Method for the production of high purity SC-47 with intermediate energy cyclotrons (35 MEV) through a multi-layer target

Abstract

The invention intends to provide a method for the production of 47Sc which has been optimized through the use of proton beams up to 35 MeV, thus both maximizing the direct production of 47Sc and minimizing the production of 46Sc and 48Sc. Another object of the present invention is to provide a target for the production of 47Sc which is neither entirely made of 50Ti nor entirely made of natural V (natV).

Description

[0001] TITLE

[0002] METHOD FOR THE PRODUCTION OF HIGH PURITY SC-47 WITH INTERMEDIATE ENERGY CYCLOTRONS (35 MEV) THROUGH A MULTI-LAYER TARGET

[0003] TECHNICAL FIELD

[0004] The present invention relates to the field of radionuclide production.

[0005] In particular, the present invention concerns the production of radionuclides for medical use.

[0006] The present invention is intended for production of47Sc with radionuclide purity higher than attainable with prior-art techniques.

[0007] BACKGROUND ART

[0008] Production of the47Sc radionuclide is of much interest in nuclear medicine, both for metabolic radiotherapy, which exploits its low-energy P" emission, and for imaging diagnostics in Single-Photon Emission Computed Tomography (SPECT), which exploits its low-energy y emission. In combination with the43Sc and44Sc radionuclides, which are known tracers employed for Positron Emission Tomography (PET), it can be used for a customized combined therapeutic and diagnostic approach known as theranostics (theragnostics). At present, most tested procedures for the production of radiopharmaceuticals containing emitters consisting of trivalent metals (Y, Lu, ...) are also applicable to scandium, so that it is not necessary to develop new specific molecules for this metal, which can thus be easily used in treatment procedures.

[0009] Various methods of production of47Sc are currently being studied, whether using nuclear reactors or particle accelerators, but no optimal method exists yet which permits producing47Sc with such yield and purity that make it suitable for medical use. In particular,47Sc can be produced through different nuclear reactions using a nuclear reactor, a linear electron accelerator, or a cyclotron [Mikolajczak, R., Huclier-Markai, S., Alliot, C. et al. EJNMMI radiopharm. chem. 6, 19 (2021)].

[0010] Production by means of a nuclear reactor exploits the47Ti(n,p)47Sc nuclear reaction by irradiating a47Ti target with fast neutrons (with energy higher than 1 MeV) to produce47Sc. The applicability of this method is limited by the poor availability of plants capable of providing a source of fast neutrons. Alternatively, it is possible to produce47Sc by irradiating a46Ca target with thermal neutrons, according to the46Ca(n,y)47Ca ->47Sc reaction. Such method is limited by the cost of46Ca targets and their low enrichment level. Production by means of photonuclear reactions, also referred to as photoproduction, uses an electron beam generated by a linear accelerator, which is made to collide with a tungsten element to produce braking y radiation, or bremsstrahlung, which is then used to irradiate targets made of natural Ti or48Ca in order to produce47Sc according to the48Ti(y,p)47Sc or48Ca(y,n)47Ca ->47Sc reactions, respectively. Such methods are limited by poor interaction between photons and matter, resulting in low yield and requiring very long irradiation times or the use of high-mass, and hence very expensive, targets.

[0011] Cyclotron-based production can be effected by irradiation with a particles or deutons or protons [G Pupillo et al. (2022), Nuclear data for light charged particle induced production of emerging medical radionuclides, https: / / doi.org / 10.1515 / ract-2022-0011]. Production by means of proton beams occurs through irradiation of a48Ti target, exploiting the48Ti(p,2p)47Sc reaction. The most important limitation of this reaction is coproduction of46Sc, which is a y emitter and causes problems in controlling the radiation dose when the material is used as a radiopharmaceutical. Some alternative reactions which can be employed for the production of47Sc make use of targets of48Ca or natural V irradiated with protons. Usually, increasing proton energy leads to higher radionuclide production to the detriment of the purity of the produced radionuclide, because as energy increases new reaction channels are opened, which produce further radioisotopes. Production of isotope contaminants is particularly troublesome, in that they jeopardize production purity and cannot be removed by radiochemical purification.

[0012] At present, all methods are affected by the presence of contaminating radionuclides co-produced during the reaction. Therefore, the need is still felt for identifying a method and a target for47Sc production with high yield and purity. Production estimates for the radionuclides of interest for the present invention were developed by using the TALYS nuclear reaction code (version 1.96; www.talys.eu) with calculation validation based on measured data available in the literature. In particular, the optimized calculations reported in the reference [F. Barbaro, L. Canton, M. P. Carante, A. Colombi, L. De Dominicis, A. Fontana, F. Haddad, L. Mou, and G. Pupillo, New results on proton-induced reactions on vanadium for 47Sc production and the impact of level densities on theoretical cross sections Phys. Rev. C 104, 044619 - (2021); https: / / doi.org / 10.1103 / PhysRevC.104.044619] were used for the calculations concerningnatV. Evaluations about50Ti were made by using the TALYS code (vl.96) validated and optimized with reference to the recent measurements reported in [G. Dellepiane et al,47Sc and46Sc cross-section measurement for an optimized47Sc production with an 18 MeV medical PET cyclotron, Applied Radiation and Isotopes, (2022); https: / / doi.Org / 10.1016 / i.apradiso.2022.110428]. Analyses of yields and purities produced by the irradiation conditions discussed in the present invention were conducted as described in the reference [Canton, L., Fontana, A. Nuclear physics applied to the production of innovative radiopharmaceuticals. Eur. Phys. J. Plus 135, 770 (2020). https: / / doi.org / 10.1140 / epjp / sl3360-020-0073Q-z]. OBJECTS OF THE INVENTION

[0013] It is one object of the present invention to overcome the drawbacks of the prior art.

[0014] In particular, it is one object of the present invention to provide a method for the production of47Sc which has been optimized through the use of proton beams up to 35 MeV, thus both maximizing the direct production of47Sc and minimizing the production of46Sc and48Sc. Another object of the present invention is to provide a target for the production of47Sc which is neither entirely made of5(>Ti nor entirely made of natural V (natV).

[0015] These and other objects of the present invention are achieved through a method and a target incorporating the features set out in the appended claims, which are an integral part of the present description.

[0016] The inventors discovered the possibility of using two different materials for a target for the production of the47Sc radionuclide.

[0017] Advantageously, the present invention is industrially applicable to produce thick targets which are useful to optimize the production of47Sc, specifically for medical applications.

[0018] In addition, the present invention advantageously promotes the industrial development of automatic modules for extraction and purification of47Sc from the irradiated material.

[0019] Further advantageous features of the method and target will become apparent in light of the detailed description that follows.

[0020] DETAILED DESCRIPTION OF THE INVENTION

[0021] While the invention is susceptible of several modifications and alternative constructions, the following will describe in detail some preferred, but non-limiting and merely illustrative, embodiments thereof.

[0022] It is nevertheless understood that there is no intention to limit the invention to the specific embodiments shown herein. On the contrary, the invention is meant to cover any modifications or equivalent alternative constructions falling within the scope of the invention as set out in the claims.

[0023] In the following description, therefore, the use of "for example", "etc.", "or" will indicate, unless otherwise stated, non-exclusive and non-limiting alternatives. Unless otherwise specified, "also" will mean "including, but not limited to". Unless otherwise specified, "includes / comprises" will mean "includes / comprises, without being limited to". In the present description, the expression "chemical unit" refers to an apparatus or a system in which a chemical reaction or a series of chemical reactions occur; in particular, this expression indicates herein a radiochemical laboratory equipped with devices dedicated to radiopharmaceutical production.

[0024] In the present description, the expression "nuclear reaction" refers to the physical process of interaction between the protons of an incident beam and the atoms of the target material.

[0025] In the present description, the expression "shock cross-section" refers to the probability that, as the energy of the incident beam varies, a certain nuclear reaction will occur.

[0026] The inventive concept at the basis of the present invention is to use two different material layers as a target for the production of the47Sc radionuclide, thereby reducing the co-production of48Sc and46Sc contaminants.

[0027] More specifically, the inventors have conceived a novel method and a novel target for47Sc production, utilizing cyclotrons that can provide up to 35 MeV of proton energy. The method can also be used in the presence of accelerators with proton beams having energy in excess of 35 MeV, by employing a further layer, e.g. made of aluminium or graphite, to be positioned in front of the composite50Ti-natV target, for the purpose of degrading the proton energy down to the 35 MeV necessary for irradiating the composite target. As will be explained hereafter, it is also possible to employ cyclotrons with proton beams having energy lower than 35 MeV.

[0028] The inventors have verified, in fact, that by aligning a5(>Ti target with a target made of natural vanadium (natV) when, as energy increases, the production resulting from the50Ti(p,a)47Sc reaction becomes disadvantageous because of co-production of contaminants, production thorugh thenatV(p,x)47Sc reaction starts being effective, and such reaction remains favourable and advantageous up to an energy of the incident protons of 35 MeV.

[0029] As aforesaid, the method and the target according to the present invention, as conceived by the present inventors, make it possible to maximize the production of47Sc and minimize the co-production of48Sc and46Sc by using accelerated proton beams with a maximum energy of 35 MeV.

[0030] According to the generally preferred embodiment of the method according to the present invention, illustrated in FIG. 1, a multi-layer target 1 is provided, which comprises a first layer 2, in turn comprising vanadium having the natural isotope composition (natV), and a second layer 3, in turn comprising titanium enriched in50Ti, placed adjacent to the first layer 2, so as to cover the 35-22 MeV energy range (for the target made ofnatV) and, respectively, the 22-9 MeV energy range (for the target made of5(>Ti); in such specific energy ranges, the47Sc / (46Sc+47Sc+48Sc) production ratio is maximized regardless of irradiation times (as can be inferred from the shock cross-section ratios shown in FIG. 2). The layer 2 may be made ofnatV in metallic form or vanadium oxide.

[0031] Likewise, the layer 3 of titanium enriched in5(>Ti may be made of Ti in metallic form or titanium oxide.

[0032] For proton beams having energy in excess of 35 MeV, in front of thenatV layer a further layer 4 of absorbing material is added, the thickness of which is such as to reduce the energy of the proton beam down to 35 MeV at thenatV layer. Some examples of absorbing materials are graphite and aluminium.

[0033] The method for the production of47Sc according to the present invention further includes: i. providing a proton beam 5; ii. exposing, for a predetermined time, the target 1 to said proton beam 5 on the side of the first layer 2, so that the proton beam 5 will pass through, in succession, the first layer 2 and the second layer 3; ill. subjecting the target 1 to a radiochemical treatment in a radiochemical unit 6.

[0034] The proton beam 5 collides with the surface of the layer 2 at an energy of 35 MeV, and the thickness of the layer 2 is such that the proton beam 5 going through it will arrive at the second layer 3 with, preferably, an energy of 22 MeV. If the proton beam has an energy higher than 35 MeV, an additional absorbing layer 4, e.g. made of graphite or aluminium, is placed before the layer 2, the thickness of which is such as to reduce the energy of the proton beam and cause it to collide with the surface of the layer 2 at an energy of 35 MeV.

[0035] One may also choose to increase the thickness of the layer 2 in order to have the proton beam reach the layer 3 with an energy of less than 22 MeV. In such a case, a smaller quantity of47Sc will be produced, but its radionuclide purity will be higher. With the specified thickness of the layer 3, the output energy of the proton beam is 9 MeV. By increasing the thickness, it could be possible to reach even lower output energy values. However, it should be taken into account that, for such energy values, residual production of47Sc in5(>Ti is minimal, and therefore any further increase in the thickness of the target 3, resulting in lower proton output energy, would not lead to appreciable results in relation to the produced quantity.

[0036] The following Table 1 lists the optimal thickness values that maximize the yield of47Sc in each energy range, considering proton beams with an initial energy of 35 MeV and 30 MeV.

[0037] Table 1: Thicknesses of thenatV and50Ti layers when the enriched material is oxide or metal.

[0038]

[0039] When compared with a target entirely made ofnatV in the whole 35-9 MeV range, a target composed of a first layer ofnatV and a second layer of50Ti like the target 1 according to the present invention gives a47Sc production increase of approximately 300% along with a non-significant increase in46Sc+48Sc co-production; such estimates were made considering an irradiation time of 1 hour, corresponding to a47Sc saturation factor of 0.93%.

[0040] This advantage makes it possible to produce larger amounts of47Sc of high radionuclide purity, the irradiation conditions being equal, in comparison with a target wholly made ofnatV.

[0041] By way of non-limiting example, the optimum target 1 for covering the entire 35-9 MeV energy range preferably comprises:

[0042] - first layer 2:natV; 1.62 mm (metallic form); 35-22 MeV.

[0043] - second layer 3:5(>Ti; 1.40 mm (metallic form) or 2.49 mm (TiCh oxidized form); 22-9 MeV

[0044] - Several methods of radiochemical treatment, to which the target 1 can be subjected in the radiochemical unit 5 in order to extract scandium from titanium and / or vanadium, are known in the literature [Mikolajczak, R. et al., EJNMMI radiopharm. chem. 6, 19 (2021); C.S. Loveless et al. (2021), https , which envisage the use of combinations of resins to extract and purify the radionuclide of interest.

[0045] In particular, it must be pointed out that, since the target 1 is a multi-layer one, the two layers ofnatV and50Ti have to be kept separate from each other and individually subjected to the radiochemical treatment, so that the material enriched in50Ti can subsequently be recovered and reused to lower the production costs.

[0046] The final solutions, obtained from the radiochemical treatment of the layers 2 and 3 that compose the target 1, can then be mixed and used together, since they all contain47Sc of high radiochemical purity.

[0047] With reference to FIG. 1, which schematically shows an equipment for implementing the above-described method, such equipment comprises: - an apparatus for emitting a proton beam 5;

[0048] - a target 1, in turn comprising:

[0049] - a first layer 2 of natural vanadium (natV), and

[0050] - a second layer 3 of titanium enriched in50Ti; and

[0051] - a radiochemical unit 6.

[0052] As aforesaid, the proton beam 5 passes through, in succession, the first layer 2 and the second layer 3.

[0053] The target 1 exposed to the proton beam 5 with 35 MeV energy (output energy of 9 MeV) for an irradiation time of 1 hour yields a47Sc content of 12.962 MBq / pA and a (46Sc +48Sc) and a content of (0.064 + 0.0015) MBq / pA, corresponding to a radionuclide purity of 99.45%.

[0054] In comparison, a target wholly made ofnatV yields, under the same irradiation conditions (35 MeV proton beam, with output energy of 9 MeV, and irradiation for 1 hour), a47Sc content of 4.227 MBq / pA and a (46Sc +48Sc) content of (0.016 + 0.0005) MBq / pA is obtained, corresponding to a radionuclide purity of 99.59%.

[0055] When exposed to a proton beam 5 with 30 MeV energy (output energy of 9 MeV) for an irradiation time of 1 hour, the target 1 yields a47Sc content of 10.273 MBq / pA and a (46Sc +48Sc) content of (0.0486 + 0.001) MBq / pA, corresponding to a radionuclide purity of 99.46%.

[0056] In comparison, a target wholly made ofnatV yields, under the same irradiation conditions (30 MeV proton beam, with output energy of 9 MeV, and irradiation for 1 hour), a47Sc content of 1.538 MBq / pA and a (46Sc +48Sc) content of (0.0006 + 0.0000007) MBq / pA, corresponding to a radionuclide purity of 99.96%.

[0057] Therefore, by using the target 1 according to the present invention, and considering a proton beam 5 with 35 MeV energy (output energy of 9 MeV) irradiated for 1 hour, an increase in the production of47Sc of approximately 300% is obtained, with a radionuclide purity comparable with that obtainable from a target wholly made ofnatV.

[0058] The use of a proton beam 5 with 30 MeV energy (output energy of 9 MeV), irradiated for 1 hour, results in an increase in the production of47Sc of 670%, with radionuclide purity of 99.465%, which is only negligibly less than can be obtained from a target wholly made ofnatV, i.e. 99.96%.

[0059] In other words, advantageously, the target 1 according to the present invention is intended for production of47Sc with a47Sc content much exceeding, and a radionuclide purity comparable with, those obtainable from prior technical solutions, which make use of neutrons produced by nuclear reactors or accelerated electron beams, with a higher yield than attainable by using techniques employing accelerated proton beams on targets consisting of a single layer of material, such as, for example, natural vanadium (natV). By way of example, if we compare the production of47Sc provided by the present invention with the technique that uses proton beams incident on a target of natural vanadium (natV), assuming an irradiation time of 1 hour and a 35 MeV proton beam (target output energy of 9 MeV), the target made in accordance with the present invention yields a production of 12.962 MBq / pA of47Sc with a (46Sc +48Sc) content of (0.064 + 0.0015) MBq / pA and a radionuclide purity of 99.45%, while a target wholly made ofnatV yields, under the same irradiation conditions, a47Sc content of 4.227 MBq / pA and a (46Sc +48Sc) content of 0.016 + 0.0005) MBq / pA, i.e. a radionuclide purity of 99.59%. Productivity increases, therefore, by 300%.

[0060] In the case wherein the proton beam 5 has 30 MeV energy (output energy of 9 MeV), for an irradiation time of 1 hour, the production of47Sc obtained in accordance with the present invention is 10.273 MBq / pA and the (46Sc +48Sc) content is (0.0486 + 0.001) MBq / pA, to be compared with a target wholly made ofnatV, which, under the same irradiation conditions, yields a production of47Sc amounting to 1.538 MBq / pA and a (46Sc +48Sc) content amounting to (0.0006 + 0.0000007) MBq / pA. A 670% increase in the production of47Sc is thus obtained, with a radionuclide purity of 99.465 %, which is suitable for medical applications, though slightly lower than obtainable from a target wholly made ofnatV, i.e. 99.96%.

[0061] The estimated results are summarized in Table 2.

[0062] Table 2: Production of47Sc and main contaminants under the two irradiation conditions selected as examples, assuming an irradiation time of 1 hour.

[0063] It must be taken into account that large quantities of 100% enriched titanium are not commercially available. Therefore, the use of an isotope composition of the target consisting of 98%50Ti and 2%49Ti was also considered. The use of49Ti was taken into consideration because, among all isotopes, it is the one that produces the largest amount of46Sc, which is the most critical contaminant.

[0064] By way of example, the production of47Sc in accordance with the present invention can be compared between the cases of 98% enrichment and 100% enrichment in50Ti.

[0065] Considering an irradiation time of 1 hour and a 35 MeV proton beam (target output energy of 9 MeV), the target made in accordance with the present invention, but with 98% enrichment of the layer 3, yields a production of 12.786 MBq / pA of47Sc, with a (46Sc +48Sc) content of (0.072 + 0.0045) MBq / pA, i.e. a nucleotide purity of 99.35%, while a target in which the layer 3 is wholly made of50Ti yields, under the same irradiation conditions, a47Sc content of 12.962 MBq / pA and a (46Sc +48Sc) content of (0.064 + 0.0015) MBq / pA, i.e. a nucleotide purity of 99.45%. Therefore, productivity decreases by only 1.36%, while the decrease in radionuclide purity is as small as 0.1% (Errore. L'origine riferimento non e stata trovata.).

[0066] Table 3: Comparison between two different levels of enrichment in50Ti for the multi-layer targets of the present invention The target 1 according to the present invention can be made by using methods known in the literature. Merely by way of example, reference can be made to the assembly procedure for making a target for radionuclide production described in detail in [C.S. Loveless et al. (2021), https: / / doi.org / 10.2967 / jnumed.120.242941; G. Dellepiane et al. (2022), https: / / doi.Org / 10.1016 / j.apradiso.2022.110428],

[0067] It is apparent from the above detailed description of the method and target according to the present invention that the latter makes it possible to optimize47Sc production in the 35-9 MeV energy range, both by maximizing the direct production of47Sc and by minimizing the production of46Sc +48Sc compared with a target wholly and exclusively made ofnatV.

[0068] While the present invention has been illustrated, described and defined herein with reference to some preferred embodiments thereof, any references and implementation examples in the above description should not be assumed to limit the invention by any means; it is clear, in fact, that many modifications and variations are possible without departing from the broader protection scope of the technical concept illustrated herein.

[0069] The preferred embodiments illustrated herein are merely explanatory and do not bound the protection scope of the technical concept presented herein; therefore, the protection scope is not limited to the preferred embodiments described in the detailed description, being exclusively limited by the claims that follow.

Claims

CLAIMS1. Method for the production of47Sc comprising the following steps:- providing a target (1) comprising:- a first layer (2) ofnatV, and- a second layer (3) comprising titanium enriched in50Ti placed adjacent to said first layer;- providing a proton beam (5);- exposing, for a predetermined time, the target (1) to said proton beam (5) on the side of the first layer (2), so that the proton beam (5) will pass through, in succession, the first layer (2) and the second layer (3);- subjecting the target (1) to a radiochemical treatment for purification of the products.

2. Method according to claim 1, wherein said target (1) further comprises a third layer of absorbing material (4) placed before said layers (2) and (3), so that the proton beam passing through said layer (4) will reach the surface of said first layer (2) with energy equal to or lower than 35 MeV and preferably ranging between 30 and 35 MeV.

3. Method according to claim 1 or 2, wherein the thickness of said first layer (2) is such that said proton beam (5) crossing it will reach said second layer (3) with energy lower than 30 MeV, preferably with energy equal to or lower than 22 MeV.

4. Target (1) for the production of47Sc by irradiation thereof with a proton beam in the 35-9 MeV energy range, comprising:- a first layer (2) comprisingnatV;- a second layer (3) comprising50Ti;5. Target according to the preceding claim, further comprising:- a third layer of absorbing material (4) placed before said first (2) and second (3) layers.

6. Target (1) according to one of claims 4 or 5, wherein the first layer (2) is made ofnatV in metallic form.

7. Target (1) according to one of claims 4 to 6, wherein the second layer (3) comprises titanium enriched in5(>Ti in metallic form.

8. Target (1) according to one of claims 4 to 6, wherein the second layer (3) comprises titanium oxide enriched in50Ti.

9. Target (1) according to claim 6, wherein the first layer (2) has a thickness ranging between 0.93 mm and 1.62 mm.

10. Target (1) according to claim 7, wherein the second layer (3) has a thickness equal to about 1.40 mm.

11. Target (1) according to claim 8, wherein the second layer (3) has a thickness equal to about 2.49 mm.

12. Target (1) according to one of the preceding claims, wherein the third layer (4) is made of aluminium.

13. Target (1) according to one of the preceding claims, wherein the third layer (4) is made of graphite.

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