable target from a hard powder such as a Ba salt.
In some embodiments, the irradiated target comprises BaCOs and Al in a predetermined w/w ratio, where the predetermined w/w ratio of BaCOs/AI is between 0.25 and 4, such as between 0.3 and 3, such as between 0.4 and 2, such as between 0.45 and 1.0.
In some embodiments, the irradiated target comprises a predetermined ratio of X/Y, where X is the combined amount of Ba and La atoms, and where Y is the amount of Al atoms, and wherein the predetermined ratio of X/Y is between 0.034 and 0.55, such as between 0.041 and 0.41 , such as between 0.055 and 0.27, such as between 0.062 and 0.14. In some embodiments, dissolving the target in HCI comprises placing the irradiated target in a first solution of HCI having a first molarity, and using a second solution of HCI having a second molarity to produce the precipitate of BaCh, wherein the second molarity is higher than the first molarity. In some embodiments, the second solution of HCI is made by increasing the molarity of the first solution of HCI.
In some embodiments, extracting La from the supernatant comprises performing a solid phase extraction (SPE) on the supernatant.
In some embodiments, the SPE comprises using a DGA resin, such as a branched DGA resin, and a TK200 resin. DGA resin and TK200 resin are commercially available resins. DGA resin comprises the functional group N,N,N’,N’-tetra-2-ethylhexyl diglycolamide. TK200 resin comprises the functional group trioctylphosphine oxide. Thus, in some embodiments, the SPE comprises using a first resin comprising the functional group N,N,N’,N’-tetra-2-ethylhexyl diglycolamide and a second resin comprising the functional group trioctylphosphine oxide.
In some embodiments, the SPE comprises the step of: passing the supernatant through first a DGA resin and then a TK200 resin. In other embodiments, the SPE comprises the step of: passing the supernatant through first a TK200 resin and then a DGA resin.
In some embodiments, using a DGA resin and a TK200 resin comprises using a single cartridge comprising both DGA resin and TK200 resin with the DGA resin being on top in the cartridge, where being on top means that the DGA resin is closer to the end of the cartridge in which liquid is added. That is, in some embodiments using the first resin and the second resin comprises using a single cartridge comprising both the first resin and the second resin with the first resin being upstream in the cartridge.
In some embodiments, the SPE comprises the steps of: washing the cartridge with a third solution of HCI having a third molarity, the third solution of HCI being configured to wash out Ba2+, and eluting the cartridge with a fourth solution of HCI having a fourth molarity, the fourth solution of HCI being configured to elute La3+.
In some embodiments, the third solution of HCI is further configured to wash out Al3+.
In the second aspect, a proton bombardment target is provided. The proton bombardment target comprises a plurality of powders pressed into a pellet, the plurality of pressed powders comprising a first powder and a second powder, the first powder comprising Barium (Ba), the first powder and the second powder being present in the target in a predetermined ratio, wherein the second powder comprises Aluminium (Al).
In some embodiments, the first powder comprises a Barium (Ba) salt.
In some embodiments, the first powder comprises Barium carbonate (BaCCh).
In some embodiments, the first powder is enriched with Barium-135 and/or with Barium-136. In some embodiments, the first powder comprises [135Ba]BaCC>3 and/or [136Ba]BaCC>3.
In some embodiments, the second powder comprises Aluminium (Al) powder having a purity equal to or above 85% trace metals basis, such as equal to or above 90% trace metals basis, such as equal to or above 95% trace metals basis, such as equal to or above 99% trace metals basis, such as equal to or above 99.5% trace metals basis.
In some embodiments, the predetermined ratio is a ratio of X/Y, where X is the combined amount of Ba and La atoms and Y is the amount of Al atoms and wherein the predetermined ratio of X/Y is between 0.034 and 0.55, such as between 0.041 and 0.41 , such as between 0.055 and 0.27, such as between 0.062 and 0.14.
In the third aspect, a method for production of a Ba-comprising proton bombardment target is provided. The method comprises: providing a first powder, the first powder comprising Barium (Ba), providing a second powder, mixing the first powder and the second powder in a predetermined ratio to produce a mixed powder, pressing a pellet comprising the mixed powder, the pellet being configured for use as a proton bombardment target, wherein the second powder comprises Aluminium (Al).
In some embodiments, the first powder comprises a Barium (Ba) salt.
In some embodiments, the first powder comprises Barium carbonate (BaCOs).
In some embodiments, the first powder is enriched with Barium-135 and/or with Barium-136.
In some embodiments, the first powder comprises [135Ba]BaCC>3 and/or [136Ba]BaCC>3.
In some embodiments, the second powder comprises Aluminium (Al) powder having a purity equal to or above 85% trace metals basis, such as equal to or above 90% trace metals basis, such as equal to or above 95% trace metals basis, such as equal to or above 99% trace metals basis, such as equal to or above 99.5% trace metals basis.
In some embodiments, the predetermined ratio is a ratio of X/Y, where X is the combined amount of Ba and La atoms and Y is the amount of Al atoms and wherein the predetermined ratio of X/Y is between 0.034 and 0.55, such as between 0.041 and 0.41 , such as between 0.055 and 0.27, such as between 0.062 and 0.14.
BRIEF DESCRIPTION OF THE DRAWINGS
In the following, exemplary embodiments of the invention are described in more detail with reference to the appended drawings, wherein:
FIG. 1 shows a flow diagram of a method for extraction of Barium (Ba) and Lanthanum (La) from an irradiated target according to some embodiments,
FIG. 2 shows a flow diagram of a method for extraction of Barium (Ba) and Lanthanum (La) from an irradiated target according to some embodiments,
FIG. 3 shows a flow diagram of part of a method for extraction of Barium (Ba) and Lanthanum (La) from an irradiated target according to some embodiments,
FIG. 4A illustrates a proton bombardment target according to some embodiments, and
FIG. 4B shows a photograph of a produced proton bombardment target according to some embodiments.
DETAILED DESCRIPTION
In the following various exemplary embodiments are described with reference to the appended drawings. The skilled person will understand that the accompanying drawings are schematic and simplified for clarity and therefore merely show details which are essential to the understanding of the invention, while other details have been left out. The elements shown in the drawings are not necessarily drawn to scale, but may primarily be illustrative of relative position, orientation, and function. Like reference numerals refer to like elements throughout. Like elements will therefore not necessarily be described in detail with respect to each figure.
FIG. 1 shows a flow diagram of a method for extraction of Barium (Ba) and Lanthanum (La) from an irradiated target according to some embodiments. In step 103 an irradiated target comprising Ba and Al is dissolved and during separation step 109 BaCh is precipitated. An extraction procedure is performed in step 125 to extract La from the supernatant. The extraction procedure could be a Solid Phase Extraction (SPE) during which La ions are eluted.
By causing the precipitation of Ba in the form of BaCh, the Ba can be reused in a new target. Making the Barium used in the target as least partially recyclable is advantageous, especially so as the Barium used in the target will usually be enriched Ba-135, which is expensive.
FIG. 2 shows a flow diagram of a method for extraction of Barium (Ba) and Lanthanum (La) from an irradiated target according to some embodiments.
In step 103 an irradiated target comprising BaCCh and Al is dissolved in a first solution of HCI having a first molarity. The first molarity may be 3 M. This produces a solution comprising BaCOs, La-135, Al and impurities dissolved in HCI. Following this, in step 105, the dissolved target is evaporated to dryness, and then, in step 107, the solid is taken up in a small amount of HCI solution, for example a few mL of HCI 0.01 M.
In a separation step 109, the solid is placed in a second solution of HCI having a higher molarity than the first solution of HCI, where the molarity of the second solution is configured to form a precipitate of BaCh. For example, the second molarity may be 8 M. Thus, in step 111 BaCh is precipitated. The precipitate is then further separated by centrifugation in step 113.
The centrifugation produces a pellet of BaCh allowing for easy removal of BaCh leaving a supernatant comprising metal ions: La-135, Al and impurities, such as e.g. Zn, Fe, and leftover Ba, dissolved in HCI. The pellet of BaCh and the supernatant can now easily be further treated separately.
This now allows the Ba to be reused in a new target. Advantageously, the Ba can be added to a new target as BaCCh. By having the Ba in the form of BaCh allows for easy recycling and conversion to BaCCh by dissolution of the BaCh in a small amount of water, step 117, and addition of (NH^CCh, step 119. In this way, BaCCh is recovered in step 121 and can be reused. Making the Barium used in the target as least partially recyclable is advantageous, especially so as the Barium used in the target will usually be enriched with Ba-135, which is expensive.
To extract La-135 from the supernatant, a Solid Phase Extraction (SPE) is performed in step 125, wherein resins having suitable functional groups are used to bind various metal ions. Depending on the HCI concentration the metal ions will form various species making it possible to load/elute them from the column(s) during the Solid Phase Extraction procedure. Advantageously, a combined column comprising both DGA resin and TK200 resin, i.e. in a single cartridge, with the DGA resin being on top can be used. As an alternative, a column comprising DGA resin and a separate column comprising TK200 resin may be used, see FIG. 3 and its description.
As a first sub-step of the SPE, the supernatant is loaded on the combined column, where the DGA resin retains the La3+ ions and lets the Al3+ ions pass through when a suitable concentration of HCI is used as eluent. The DGA resin is, however, not optimal for removing impurities such as Fe3+ ions and Zn2+ ions, which tend to at least partially follow the La3+ during a later elution step. Therefore, a TK200 resin is arranged below the DGA resin, and the TK200 resin is able to retain Fe and Zn ions when a suitable concentration of HCI is used as eluent. For use in targeted radionuclide therapy (TRT) the radionuclide La-135 will be bonded to a chelator molecule and Fe and Zn may be able to bond to the chelator as well. Thus, for some chelators it is important to reduce the amount of Fe and Zn if the produced La- 135 is to be used in targeted radionuclide therapy (TRT). Trace amounts of Al is less critical as the chelators used for La often have less affinity to bind Al.
Following this, the combined column is then washed with a third solution of HCI having a third molarity, where the third solution of HCI is configured to wash out Ba2+. Finally, in step 127, the combined column is eluted with a fourth solution of HCI having a fourth molarity, the fourth solution of HCI being configured to elute La3+.
By using a single cartridge during the SPE the time spent extracting La-135 is made significantly shorter than if more than one cartridge is used, which is highly advantageous.
In step 129, the eluted fraction is evaporated to dryness and, in step 131 , taken up in HCI, now ready for labelling.
Using the combined column of resins, where the DGA specifically separates Ba and Al from the La-135, while TK200 removes Zn and Fe, is highly advantageous and can provide a final product of radiopharmaceutical quality.
FIG. 3 shows a flow diagram of part of a method for extraction of Barium (Ba) and Lanthanum (La) from an irradiated target according to some embodiments.
As an alternative to the use of a combined column comprising both DGA resin and TK200 resin, as shown in fig. 2 and described above, the method may comprise using a column comprising DGA resin and a separate column comprising TK200 resin. An example of this according to some embodiments is shown in fig. 3, wherein the Solid Phase Extraction (SPE) in step 125 comprises first loading the supernatant on a column containing DGA resin. The column comprising DGA resin is then washed with a third solution of HCI having a third molarity, where the third solution of HCI is configured to wash out Ba2+, e.g. with 8 M HCI.
Finally, the column comprising DGA resin is eluted with a fourth solution of HCI having a fourth molarity, the fourth solution of HCI being configured to elute La3+, e.g. with 3 M HCI. This will provide an eluate comprising La and impurities such as e.g. Zn and Fe.
This eluate comprising La and impurities can then be loaded on a column containing TK200 resin and eluted again, whereby impurities such as Zn and Fe will stay on the resin, while La, which doesn’t bind to the TK200 resin, can be collected. FIG. 4A illustrates a bombardment target pellet according to some embodiments. The Ba-comprising proton bombardment target may be prepared as a pellet 1 held within a holder 3. The pellet 1 is made using a plurality of powders, which are pressed into the shape of the pellet 1. An Aluminium-comprising powder is mixed with a Barium-comprising powder, which has the possible advantages that the Al- comprising powder may aid in the packing of the Ba-comprising powder, and that the Al- comprising powder may aid in diverting heat from the Ba-comprising powder during bombardment, such as during proton bombardment.
The holder for the target pellet 1 may comprise or be made almost entirely of Silver (Ag) in the form of a disc having an indentation in which the pellet may be pressed.
FIG. 4B shows a photograph of a prepared proton bombardment target according to some embodiments. The proton bombardment target shown comprises a 1 :2 natBaCO3:AI w/w pellet 1 having a diameter of 9 mm. The target pellet was pressed in a Silver (Ag) disc 3 having a circular centre indentation. See details for the preparation in the section describing Experiment 2.
EXPERIMENTAL RESULTS
Figure imgf000011_0001
In an experiment performed using the improved purification procedure, La-135 was extracted from a 150-200 mg 1 :2 BaCO3:AI w/w target. Thus, the proton bombardment target used in the experiment comprised natural Ba; The reason for this being that enriching the Ba with Ba-135 is expensive and the experiment was done to demonstrate the efficacy of the purification method.
The target was first dissolved at 60°C in HCI 3 M. After evaporation of the dissolved target to dryness, the solid was taken up in a few mL of HCI 0.01 M. Addition of concentrated HCI (30% w/w) in order to reach an HCI concentration around 8 M, led to the precipitation of most of the Barium in the form of BaCh. The precipitate was removed by centrifugation and stored separately. This removed most of the radiochemical impurity Ba-135m.
As part of the purification procedure optimization, two successive columns were used to remove the Al as well as trace metal impurities (essentially Fe and Zn). In order to shorten the procedure time, a single column (1 mL volume) was developed. The single column was packed with a combination of two resins: a layer of TrisKem DGA resin (branched, 300 mg) on the top and TK200 (100 mg) at the bottom. The DGA resin was found to efficiently retain the La and to let the Al pass through with high concentrations of HCI as eluent; It is however not optimal for removing impurities such as Fe and Zn that tend to partially follow the La during the later elution step. The TK200 resin is able to retain Fe and Zn when HCI 3 M is used as eluent. As La can be eluted with HCI concentrations of 3 M and below the combination of both resins creates a suitable column that lets the Al be washed out first, while the trace impurities are retained during the La elution with HCI 3 M.
After removal of the Ba precipitate, the supernatant was loaded on the combined column previously washed with HCI 3 M and conditioned with HCI 8 M. The column was then washed with 20 mL HCI 8 M followed by elution of the La with HCI 3 M. The eluted fraction was evaporated to dryness and taken up in HCI 0.001 M, ready for labelling.
The remaining impurities measured by ICP-OES analysis are essentially Al (around 1.0 pg in the whole sample) and traces of La and Ba. The y spectrum of the purified sample shows the presence of three La isotopes, La-132, La-133, and La-135, as well as some Co-56, a radiochemical impurity.
Experiment 2 - proton bombardment target
As holder for the target pellet was used a Silver (Ag) disc with a diameter of 28 mm and a thickness of 5 mm. The disc had a circular centre indentation with a diameter 9 mm and a depth of 3 mm. A homogeneous natBaCO3:AI powder mixture (1 :2, w/w, 150 mg) was pressed into the centre indentation using a hydraulic press providing 0.5-1 t pressure. A photograph of the prepared target before irradiation is shown in fig. 4B.
Mixing BaCOswith Al powder has many advantages. BaCOs is a stable compound, but on its own it is difficult to press into a workable target on an Ag disc. Mixing the BaCOs with Al powder, however, facilitates the pressing of a target pellet. Further, the Al helps with heat dissipation. Experimentally, the mixing of Al powder with the BaCOs has shown that 20 pA of current could be used compared to only 10 pA of current when using a target made of pure BaCOs. Al is also a light material, which means it only provides little stopping of a proton beam. Lastly, the reaction product from a proton bombardment of Al is Si-27, which has a very short half-life (about 4 seconds), which means the reaction product will have decayed shortly after its production.
The Ag disc was mounted on a target holder with direct water cooling being supplied to the backside of the Ag disc. A 50 pm thick Niobium (Nb) foil was placed in front of the target.
The target was irradiated with a 16.5 MeV proton beam at 10-20 A for 30-120 min and left overnight on the cyclotron before handling to allow for short-lived isotopes to decay. The La- 135 activity produced at end of bombardment reached a saturation yield of 1.49 ± 0.07 GBq (or 74.73 ± 3.59 MBq/pA, n = 2, where n is the number of experiments for the data) for La-135.
Experiment 3 - proton bombardment target, larger diameter
As holder for the target pellet was used a Silver (Ag) disc with a diameter of 28 mm and a thickness of 5 mm. The disc had a circular centre indentation with a diameter 14 mm and a depth of 3 mm. A homogeneous natBaCO3:AI powder mixture (1 :2, w/w, 361 mg) was pressed into the centre indentation using a hydraulic press providing 2.5 t pressure. The Ag disc was mounted on a target holder with direct water cooling being supplied to the backside of the Ag disc. A 50 pm thick Nb foil was placed in front of the target.
The target was irradiated with a 16.5 MeV proton beam at 20 pA for 1 h and left overnight on the cyclotron before handling to allow for short-lived isotopes to decay. Unfortunately, after opening it, it was clear that the target did not withstand the heat due to its larger diameter, which reduced the thermal conductivity of the silver disc. The target material presented as black and crumbly, and the Nb foil was strongly deformed. The La-135 activity produced at end of bombardment reached 65 MBq.
Experiment 4 - proton bombardment target, larger BaCOs/AI ratio
As holder for the target pellet was used a Silver (Ag) disc with a diameter of 28 mm and a thickness of 5 mm. The disc had a circular centre indentation with a diameter 9 mm and a depth of 3 mm. A homogeneous natBaCO3:AI powder mixture (1 :1 , w/w, 152 mg) was pressed into the centre indentation using a hydraulic press providing 0.5-1 t pressure. The Ag disc was mounted on a target holder with direct water cooling being supplied to the backside of the Ag disc. A 50 pm thick Nb foil was placed in front of the target. The target was irradiated with a 16.5 MeV proton beam at 20 pA for 1 h and left overnight on the cyclotron before handling to allow for short-lived isotopes to decay. Unfortunately, after opening it, it was clear that the target did not withstand the heat due to its larger amount of BaCOs, which reduced the thermal conductivity of the target material. The target material presented as black and crumbly. The La-135 activity produced at end of bombardment reached 66 MBq.
Figure imgf000014_0001
Two experiments were performed using the purification procedure from Experiment 1 , but this time on irradiated targets that were prepared as enriched proton bombardment targets comprising [135Ba]BaCC>3 with an Ba-135 enrichment of 94.90%. Natural Ba only contains about 6.6% of Ba-135. Thus, using Ba enriched with Ba-135 will increase the amount of La- 135 made during the proton bombardment.
The BaCC>3:AI ratio was kept at 1 :2 (w/w) as in Experiment 1. One target was made to have 150 mg of the target material, while the other was made to have 200 mg of target material, and both targets were made to have a diameter of 9 mm.
As the aim of the experiment was to reach a high La- 135 activity, the target was irradiated for 4 hours with a 16.5 MeV proton beam at 20 pA. By using an enriched target the formation of multiple La isotopes is reduced and the target could be handled already 30 minutes after End of Beam (EOB). The only radionuclides detected besides La-135 were Ba-135m, Cd-107, Cs-132, and Co- 56.
The activity produced at end of bombardment ranged from 1.46 ± 0.11 GBq (150 mg target, n = 6) to 1.62 ± 0.18 GBq (200 mg target, n = 5). This corresponds to saturation yields of 10.70 ± 0.80 GBq (or 535 ± 39.96 MBq/pA) and 11.91 ± 1 .31 GBq (or 596 ± 65.63 MBq/pA), respectively.
After dissolution in HCI 3 M followed by evaporation to dryness, the solid was taken up in HCI 0.01 M. Addition of HCI 30% (w/w) led to the precipitation of most of the Ba-135 in the form of [135Ba]BaCl2. After centrifugation, followed by washing, the supernatant was loaded on a column packed with DGA resin on the top and TK200 resin at the bottom washed with HCI 3 M and conditioned with HCI 8 M prior to loading. The column was washed with HCI 8 M, and the La-135 was eluted with HCI 3 M. After evaporation to dryness, the elute fraction was taken up in HCI 0.001 M. 1.41 ± 0.10 GBq (150 mg target, n = 6) and 1.57 ± 0.20 GBq (200 mg target, n = 5) of La-135 decay corrected to time of EOB was obtained at the end of the purification.
An ICP-OES measurement showed that the procedure provided a rather clean [135La]LaCl3 formulation with Al (37.4 ± 17.5 nmol), Ba (0.3 ± 0.2 nmol), Fe (1.3 ± 2.5 nmol), Zn (1.1 ± 2.9 nmol), and La (1.3 ± 0.3 nmol) detected as total amounts of impurities in the total batch, which corresponded to a decay corrected molar activity of 1277 ± 383 MBq/nmol (150 mg target, n = 6) and 1119 ± 50 MBq/nmol (200 mg target, n = 3) and a decay corrected apparent molar activity of 28.4 ± 10.1 MBq/nmol (150 mg target, n = 6) and 86.5 ± 39.5 MBq/nmol (200 mg target, n = 3). Titrations of samples of [135La]LaCl3 with DOTA, DTPA and CHX-A”-DTPA gave decay corrected effective molar activities of 57.6 ± 15.1 MBq/nmol (150 mg target, DOTA, n = 3), 79.6 ± 25.3 MBq/nmol (200 mg target, DOTA, n = 4), 104.0 ± 40.4 MBq/nmol (200 mg target, DTPA, n = 2) and 186.5 ± 83.8 MBq/nmol (200 mg target, CHX- A”-DTPA, n = 2).
The [135Ba]BaCl2 can be recycled and converted back to [135Ba]BaCO3 by dissolution in a few mL of water and addition of Ammonium carbonate, (NH4)2CO3. After centrifugation and thorough drying, the precipitated [135Ba]BaCO3 can be used to prepare a new target.
Apart from the increased La-135 production yield, when compared with starting from a proton bombardment target comprising natural Barium as in Experiment 1 , the enriched [135Ba]BaCC>3 target material allows for a much higher radiochemical purity. La-135 was the only La isotope detected in the final sample with Co- 56 being present as a minor impurity. As the Co- 56 comes from the Fe impurity present in the Al powder used in the target, the amount of this impurity could be significantly reduced by using an Al powder of higher purity.
LIST OF REFERENCES
1 Ba-comprising proton bombardment target pellet
3 Holder for target pellet
100 method for extraction of Ba and La
103 Target dissolution
105 Evaporation
107 Uptake of dissolved target
109 Separation of precipitate
111 Precipitation of BaCh
113 Centrifugation 117 Water added 119 (NH4)2CO3 added
121 Ba recovery
125 Solid Phase Extraction
127 Elution of La3+ 129 Evaporation
131 Uptake of elute fraction

Claims

1. A proton bombardment target comprising a plurality of powders pressed into a pellet, the plurality of pressed powders comprising a first powder and a second powder, the first powder comprising Barium (Ba), the first powder and the second powder being present in the target in a predetermined ratio, wherein the second powder comprises Aluminium (Al).
2. A proton bombardment target according to claim 1 , wherein the first powder comprises a Barium (Ba) salt.
3. A proton bombardment target according to any of the previous claims, wherein the first powder comprises Barium carbonate (BaCOs).
4. A proton bombardment target according to any of the previous claims, wherein the first powder is enriched with Barium-135 and/or with Barium-136.
5. A proton bombardment target according to any of the previous claims, wherein the first powder comprises [135Ba]BaCC>3 and/or [136Ba]BaCC>3.
6. A proton bombardment target according to any of the previous claims, wherein the second powder comprises Aluminium (Al) powder having a purity equal to or above 85% trace metals basis, such as equal to or above 90% trace metals basis, such as equal to or above 95% trace metals basis, such as equal to or above 99% trace metals basis, such as equal to or above 99.5% trace metals basis.
7. A proton bombardment target according to any of the previous claims, wherein the predetermined ratio is a ratio of X/Y, where X is the combined amount of Ba and La atoms and Y is the amount of Al atoms and wherein the predetermined ratio of X/Y is between 0.034 and 0.55, such as between 0.041 and 0.41 , such as between 0.055 and 0.27, such as between 0.062 and 0.14.
8. A proton bombardment target according to any of the previous claims, wherein the Al- comprising powder is an alloy, i.e. a powder of an alloy.
9. A method for production of a Ba-comprising proton bombardment target, the method comprising: providing a first powder, the first powder comprising Barium (Ba), providing a second powder, mixing the first powder and the second powder in a predetermined ratio to produce a mixed powder, pressing a pellet comprising the mixed powder, the pellet being configured for use as a proton bombardment target, wherein the second powder comprises Aluminium (Al).
10. A method according to claim 9, wherein the first powder comprises a Barium (Ba) salt.
11. A method according to any of claims 9 - 10, wherein the first powder comprises Barium carbonate (BaCO3).
12. A method according to any of claims 9 - 11 , wherein the first powder is enriched with Barium-135 and/or with Barium-136.
13. A method according to any of claims 9 - 12, wherein the first powder comprises [135Ba]BaCO3 and/or [136Ba]BaCO3.
14. A method according to any of claims 9 - 13, wherein the second powder comprises Aluminium (Al) powder having a purity equal to or above 85% trace metals basis, such as equal to or above 90% trace metals basis, such as equal to or above 95% trace metals basis, such as equal to or above 99% trace metals basis, such as equal to or above 99.5% trace metals basis.
15. A method according to any of claims 9 - 14, wherein the predetermined ratio is a ratio of X/Y, where X is the combined amount of Ba and La atoms and Y is the amount of Al atoms and wherein the predetermined ratio of X/Y is between 0.034 and 0.55, such as between 0.041 and 0.41 , such as between 0.055 and 0.27, such as between 0.062 and 0.14.
16. A method according to any of claims 9 - 15, wherein the Al-comprising powder is an alloy, i.e. a powder of an alloy.
17. A proton bombardment target produced using the method according to any of claims 9 - 16.
18. A method for extraction of Ba and La from an irradiated target, the method comprising the steps of: providing an irradiated target comprising Ba and La, dissolving (103) the irradiated target in HCI so as to produce a precipitate of BaCI2 and a supernatant, and extracting La from the supernatant.
19. A method according to claim 18, wherein dissolving (103) the target in HCI comprises placing the irradiated target in a first solution of HCI having a first molarity, and using a second solution of HCI having a second molarity to produce the precipitate of BaCh, wherein the second molarity is higher than the first molarity.
20. A method according to any of claims 18 - 19, wherein extracting La from the supernatant comprises performing (121) a solid phase extraction (SPE) on the supernatant.
21. A method according to claim 20, wherein the SPE comprises using a first resin comprising the functional group N,N,N’,N’-tetra-2-ethylhexyl diglycolamide and a second resin comprising the functional group trioctylphosphine oxide.
22. A method according to claim 21, wherein the SPE comprises the step of: passing the supernatant through firstly the first resin and subsequently the second resin.
23. A method according to any of claims 21-22, wherein using the first resin and the second resin comprises using a single cartridge comprising both the first resin and the second resin with the first resin being on top, i.e. upstream, in the cartridge.
24. A method according to any of claims 20-23, wherein the SPE comprises the steps of: washing the cartridge with a third solution of HCI having a third molarity, the third solution of HCI being configured to wash out Ba2+, and eluting the cartridge with a fourth solution of HCI having a fourth molarity, the fourth solution of HCI being configured to elute La3+.
25. A method according to any of claims 18-24, wherein the irradiated target is made of compressed powders.
26. A method according to any of claims 18-25, wherein at least part of the Ba is comprised in a Ba salt.
27. A method according to any of claims 18-26, wherein most of the Ba is comprised in a Ba salt.
28. A method according to any of claims 26 - 27, wherein the Ba salt is Barium Carbonate (BaCO3).
29. A method according to any of claims 18 - 28, wherein the Ba is enriched with Barium- 135 and/or with Barium-136.
30. A method according to any of claims 18 - 29, wherein the irradiated target further comprises Aluminimum (Al), such as Al powder or an Al-comprising powder.
31. A method according to claim 30, wherein the Al-comprising powder is an alloy, i.e. a powder of an alloy.
32. A method according to any of claims 30 - 31 , wherein the irradiated target further comprises Aluminium (Al) powder having a purity equal to or above 85% trace metals basis, such as equal to or above 90% trace metals basis, such as equal to or above 95% trace metals basis, such as equal to or above 99% trace metals basis, such as equal to or above 99.5% trace metals basis.
33. A method according to any of claims 30 - 32, wherein the irradiated target comprises BaCOs and Al in a predetermined w/w ratio, where the predetermined w/w ratio of BaCOs/AI is between 0.25 and 4, such as between 0.3 and 3, such as between 0.4 and 2, such as between 0.45 and 1.0.
34. A method according to any of claims 31-33, wherein the irradiated target comprises a predetermined ratio of X/Y, where X is the combined amount of Ba and La atoms, and where Y is the amount of Al atoms, and wherein the predetermined ratio of X/Y is between 0.034 and 0.55, such as between 0.041 and 0.41 , such as between 0.055 and 0.27, such as between 0.062 and 0.14.
35. A method according to claim 24, wherein the third solution of HCI is configured to wash out Al3+.
36. A method of producing La-135 according to any of claims 18 - 35, the method further comprising:
- providing a target according to any of claims 1 - 8, or providing a target produced according to any of method claims 9 - 17,
- irradiating the provided target with a proton beam to produce an irradiated target comprising Ba and La.
PCT/EP2023/067985 2022-07-01 2023-06-30 Production of the radionuclide lanthanum-135 WO2024003344A1 (en)

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