The present invention generally relates to a method for producing Acti n-ium-225.

Production of Actinium-225 (Ac-225) and its daughter Bismuth-213 (Bi-213) is of great interest for cancer therapy, as they constitute preferred radionuclides for alpha-immunotherapy purposes. Indeed, to selectively irradiate cancer cells, alpha-immunotherapy uses alpha-emitters such as Bi-213 and possibly Ac-225 that are linked, through a bifunctional chelator, to monoclonal antibodies or peptides.

EP-A-0 962 942 discloses a method for producing Ac-225, which consists in irradiating a target containing Ra-226 with protons in a cyclotron, so that metastable radionuclei are transformed into Actinium by emitting neutrons. It is to be noted that this method allows to obtain the desired Ac-225, but also considerable quantities of other highly undesired radionuclides, especially Ac-224 and Ac-226. In order to eliminate these undesired radionuclides, the post-irradiation process is delayed since Ac-224 and Ac-226 present a relatively short half-life compared with Ac-225 (half-life 10 days). This waiting period however also leads to a considerable loss of Ac-225.

In order to increase the yield of Ac-225, EP-A-0 962 942 proposes to irradiate a target of Ra-226 with protons having an incident energy of between 10 and 20 MeV, preferably of about 15 MeV.

A disadvantage of these methods is however the need for a cyclotron.

The object of the present invention is to provide an alternative method for producing Actinium-225. This object is achieved by a method as claimed in claim 1.

In accordance with the present invention, a method for producing actinium-225 (Ac-225) comprises directing a high-intensity laser beam onto a converting means to produce an irradiating field and irradiating a target of radium-226 (Ra-226) in the irradiating field.

It will be appreciated that the present method uses a laser to produce the irradiating field that will induce the nuclear reactions in the Ra-226 target, which eliminates the need for a cyclotron. The interaction of the high-intensity laser beam with the converting means allows the production of an irradiating field of photons or protons, depending on the laser intensity and the converting means. The use of a laser beam to produce Ac-225 proves extremely advantageous over methods requiring a cyclotron, in terms of cost, size, operation and maintenance. So-called tabletop-lasers are very compact and can be installed in hospitals. This means in particular that hospitals or other radiotherapy treatment centers would be capable of managing their Ac-225 production themselves, without relying on a distant cyclotron facility.

In case of a photon field, Ra-226 is converted to Ra-225 through a photodisintegration reaction, where absorption of high-energy electromagnetic radiation in the form of gamma-ray photons―produced by the interaction of the laser with the converting means ―causes a Ra-226 nucleus to eject a neutron, resulting in the formation of Ra-225. This reaction is noted Ra-226(γ, n)Ra-225. Ac-225 is then obtained due to the natural decay process of Ra-225.

When the target of Ra-226 is irradiated in a proton field, Ra-226 is transformed into Ac-225 by emitting neutrons according to the nuclear reaction Ra-226(p, 2n)Ac-225.

The intensity of the laser beam used to produce the irradiating field by interaction with the converting means needs to be of sufficient energy so that the photons, respectively the protons, produced are of sufficient energy to drive the (γ, n) reaction, respectively the (p, 2n) reaction. Preferably, the intensity of the laser is of at least 10¹⁹ W/cm², more preferably about 10²⁰ W/cm².

For the (γ, n) reaction, the laser intensity should preferably be sufficient to produce photons having an energy of at least 1 MeV, more preferably between 10 and 25 MeV.

For the (p, 2n) reaction, the laser intensity should preferably be sufficient to produce protons having an energy between 10 and 20 MeV. More preferably, the protons in the irradiating field should have an energy of between 14 and 17 MeV, as this allows producing Ac-225 with high purity and yields.

The nature of the converting means on which the laser beam impinges is advantageously selected in function of the irradiating field to be produced.

To generate photons, the converting means preferably includes a piece or foil of a metal such as e.g. tungsten, tantalum, platinum or copper. In particular, the converting means preferably includes a first part in the form of a Ta foil having a thickness of about 50 µm, and directly behind a second part in the form of a 1 mm thick Ta foil. The laser beam is directed onto the first part where it produces a plasma. The plasma electrons then impinge onto the second part, which serves as an efficient bremsstrahlung converter. Alternatively, the converting means may simply consist of a Ta foil having a thickness in the range of e.g. 1.5 to 5 mm.

In order to produce a proton irradiating field, the converting means preferably takes the form of a foil or piece of a carbon and hydrogen containing material, onto which the laser beam impinges.

In the present process, the target of Ra-226 is preferably prepared in the form of pellets, e.g. of RaCl₂ or RaCO₃. The pellets are then advantageously placed into a sealed capsule, preferably of Ag. In addition, the capsule is preferably cooled by a cooling circuit during irradiation.

The present method preferably comprises a further step of separating the Ac-225 from the irradiated target material. This may be done by conventional chemical separation.

It is to be noted that the present method allows ample production of Ac-225 with consistent radiochemical and radionuclidic purity. It is safe and dependable, and does not generate appreciable quantities of radioactive waste.

The present invention will now be described, by way of example, with reference to the accompanying drawings in which:

• FIG.1: is a sketch of the experimental set-up used to implement a first embodiment of the present method;
• FIG.2: is a sketch of the experimental set-up used to implement a second embodiment of the present method.

The present method allows production of Ac-225 from Ra-226 by means of a laser, which is clearly advantageous in terms of cost and flexibility of use with regard to conventional methods requiring a particle accelerator (e.g. a cyclotron).

Two preferred methods for producing Ac-225 will be presented herebelow, one using the (γ, n) nuclear reaction and the other one the (p, 2n) nuclear reaction.

The target nuclide used in these methods is Ra-226. The target of Ra-226 is preferably in the form of RaCl₂ (radiumchloride), obtained from precipitation with concentrated HCl, or radium carbonate RaCO₃. This material is then pressed into target pellets. Prior to irradiation, these pellets are advantageously heated to above 150°C in order to release crystal water therefrom before being sealed in a capsule made of silver.

A preferred embodiment of the present method, wherein Ac-225 is produced via the (γ, n) reaction will now be described in detail with regard to Fig. 1.

According to this method, a high-intensity laser beam 10 is focused onto a converting means generally indicated 12. The angle of incidence of the laser beam 10 is preferably less than 45° in parallel polarization, as this geometry allows for high absorption of laser light into a plasma. The converting means 12 itself preferably comprises two parts, more specifically two sheets 14, resp. 16, of tantalum with a thickness of 50 µm and 1 mm, respectively. The second part 16 is placed behind the first part 14 (with regard to the incident laser beam). A target of Ra-226, i.e. a capsule indicated 18 containing e.g. RaCl₂ pellets, is placed behind the second part 16. During irradiation, the capsule 18 is preferably cooled by a closed water circuit with an alpha monitor (not shown) to detect any leakage of radon from the capsule. Such a cooling circuit comprises e.g. a pump and a heat exchanger for extracting the heat produced by the irradiation in the capsule 18.

The incident laser beam 10 is preferably generated by means of a so-called tabletop laser. Preferred laser parameters are the following:

• Laser pulse energy: 1 J (1 Joule)
• Laser pulse length: 50x10^-15 s (50 femtoseconds)
• Laser intensity: 10²⁰ W/cm²
• Focal spot diameter: 5 µm²

The high-intensity laser beam 10 produces a relativistic plasma on the surface of the first part 14. Plasma electrons are accelerated to relativistic energies within the intense laser field. These fast electrons impinge on the second part 16, which serves as an efficient bremsstrahlung converter. As a result, an irradiating field of high-energy bremsstrahlung photons is produced behind the second part 16 (schematically illustrated by γ waves in Fig. 1), whereby the target of Ra-226 is irradiated with these bremsstrahlung photons. With these laser operating parameters, photons having an energy of up to 30 MeV and more can be obtained.

The irradiation of the Ra-226 target by use of the high-energy photons primary leads to the production of Ra-225. Indeed, Ra-226 is excited into a higher energy state by the absorption of a high-energy photon (denoted γ). The excited nucleus then de-excites by the emission of a neutron (denoted n). This reaction is a so-called photonuclear reaction that is written as: Ra-226(γ, n)Ra-225.

The initial target of Ra-226 then consist of a mixture of Ra-226 and Ra-225 atoms. Subsequently to the irradiation, the radioactive Ra-225 atoms will decay to Ac-225 by a natural decay process in which a β^- particle is emitted. The half-life of this process is 14.9 days. This process is denoted by: Ra-225 → Ac-225 + β^-.

It has been observed that the Ac-225 activity reaches a maximum value of approximately 40% of the initial Ra-225 activity after approximately 15 days. By that time, the target sample, which contained originally Ra-226, will contain Ra-226, Ra-225 and Ac-225.

It will be understood that since only Ac-225 is desired for applications such as radiotherapy, the method then advantageously comprises a separation step to separate Ac-225 from radium isotopes of the irradiated target material. Due to the above described decay process, this separation step is advantageously not carried out earlier than the fifteenth day following irradiation. Ac-225 is preferably separated from the Radium isotopes in a chemical process. The target material containing the mixed Ra and Ac isotopes are dissolved in acid and then treated in a conventional way to separate Ac from Ra, e.g. in ion exchangers.

It will further be understood that the amount of Ra-225, and thus of Ac-225, that can be produced with the present method depends on the laser beam intensity but also on the laser repetition rate. It is expected that with the developments in laser technology that are being made, high-intensity laser systems with pulse repetition rates of up to 10 Hz and more, and with increase pulse energy, will soon be available. The present method will thus be even more interesting since it will allow considerable productivity improvements.

A preferred embodiment of the present method, wherein Ac-225 is produced via the (p, 2n) reaction will now be described in detail with regard to Fig.2.

According to this method, a high-intensity laser beam 40 is focused onto a converting means 42. The angle of incidence of the laser beam 40 is preferably less than 45° in parallel polarization, as this geometry allows for high absorption of laser light into a plasma. The converting means 42 preferably is a foil of carbon and hydrogen containing material, having e.g. a thickness in the range of 0.5 to 5 mm. In contrast to the previous method, the target of Ra-226, i.e. a capsule 44 containing RaCl₂ pellets, is preferably placed on the same side of the converting foil 42 on which the laser beam 40 impinges. During irradiation, the capsule 44 is advantageously cooled by a closed water circuit with an alpha monitor to detect any leakage of radon from the capsule.

The high-intensity laser beam interacts with the converting foil 42 in such a way that fast protons are produced. Hence, an irradiating field of high-energy protons is produced, whereby the target of Ra-226 is irradiated with these protons.

The proton irradiation of the target of Ra-226 leads to the transformation of the Ra-226 into AC-225 with the emission of two neutrons. This nuclear reaction is written as:

• Ra-226(p, 2n)Ac-225.

Hence, the induced reaction allows the direct transformation of Ra-226 into the desired product, i.e. Ac-225. The laser beam intensity is preferably adjusted in such a way that the protons falling on the target of Ra-226 have an energy of between 10 and 20 MeV, more preferably between 14 and 17 MeV. This last energy range allows producing Ac-225 with high purity and yields.

The Ac-225 is then separated from the Radium isotopes. This may be done by a conventional chemical separation step as described in the above method.

It remains to be noted that in both methods it is possible to improve photon, respectively proton, production by adapting the laser intensity and selecting a more appropriate material for the converting means.