Accelerator driven neutron activator for brachytherapy

Abstract

A neutron activator for neutron activation of a material, the neutron activator being configured to produce neutrons by interaction with a proton beam (7), the neutron activator comprising: - a neutron source comprising a metal target (1), and - a beryllium first reflector-slower (4) located at the periphery of the neutron source and comprising a neutron activation zone (10) configured to house the neutron source and the material to be activated, the neutron activation zone (10) of the first reflector-slower (4) comprising an aperture configured to house the neutron source.

Description

[0001] This application is a divisional application of PCT application No. PCT / EP2018 / 060416, filed on April 24, 2018, and entered into the Chinese national phase on October 24, 2019, under the national application No. 201880027293.9, entitled “Accelerator-driven neutron activator for brachytherapy”. TECHNICAL FIELD

[0002] The field of the invention is the field of activating a dose of injectable granule suspension by preparing a suitable neutron field.

[0003] The invention particularly relates to a neutron activator for the production of a target radioisotope, the working principle of which is based on the interaction of a proton beam with a solid target, which produces neutrons, which are then slowed down / reflected in a solid assembly to obtain a favorable neutron spectrum for the (n, y) reaction of the target isotope (e.g. 165 Ho and 176 Lu). BACKGROUND

[0004] The treatment of cancer tumors is based on three main categories of treatment (usually used in combination to increase the chances of recovery): surgery, chemotherapy and external radiotherapy.

[0005] In addition to surgical intervention or chemotherapy (as in breast tumors or cervical tumors), it is usually recommended to perform brachytherapy or "in situ" radiotherapy, or as an alternative, to constitute the sole first-line treatment (as in the treatment of prostate cancer, liver cancer or other liver tumors in the United States).

[0006] Rapidly dividing cells are particularly sensitive to radiation damage. Thus, it is possible to control or eliminate some cancer cell growth by administering or implanting small radioactive sources, usually gamma or beta emitters, within the target area.

[0007] The main advantages of brachytherapy are that they expose the human body to less total radiation, expose healthy tissues to a minimum and are more localized to the target tumor, and are cost-effective.

[0008] Radioisotopes emitting beta - rays can be produced by neutron irradiation of the corresponding stable isotopes.

[0009] At present, such isotopes are only produced in research nuclear reactors, but the main drawback is the low reactor utilization for medical use in Europe, combined with time crunch and aging problems.

[0010] Therefore, there is still a need for an alternative method for the efficient production of neutron-activated radioisotopes for medical applications using a cyclotron.

[0011] One object of the present disclosure is to propose an alternative method of producing radioisotopes for medical use in a nuclear reactor.

[0012] Another object is to improve the efficiency of the method of producing radioisotopes for medical use.

[0013] Another object of the present invention is to provide a device and a method for the neutron activation of a material to produce radioisotopes.

[0014] WO 98 / 59347 discloses a material exposed to a neutron flux by distributing the material in a neutron diffusion medium around a neutron source, which can be used to produce useful radioisotopes from the transmutation of readily available isotopes contained in the exposed material, in particular for medical applications. The neutron source consists of a beryllium or lithium target bombarded by a charged particle beam.

[0015] The main drawback of this method is that the size of the activator is very large to contain the neutrons in the material in the elastic scattering path in the system. This also leads to a corresponding dilution of the neutron flux, in particular at lower energies (after several scattering interactions).

[0016] WO 2016 / 037656 discloses a method and an activator that enhance the capture in the resonance region. The intensity of the neutron flux is optimized by reflectors and / or moderators.

[0017] With regard to WO 98 / 59347, it proposes some general methods aimed at taking advantage of the neutron elastic scattering properties of lead and thus of the adiabatic resonance crossing principle in the activation zone, while reducing the size of the activator. The inventors have carried out numerical and experimental analyses of this method from 2005 to 2009 and have experimentally validated an activator with lead nuclei and graphite reflectors. The results of such studies led to the conclusion that the most efficient method to activate the considered isotopes is not to take advantage of the particular properties of lead (transparency and elastic scattering), but to focus on efficient moderation-reflection, which provides the solution of the present invention. Furthermore, in the preferred embodiment of the present invention, the optimal position of the sample is as close as possible to the proton target, and not at a specific position in the so-called diffuser.

[0018] WO 2016 / 022848 discloses a neutron source comprising a spherical metal target and a spherical reflector-moderator surrounding the target, the target and the reflector-moderator being immersed in a medium containing the material to be activated.

[0019] Using the neutron source of WO 2016 / 022848, the material is activated randomly, which increases the time of activating the material and does not allow obtaining a large amount of activated material. In addition, the recovery of the activated material is complex and not suitable for radioisotopes suitable for nuclear medicine therapy with short half-life, as in the case of the present invention. The configuration of the neutron activator, in particular the position of the reflector of WO 2016 / 022848, will not allow an advantageous activation rate of radioisotopes other than Mo-99 by the following neutron capture reaction Mo-98(n, y)Mo-99. The size of the reflector and the material based on the potential, such as heavy water as described in the description, implies a complexity of the industry and maintenance, as well as hindering a compact process. Finally, the cooling process involves a cryogenic method, as opposed to the use of water cooling, which will result in a more complex use and maintenance.

[0020] Therefore, another object of the present disclosure is to provide an improved system compared to the activators disclosed in WO 98 / 59347, WO 2016 / 037656 and WO 2016 / 022848. SUMMARY

[0021] These and other objects are achieved by the presently disclosed neutron activator for neutron activation of a material, configured to produce neutrons by interaction with a proton beam emitted along a beam axis, the proton beam having an energy of 16 MeV to 100 MeV, preferably 30 MeV to 70 MeV, and a beam intensity of up to 1 mA, preferably up to 350 eV for 70 MeV and up to 1 mA for 30 MeV, the neutron activator comprising:

[0022] - a neutron source comprising a metal target having a longitudinal axis intended to be arranged parallel to, in particular coaxial with, the beam axis, and

[0023] - a beryllium reflector-decelerator located at the periphery of the neutron source and comprising a neutron activation zone configured to accommodate the neutron source and a material to be activated, the neutron activation zone of the beryllium reflector-decelerator comprising a bore extending along a bore axis and configured to accommodate the neutron source such that the bore axis and the longitudinal axis are coaxial.

[0024] The neutron activation zone of the beryllium reflector-decelerator can further comprise at least one activation channel extending along a channel axis parallel to the bore axis in the vicinity of the bore, the activation channel being configured to be loaded with a material to be activated.

[0025] The neutron activation zone can comprise a plurality of activation channels distributed, in particular uniformly distributed, around the bore.

[0026] The metallic target can have a hollow conical shape, the longitudinal axis of the conical target being aligned with the proton beam, and the neutron activator further comprises a cooling zone in direct contact with the outer surface of the target for receiving a flow of fluid for cooling the target during the neutron production process. The cooling fluid can be a liquid, such as water. The provision regarding the shape of the metallic target can be in addition to or in replacement of the aforementioned provision regarding the beryllium reflector-degrader. That is, the shape of the metallic target can be provided independently of the provision regarding the beryllium reflector-degrader.

[0027] In these embodiments, the opening of the conical target and the thickness of its lateral wall can be optimized so that (i) the portion of protons received from the proton beam has sufficient energy to release a portion of thermal energy corresponding to a Bragg peak outside the target,

[0028] (ii) the power density inside the target is reduced by at least 50% compared to the power density inside the target for all protons received from the proton beam to release their thermal energy inside the target, and

[0029] (iii) the number of neutrons produced inside the target is equal to at least 70% of the number of neutrons produced inside the target with a thickness for which all protons received from the proton beam release their thermal energy inside the target.

[0030] Alternatively, the opening of the conical target and the thickness of its lateral wall can be optimized so that

[0031] (i) the protons received from the proton beam lose all their energy inside the metallic target, and

[0032] (ii) the stress generated by the temperature gradient inside the target is kept within the elastic limit of the metallic target while still keeping the cooling liquid temperature below the boiling point.

[0033] Advantageously, the opening of the hollow conical target is between 20 targets and 45 targets.

[0034] The neutron activator can further comprise, housed in the reflector-degrader:

[0035] - an inlet channel for delivering a cooling fluid to the flow director,

[0036] - a flow director delimiting a cooling zone for guiding the cooling fluid along the outer surface of the target and obtaining the required flow rate of the flow from the inlet channel to the outlet channel,

[0037] - an outlet channel for removing the cooling fluid from the flow director.

[0038] Preferably, the aforementioned flow director is at least partially conical so that said conical flow director covers the outer surface of the conical target, thereby delimiting a cooling zone around the outer surface of the target.

[0039] In a particular embodiment, which can be combined with any of the aforementioned embodiments, the metallic target is made of beryllium or tantalum.

[0040] In a particular embodiment, which can be combined with any of the preceding embodiments, the beryllium reflector-decelerator is cylindrical along the bore axis.

[0041] Typically, the overall size of the neutron activator is the volume of a cube of not more than 1 meter side, preferably 0.75 meter side, for example 0.50 meter side.

[0042] The neutron activator can further comprise a second reflector-decelerator embedded in said beryllium reflector-decelerator.

[0043] The present invention also relates to a neutron activation system for the neutron activation of a material, comprising:

[0044] - a generator configured to produce a proton beam along a beam axis, the energy of the proton beam being comprised between 16 MeV and 100 MeV, preferably between 30 MeV and 70 MeV, and the beam intensity being at most 1 mA, preferably at most 350 pA for 70 MeV and at most 1 mA for 30 MeV,

[0045] - a neutron activator arranged as previously defined, which makes the longitudinal axis of the target parallel to the beam axis, in particular coaxial with the beam axis.

[0046] When the neutron activation zone of the beryllium reflector-decelerator comprises at least one activation channel, the neutron activation system can further comprise a supply device for loading the material to be activated, the supply device being connected to the activation channel and being configured to move the material sample along the activation channel.

[0047] The present invention also relates to the use of a neutron activator as previously described for the production of a radioisotope, preferably a radiopharmaceutical. For example, the radioisotope is a radioisotope emitting beta - rays suitable for nuclear medicine applications, preferably 166 Ho, 186 Re, 188 Re, 177 Lu, 198 Au, 90 Y, 227 Ra and 161 Tb.

[0048] Another object of the present invention is a method for the neutron activation of a material, said method comprising:

[0049] a) providing a material to be activated,

[0050] b) placing the material in the activation zone of the neutron activator as previously defined,

[0051] c) producing a proton beam at an energy suitable for the neutron activation of said material,

[0052] thereby activating said material.

[0053] In a particular embodiment of the above method using a neutron activator with a conical target as described above, the target is cooled by a flow of cooling liquid, preferably water, at a static pressure of 1 to 20 bar and at a velocity close to the target surface of 8 to 15 m / s.

[0054] In another particular embodiment of the method, said material to be activated is contained in or in the form of microparticles or nanoparticles, for example holmium oxide microparticles / nanoparticles. Typically, the microparticles / nanoparticles are in a liquid suspension.

[0055] In a particular embodiment, said material is contained in capsules and said capsules are placed in the activation zone by moving the capsules within an activation channel embedded in the reflector-decelerator. BRIEF DESCRIPTION OF DRAWINGS

[0056] The present application will be more clearly understood from the following detailed description of preferred but non-limiting embodiments. This detailed description is given with reference to the accompanying drawings, in which:

[0057] - Figure 1 is a schematic view of a neutron activator according to the present disclosure,

[0058] - Figure 2 is a schematic view of a cylindrical target assembly comprising a hollow conical target and its cooling system,

[0059] - Figure 3 is a schematic view of a method for neutron activation using a neutron activator according to the present disclosure,

[0060] - Figure 4 is a schematic view of the position of the activation sample relative to the hollow conical target,

[0061] - Figure 5 is a graph representing 165 Ho(n,γ) 166 Ho and 176 Lu(n,γ) 177 Lu transmutation cross-sections,

[0062] - Figure 6 is a graph representing the neutron spectrum with various moderators. DETAILED DESCRIPTION

[0063] The present disclosure relates to a neutron activation system for the neutron activation of a material, comprising:

[0064] - a neutron source comprising a metallic target, suitable to receive a proton beam energy comprised between 16 MeV and 100 MeV, preferably between 30 MeV and 70 MeV, and capable of sustaining a beam intensity of up to 1 mA, preferably up to 350 mA for 70 MeV and up to 1 mA for 30 MeV, and

[0065] - a beryllium first reflector-decelerator, peripheral to the neutron source and containing a neutron activation zone,

[0066] - optionally, a second reflector-decelerator embedded in said beryllium reflector-decelerator.

[0067] The neutron activator according to the present application advantageously provides an optimized neutron flux having a target energy in the local region around the sample to be activated, while maintaining sufficient compactness for use in small and medium-sized cyclotrons.

[0068] It is therefore suitable for carrying out the routine and industrial production of radioisotope activation doses for preclinical and clinical studies and for product commercialization.

[0069] In Figure 1 Embodiments of a neutron activator according to the present disclosure are illustrated in the accompanying drawings.

[0070] More specifically, the neutron activator of the present disclosure can comprise:

[0071] - a metallic hollow conical target as neutron source,

[0072] - a cooling system comprising a flow guide and a cooling vessel for guiding a cooling fluid along the outer surface of the conical target,

[0073] - a first beryllium reflector-decelerator surrounding the cooling vessel and housing an activation channel arranged around the target,

[0074] - a second reflector-decelerator embedded in the first beryllium reflector-decelerator.

[0075] In particular, the neutron activator can comprise, housed in the reflector-decelerator:

[0076] - a metallic hollow conical target as neutron source,

[0077] - a flow guide delimiting a cooling zone for guiding a cooling fluid as a flow from an inlet channel to an outlet channel along the outer surface of the target,

[0078] - an inlet channel for delivering the cooling fluid to the flow guide,

[0079] - an outlet channel for removing the cooling fluid from the flow guide.

[0080] Figure 2Embodiments of a cylindrical target assembly are provided, comprising a hollow conical metal target and a cooling system thereof. In such specific embodiments, the target as a neutron source is a hollow conical metal target, whose longitudinal axis is aligned with the beam axis of the proton beam. The cooling system comprises (i) a cooling vessel defining an inlet channel and an outlet channel for circulation of a cooling fluid, and (ii) a flow guide defining a cooling zone for guiding the cooling fluid as a flow from the inlet channel to the outlet channel along the outer surface of the hollow conical metal target.

[0081] Metal target as a neutron source

[0082] The neutron source is made of a metal target having a longitudinal axis intended to be arranged in parallel to the beam axis of a proton beam, to receive the proton beam, which is advantageously generated by a cyclotron. In the illustrated embodiment, the longitudinal axis and the beam axis are coaxial, i.e. superimposed. In other embodiments, the longitudinal axis and the beam axis can be parallel and spaced apart from each other.

[0083] The target body should thus be able to sustain a low energy and high intensity proton beam, for example with a proton beam energy of 16 MeV to 100 MeV, preferably 30 MeV to 70 MeV, and a beam intensity of up to 1 mA, preferably up to 350 pA for 70 MeV and up to 1 mA for 30 MeV.

[0084] Embodiments with a conical target body

[0085] The target body preferably has a hollow conical shape. The conical shape of the target, when aligned with the proton beam, is able to optimize the yield of neutrons reaching the activation zone surrounding the target. In particular, the conical shape of the target with a small opening angle advantageously increases the interaction surface between the proton beam and the inner surface of the target, thereby reducing the power density of the target, while increasing the surface for thermal cooling.

[0086] As used herein, the term "conical" is used in its broadest sense, referring to a cone with a circular or non-circular base (e.g. the base can be polygonal or elliptical or any other shape). In preferred embodiments, the conical shape is a right circular cone.

[0087] As used herein, the term "hollow" conical refers to a target that is open at its base and essentially consists of the sidewall of the cone.

[0088] The longitudinal axis of the hollow conical target is aligned with the proton beam generated by the cyclotron. The proton beam thus reaches the hollow conical target from the inner surface of the sidewall of the conical target.

[0089] The neutron activator advantageously further comprises a cooling zone in direct contact with the outer surface of the conical target, for receiving a fluid flow for cooling the target during neutron generation.

[0090] The final dimensions of the hollow conical metal target and cooling zone will be adjusted to optimize the production of neutrons.

[0091] In embodiments of the neutron activator, the opening of the conical target and the thickness of its sidewall are preferably optimized so that the portion of the protons received from the proton beam has sufficient energy to release a portion of the thermal energy corresponding to the Bragg peak outside the target in the cooling zone, where the heat is easily removed by the cooling flow. This can significantly reduce the power density of the solid target, thereby improving the thermal conditions of the target without significantly reducing the production of neutrons.

[0092] Preferably, if the target has a thickness such that all the protons received from the proton beam release their thermal energy inside it, at least 50% of the energy from the interacting protons is lost outside the target compared to the energy deposited inside the target.

[0093] In these embodiments, the opening and thickness of the conical target are optimized so that the power density is preferably reduced by at least 50% compared to the power density of a conical target with an opening and thickness in which all the protons release their thermal energy inside the target.

[0094] In addition, the opening and thickness of the conical target will be determined so that the number of neutrons produced inside the target is at least equal to 70% of the number of neutrons produced inside the target if all the protons received from the proton beam release their thermal energy inside the target.

[0095] Depending on (i) the shape of the conical target, (ii) the properties of the metal used for the target and (iii) the energy and intensity of the proton beam, the skilled person will be able to determine the range of optimization of the thickness and opening of the target using any suitable simulation software, thereby achieving an optimized neutron activation yield using a compact neutron activator.

[0096] In particular embodiments, the target has a straight circular conical shape and is made of beryllium metal, the energy of the proton beam is 65 MeV to 75 MeV, for example 70 MeV, the intensity is 0.30 mA to 0.40 mA, typically 0.35 mA, the thickness of the sidewall is preferably 4 mm to 4.6 mm, for example 3.6 mm, the axial thickness is 22.5 mm to 27.5 mm, typically 25 mm, and the opening of the conical target is preferably 18 mm to 22 mm, for example 20 mm. The circular base of the target can be provided to be 27 mm to 33 mm, for example 30 mm, to accommodate the typical beamline dimensions of a 70 MeV cyclotron.

[0097] Alternatively, in a second embodiment of the neutron activator, the opening of the conical target and the thickness of its sidewall are optimized so that

[0098] (i) the protons received from the proton beam lose all their energy inside the metal target, and

[0099] (ii) the stress generated by the temperature gradient within the target is kept within the elastic limit of the metal target.

[0100] This embodiment can be suitable when the proton beam characteristics (in terms of energy, intensity and width / current profile) do not generate very high power densities within the solid target, for example in the case of a 30 MeV - 185 μA - 30 mm beam on a water-cooled conical beryllium or a 30 MeV - 140 μA - 30 mm beam on a water-cooled conical tantalum target.

[0101] In the latter embodiment, if a liquid such as water is used as cooling fluid, it is indeed necessary to limit the thermal stress in order to avoid boiling of the cooling liquid and / or deformation of the target.

[0102] The metal target should be made of a material having a thickness and composition allowing efficient neutron production and having good thermo-mechanical properties. Suitable materials include, but are not limited to, beryllium, tantalum, tungsten and alloys thereof (e.g. tungsten-rhenium or tungsten-copper).

[0103] Typically, the metal target can be made of beryllium.

[0104] In another specific embodiment, the metal target is made of tantalum. In this embodiment, the typical oxidation-reduction phenomena of tantalum at temperatures higher than 100°C can be avoided by exposing the inner surface of the side wall of the conical target to a vacuum environment having a pressure of 10 -3 millibar or lower than 10 -3 millibar (lower oxygen concentration) while the temperature of the outer surface, which is in contact with water as cooling fluid, is kept below 200°C by the cooling action of water itself.

[0105] A preferred embodiment of a hollow conical target and of its cooling system is shown in Figure 2 Fig. 1.

[0106] In such a preferred embodiment, the cooling system comprises

[0107] - a flow guide and

[0108] - a cooling container.

[0109] In this preferred embodiment, the flow guide is in close proximity to the outer surface of the conical target, thereby limiting the cooling zone for guiding the cooling fluid along the entire outer surface of the conical target. The flow guide is connected to a cooling container comprising:

[0110] - an inlet channel for delivering the cooling fluid to the flow guide, and

[0111] - an outlet channel for removing the cooling fluid from the flow guide.

[0112] More specifically, the flow director is at least partially conical, preferably having a similar shape to the cone of the target, so that said conical flow director covers the outer surface of the conical target, defining a cooling zone around the outer surface of the target, sized to obtain an optimal velocity profile of the cooling fluid along the target wall.

[0113] In a specific embodiment, there is no direct contact between the target and the flow director, so that the cooling fluid can contact all the outer surface of the target.

[0114] Advantageously, the assembly of the hollow conical target with the flow director and the cooling vessel is cylindrical, so that it can be easily housed in a reflector-decelerator surrounding said target assembly.

[0115] In a specific embodiment, a thermocouple can be placed on or inserted into the outer surface of the target, for example at the base of the cone, to monitor the thermal state of the target.

[0116] Beryllium reflector-decelerator

[0117] The neutron activator according to the present disclosure further comprises a reflector-decelerator, which is peripheral to the neutron source and thus surrounds the target and its cooling system. The reflector-decelerator also contains the neutron activation zone. Its function is to concentrate the activating neutrons in the area containing the activated sample (activation zone), while efficiently slowing down (decelerating) the neutrons to an energy suitable for activating selected isotopes.

[0118] The reflector-decelerator is made of beryllium or contains at least 90% of beryllium metal. As shown in the examples, the use of a material operating as a reflector-decelerator has different advantages compared to other materials:

[0119] - it has a good capacity to contain neutrons in some determined spectra, thus increasing the activation efficiency of the activation zone,

[0120] - it is more suitable for the activation of target radioactive isotopes, mainly holmium particles.

[0121] Thus, the first reflector-decelerator is configured to contain the neutron source and the material to be activated. The neutron activation zone of the first reflector-decelerator comprises a hole extending along the hole axis and configured to contain the neutron source, so that the hole axis and the longitudinal axis are coaxial.

[0122] For example, in a specific embodiment of the neutron activator, the reflector-decelerator surrounds a cylindrical assembly of the hollow conical target and its cooling system (target assembly), said target assembly comprising:

[0123] - a straight conical target,

[0124] - a flow director having a similar conical shape to the target, and

[0125] - the cylindrical cooling vessel as described in the preceding sections.

[0126] In such specific embodiments, the reflector-moderator is cylindrical along the hole axis of circular cross-section. Alternatively, the reflector-moderator can be cylindrical along the hole axis of any other suitable cross-section.

[0127] The reflector-moderator is dimensioned to maximize the activation rate of the isotopes while making the reflector-moderator as small as possible. Advantageously, the overall dimensions of the activator, including the neutron source, the reflector-moderator and optionally the second reflector-moderator, do not exceed the volume of a cube of 1 meter side length, preferably 0.75 meter side length, for example 0.50 meter side length.

[0128] The reflector-moderator further comprises an activation channel for loading the material to be activated in the neutron activation zone. The activation channel should be able to load and unload the material to be activated. Said channel can be machined into the reflector-moderator. The skilled person will know how to determine the position of said activation channel with respect to the target using appropriate simulations to optimize the activation of the radioisotopes.

[0129] In specific embodiments where the hollow conical target and its cooling system are cylindrical (as described above), a plurality of activation channels can be provided on concentric rings around the target.

[0130] More specifically, the activation zone of the first reflector-moderator further comprises a plurality of activation channels extending along channel axes parallel to the hole axis in the vicinity of the hole. In particular, the activation zone comprises activation channels distributed around the hole. The activation channels are evenly distributed around the hole. For example, in the illustrated embodiment, a first series of activation channels is evenly distributed around the hole at a first distance from the hole axis, a second series of activation channels is evenly distributed around the hole at a second distance from the hole axis greater than the first distance.

[0131] Advantageously, the neutron activator further comprises a remote material loading system for allowing remote loading-unloading of the material to be activated within the activation channels.

[0132] Although a target with a conical shape is disclosed, the provisions regarding the beryllium reflector-moderator can be provided independently of the provisions regarding the target shape.

[0133] Second reflector-moderator

[0134] The purpose of the second reflector-moderator embedded in the beryllium reflector-moderator is to further slow down and scatter the already partially slowed down neutrons that escape the beryllium reflector-moderator. Its main purpose is to optimize the performance of the activator while minimizing the volume and cost of the very expensive beryllium reflector-moderator.

[0135] Preferably, the second reflector-decelerator can be made of polyethylene, typically high density polyethylene. The size of the decelerator should be such that the volume of the assembled activator including the target, its cooling system, the reflector-decelerator and the second reflector-decelerator does not exceed the volume of a cube with a side length of 1 meter, preferably 0.75 meter, and for example 0.50 meter.

[0136] Method for neutron activation

[0137] The activator according to the present application is dedicated to the neutron activation of particles.

[0138] It is therefore another object of the present application to provide a method for the neutron activation of a material, the method comprising:

[0139] a) providing a material to be activated,

[0140] b) placing the material in the activation zone of a neutron activator as described in the present disclosure,

[0141] c) generating a proton beam at an energy suitable for the neutron activation of said material,

[0142] thereby activating said material.

[0143] In a particular embodiment, said material to be activated is contained in or is in the form of microparticles or nanoparticles thereof, for example holmium oxide microparticles or nanoparticles. Examples of holmium oxide particles are described in "In curietherapy with holmium oxide submicronic particles. EANM 2009, Annual Congress of the European Association of Nuclear Medicine, October 10-14, 2009, Barcelona, Spain.

[0144] Preferably, the microparticles / nanoparticles are in a liquid suspension.

[0145] For example, said material can be contained in a capsule and said capsule is placed in the activation zone by moving the capsule within an activation channel embedded in the reflector-decelerator.

[0146] Figure 3 An embodiment of a neutron activation system is represented, which comprises:

[0147] - a generator configured to produce a proton beam along a beam axis, for example a cyclotron 13, the proton beam having an energy of 16 MeV to 100 MeV, preferably 30 MeV to 70 MeV, and a beam intensity of up to 1 mA, preferably up to 350 pA for 70 MeV and up to 1 mA for 30 MeV,

[0148] - a neutron activator arranged such that the longitudinal axis of the target is parallel to the beam axis, in particular coaxial with the beam axis, to produce neutrons by interaction with the proton beam and to activate the material to be activated, and

[0149] - a supply device for loading one or more samples of material to be activated.

[0150] In combination Figure 3 The neutron activation system of

[0151] The sample of material to be activated (activation sample), for example microparticles containing stable target isotopes, is provided in the form of suitable capsules (15). The capsules are then loaded in the activation channel (5) by a supply device, which can comprise for example a shielded capsule loader (16) and a transfer system (14).

[0152] The supply device is connected to the activation channel (5) and is configured to move the sample of material to be activated along the activation channel (5), preferably in an automated manner. Advantageously, the method comprises the use of a pneumatic loading and unloading system, allowing remote loading-unloading of capsules within the activation channel. For example, the capsules are moved back and forth by a compressed air rabbit system, allowing remote loading / unloading of granular suspended capsules. More advantageously, the pneumatic system also allows cooling of the heat generated by the interaction of neutrons with the capsules and their contents during irradiation by the air flow flowing in all the activation channels.

[0153] The cyclotron (13) then produces a proton beam (7) having for example an energy of 16 MeV to 100 MeV, preferably 30 MeV to 70 MeV, and an intensity of up to 1 mA, up to 350 pA for 70 MeV and up to 1 mA for 30 MeV.

[0154] The proton beam is directed to the metal target (1) and the protons interact with the metal target, for example made of Be, producing fast (high energy) neutrons (12).

[0155] The target is cooled in the cooling zone using, for example, water flowing from the inlet channel to the outer surface of the target (2). In a specific embodiment, the target is cooled by a flow of cooling liquid, preferably water, at a static pressure of 1 to 20 bar and at a velocity of 8 to 24 m / s in the vicinity of the target surface. The cooling is intended to avoid boiling of the water, while limiting the corrosive effect on the solid target surface or the associated vibrations of the target structure. The amount of cooling water has the additional effect that the high-energy neutrons emerging from the target have a first deceleration effect. The relevance of this deceleration effect depends on the thickness of the water layer. In a specific embodiment of the design of the activator, however, the water layer thickness is minimized, with the advantage that the activated sample remains as close as possible to the target and the beryllium reflector as compact as possible.

[0156] The neutrons are reflected and decelerated in the first reflector-decelerator (4) to reach the activation zone (10). The neutrons that pass through the first reflector-decelerator can be further decelerated and scattered back by the second reflector-decelerator (6).

[0157] The method for neutron activation according to the invention has at least the following advantages:

[0158] - particles in injectable form can be activated, which is difficult to achieve with nuclear reactors,

[0159] - the use of a dedicated cyclotron-driven system makes it possible to produce and distribute activated radioisotopes more flexibly,

[0160] - there is no γ particle damage due to heating (typical case for nuclear reactors),

[0161] - short-lived isotopes can be used and repeated treatments can be planned to increase the efficiency of the treatment,

[0162] - different types and sizes of nanoparticles can be used to adapt the treatment method to the specific case.

[0163] Neutron activator

[0164] The invention also relates to the use of a neutron activator as described previously for the preparation of radioisotopes, preferably for use in radiopharmaceuticals and medical devices.

[0165] The choice of radioisotope depends on three main characteristics: half-life, β - energy and γ energy (Table 1). The shorter the half-life, the shorter the service life of the treatment unit (possible repeated treatments). Higher β - energy corresponds to a higher efficiency of the treatment. Higher γ energy corresponds to better detection by single photon emission computed tomography (SPECT).

[0166] Radioisotope Half-life β - energy (keV) Gamma energy (keV) Holmium 166 26.7 hours 1840 80 Lutetium 177 6.7 days 497 208 Rhenium 186 3.7 days 1077 137 Rhenium 188 17 hours 2100 155 Yttrium 90 2.7 days 2080 None Gold 198 2.7 days 1372.9 411.8 Terbium 161 6.9 days 157.4 74.5

[0167] Table 1

[0168] In a particular embodiment, the radioisotope is a beta - emitting radioisotope, preferably 166 Ho, 186 Re, 188 Re, 177 Lu, 198 Au, 90 Y, 227 Ra and 161 Tb.

[0169] Holmium is a particular target for the application of the present application, as it presents a good compromise between short half-life and high beta - energy compared to other radioisotopes.

[0170] Description of a particular embodiment of the method and device according to the application

[0171] As Figure 1 shown, the activator according to the example is a cuboid 50 cm wide, 50 cm high, 56 cm long. It consists of:

[0172] - a hollow beryllium conical target (1),

[0173] - a flow guide (2) for the delivery of a cooling fluid to an inlet channel (8) of the flow guide (2) and for the removal of the cooling fluid from the flow guide (2),

[0174] - a cylindrical cooling vessel (3) with an inlet channel and an outlet channel,

[0175] - a beryllium cylindrical reflector-decelerator (4) with an inner diameter Di = 100 mm, an outer diameter De = 160 mm and a length of 200 mm, which houses an activation channel (5) arranged coaxially around the target (1),

[0176] - a high-density polyethylene second reflector-decelerator (6).

[0177] The activation channel (5) is arranged on a ring placed in a concentric manner around the target. A ring of 16 channels can provide a total loading of 64 capsules / doses (4 each channel).

[0178] Table 2 lists the technical parameters of the activator.

[0179]

[0180]

[0181] Table 2

[0182] To limit corrosion, the cooling water velocity has been restricted to approximately 10 m / s, corresponding to a flow rate of approximately 2 kg / s for the current dimensions. Under these conditions, the maximum wall temperature at the target / water interface is expected to be approximately 150°C. To prevent boiling, the coolant (water) must be pressurized to at least 5 bar.

[0183] Table 3 summarizes the cooling characteristics of the Be target.

[0184] Property Value Maximum target temperature 250℃ Maximum temperature at target / water interface 150℃ Maximum boundary heat flux 8 MW / m 2 ]] Minimum pressure required for cooling system 5 bar Mass flow rate 2 kg / s

[0185] Table 3

[0186] To select the optimal material for the reflector-decelerator placed around the target and housing the activation channel, a set of Monte Carlo calculations were performed by comparing the following materials: water, polyethylene, beryllium, graphite, and lead.

[0187] Given 165 Ho(n,γ) 166 Cross-section of Ho transmutation ( Figure 4 and 176 Lu(n,γ) 177 The cross-section of Lu is reported together), and the most favorable neutron energy is thermal (0-10). -7 MeV) and superheat (10 -7 ÷5x10 -3 (MeV) range.

[0188] like Figure 5 As shown, Figure 4 This indicates that the neutron spectrum obtained in the activated channel is the most favorable in the case of beryllium, which suggests...

[0189] - By comparing the total neutron flux of Be and Pb, it can be seen that better neutron confinement can compensate for the higher neutron absorption of Be, thus achieving a total neutron flux comparable to that of Pb.

[0190] - In addition, Be exhibits very good deceleration compared to all other materials, produces significantly higher flux in the hot zone, and is at the same level as Pb in the ultra-hot zone.

[0191] The results are shown in Table 4. Using the Be reflector-reducer can significantly improve... 166 Ho's activation output.

[0192] Reflector-moderator Saturation activity (Bq / g / uA) Water 3.88E+08 Polyethylene 4.27E+08 Beryllium 9.19E+08 Graphite 4.33E+08 Lead 6.56E+08

[0193] Table 4

[0194] In this embodiment, the activator uses a hollow tantalum conical target instead of a hollow beryllium conical target, as shown in Table 5, and uses a Be reflector-reducer. 166 Ho activation yields much higher output.

[0195] Reflector-moderator Saturation activity (Bq / g / uA) Beryllium 2.1E+09

[0196] Table 5.

Claims

1. A neutron activator for neutron activation of a material, the neutron activator being configured to produce neutrons by interaction with a proton beam (7) emitted along a beam axis, the proton beam (7) having an energy of 16 MeV to 100 MeV and a beam intensity of up to 1 mA, the neutron activator comprising: - A neutron source comprising a metal target (1) having a longitudinal axis intended to be arranged parallel to the beam axis, wherein the metal target has a hollow cone shape and the longitudinal axis of the cone is aligned with the proton beam; and A cooling zone in direct contact with the outer surface of the metal target (1) is used to receive the fluid flow cooling the metal target (1) during neutron generation, and, - A beryllium first reflector-reducer (4), located on the periphery of a neutron source and comprising a neutron activation region (10), the neutron activation region (10) being configured to accommodate the neutron source and the material to be activated, the neutron activation region (10) of the beryllium first reflector-reducer (4) comprising a hole extending along the hole axis and configured to accommodate the neutron source, such that the hole axis and the longitudinal axis are coaxial. The optimization of the opening and sidewall thickness of the hollow, conical metal target (1) makes it possible to achieve the desired effect. i. Some of the protons received from the proton beam (7) have sufficient energy to release a portion of the thermal energy corresponding to the Bragg peak outside the metal target (1). ii. Compared to the target power density where all protons received from the proton beam (7) release their thermal energy within the metal target (1), the power density within the metal target is reduced to at least 50%, and iii. The number of neutrons generated within the metal target is equal to at least 70% of the number of neutrons generated within the metal target (1) having a thickness that allows all protons received from the proton beam (7) to release their thermal energy within the metal target (1).

2. The neutron activator according to claim 1, wherein the neutron activation region (10) of the beryllium first reflector-reducer (4) further comprises at least one activation channel (5) extending near the aperture along a channel axis parallel to the aperture axis, the activation channel (5) being configured to load material to be activated.

3. The neutron activator according to claim 2, wherein the neutron activation region (10) comprises a plurality of activation channels (5) distributed around the aperture.

4. The neutron activator according to claim 1, further comprising: housed within the beryllium first reflector-reducer (4): -Inlet channel (8), which delivers cooling fluid to the guide vane (2), - A flow guide (2), which defines a cooling zone, is used to guide cooling fluid as a flow from the inlet channel (8) to the outlet channel (9) along the outer surface of the metal target (1). -Outlet channel (9), which is used to remove cooling fluid from the guide (2).

5. The neutron activator according to claim 4, wherein the flow guide (2) is at least partially conical, such that the flow guide covers the outer surface of the metal target (1) having the conical shape, thereby defining a cooling zone around the outer surface of the metal target (1) having the conical shape.

6. The neutron activator according to claim 1, wherein the opening of the metal target (1) having the conical shape is 20° to 45°.

7. The neutron activator according to claim 1, wherein the metal target (1) is made of beryllium or tantalum.

8. The neutron activator according to claim 1, wherein the beryllium first reflector-reducer (4) is cylindrical along the hole axis.

9. The neutron activator according to claim 1, wherein the overall size does not exceed the volume of a cube with a side length of 1 meter.

10. The neutron activator according to claim 9, wherein the overall size does not exceed the volume of a cube with a side length of 0.75 meters.

11. The neutron activator according to claim 9, wherein its overall size does not exceed the volume of a cube with a side length of 0.5 meters.

12. The neutron activator according to claim 1, further comprising a second reflector-reducer (6) embedded in the beryllium first reflector-reducer (4).

13. The neutron activator according to claim 3, wherein the plurality of activation channels (5) are uniformly distributed around the hole.

14. A neutron activation system for neutron activation of materials, comprising: - A generator (13) configured to generate a proton beam (7) along the beam axis, the proton beam (7) having an energy of 16 MeV to 100 MeV and a beam intensity of up to 1 mA. - The neutron activator according to claim 1 is arranged such that the longitudinal axis of the metal target (1) is parallel to the beam axis.

15. The neutron activation system of claim 14, wherein the neutron activation region of the beryllium first reflector-reducer further comprises at least one activation channel extending near the aperture along a channel axis parallel to the aperture axis, the activation channel being configured to load material to be activated, and the neutron activation system further comprises a supply device (14, 16) for loading the material to be activated, the supply device (14, 16) being connected to the activation channel (5) and configured to move a sample of the material to be activated (15) along the activation channel (5).

16. The neutron activation system according to claim 14, wherein the generator is configured to prepare a proton beam (7) with an energy of 30 MeV to 70 MeV.

17. The neutron activation system of claim 14, wherein the generator is configured to produce a proton beam (7) with a maximum intensity of 350 μA for a 70 MeV beam.

18. The neutron activation system of claim 14, wherein the generator is configured to produce a proton beam (7) with a maximum intensity of 1 mA for a 30 MeV beam.

19. An application of a neutron activation system, wherein, The neutron activation system according to claim 14 is used to prepare radioactive isotopes that emit beta rays suitable for nuclear medicine applications.

20. The use according to claim 19, for preparing 166 Ho、 186 Re、 188 Re、 177 Lu、 198 Au、 90 Y、 227 Ra and 161 Tb.

21. A method for neutron activation of a material, the method comprising: a) Provide the materials to be activated. b) Place the material in the activation region of the neutron activator according to claim 1. c) A proton beam (7) is generated at an energy suitable for neutron activation of the material, and the proton beam (7) has a maximum intensity of 1 mA. This activates the material.

22. The method of claim 21, wherein the metal target is cooled by a coolant flow at a static pressure of 1 bar to 20 bar and a velocity of 8 m / s to 24 m / s on the surface of the metal target.

23. The method of claim 22, wherein the coolant is water.

24. The method of claim 21, wherein the material to be activated is contained in or in the form of microparticles or nanoparticles.

25. The method of claim 21, wherein the proton beam has an energy of 16 MeV to 100 MeV.

26. The method of claim 21, wherein the proton beam has an energy of 30 MeV to 70 MeV.

27. The method of claim 21, wherein the proton beam has an intensity of up to 350 μA for 70 MeV.

28. The method of claim 21, wherein the proton beam has an intensity of up to 1 mA for 30 MeV.

29. The method of claim 24, wherein the material to be activated is contained in or is in the form of holmium oxide microparticles or nanoparticles.

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