Compact cyclotron for the production of radionuclides for targeted tumor therapy

Abstract

The invention relates to a cyclotron enabling the production of α or β-emitting radionuclides.

Description

Title of the invention: Compact cyclotron for the production of radionuclides for targeted tumor therapy

[0001] The context:

[0002] The rapid development of personalized medicine relies on "theranostics," a neologism that combines therapy and diagnostics. The compact CyTHER cyclotron, with its two options, is designed to produce alpha and [3]-emitting radionuclides, meeting the rapidly growing demand for targeted therapy in oncology.

[0003] The objectives:

[0004] Producing a significant quantity of 200 MBq daily and regional doses of alpha emitters (mainly Astatine-211, half-life 7.22h, and also Terbium-149, half-life 4.1h) and [3] emitters (mainly Lutetium-177 and also Holmium-166) compatible with the growing demand from regional Nuclear Medicine centers allows: • To improve average access times to innovative radiopharmaceutical medicines (RPMs) based on these radionuclides, which are particularly long in France compared to some European neighbours. • To avoid supply tensions for Lul77 due to numerous unforeseen events, including production from an aging fleet of remote nuclear reactors. • To produce Lul77 by an alternative method to the nuclear reactor, based on a high-intensity compact accelerator driving an activator where the 176Lu(n,y) capture reactions are obtained by the ARC (Adiabatic Resonance Crossing) method developed at CERN by Pr C.Rubbia. The characteristics of the two options, designated CyTHER-a and CyTHER-[3#, described below, meet these objectives. The originality of these two options, the subject of the present invention, lies in the fact that they differ only in their injection points and distinct central regions of the cyclotron, specific to the ions to be accelerated. They therefore use the same magnet (Figure 3), the same HF accelerator system, and thus the same installed power.

[0005] Furthermore, accelerating very high intensities requires reducing space charge forces and enabling a very high extraction efficiency: • for the large production of alpha emitters, we made an original choice of the characteristics of the accelerated ions (in particular their electric charge). • for the production of [3-] emitters, the choice was made to accelerate H2+ molecular ions for the production of protons by stripping, with also a very high extraction yield.

[0006] The concept of the cyclotron 1. Characteristics of ions • For alpha emitters (mainly Astatine-211 and also Terbium-149), the following table indicates that nuclear reactions have an optimal cross section at 8 MeV / nucleon, i.e. 32 MeV kinetic for alpha and 96 MeV for 12C ions. Radionuclide Nuclear reaction Cross section 21 *At 209Bi (α,2n)21 *At 800 mbam 149Tb 142Nd (β,5n) 149Dy 149Dy (β3-) 149Tb 300 mbam The following figures present the cross sections as a function of the ion energy, where the cross sections mentioned in the table are taken.

[0007] Fig. 1 83-BI-209Cfi,2H)85-ftT-211 EXFOR Requot: 23825 / 1, 2024-Oct-28 2024:09:1? Incident Energy (HoU) Partial energy incident (MeV)

[0008] It is observed that the nuclear reaction (12C,4n) is avoided at 8 Mev / nucleon.

[0009] For CyTHER-a, the production of 4He+ by an ECR source is on the order of 5 pqA, i.e., approximately 500 ppA for the extracted beam. Similarly, for the production of 12C3+ in an ECR source, the intensity is on the order of 500 pqA, or approximately 50 ppA for the extracted beam. For [3- emitters (mainly Lutetium-177 and also Holmium-166), the neutron flux is produced from the proton reaction on Beryllium (target developed by our company). Radionuclide Nuclear Reaction Characteristics 177Lu 176Lu (n,y)17 7Lu Lu-enriched target 176 1 66Ho 1 65Ho (n,Y)166Ho Natural Holmium Target These protons are obtained by stripping molecular H2+ ions (i.e., 2 protons of 32 MeV per H2+). The neutron flux drives a mini-activator (see the FESTA experiment - FEasibility STudy of an Activator with the Medicyc cyclotron in Nice) for the production of neutron-rich isotopes by the ARC method. For Lu-177, an enriched Lu-176 target is used. The following figure represents the Lu-177 production cross-section:

[0010] Fig. 2

[0011] With proton beams of 32 MeV and an intensity of 3 milliAmperes, i.e. 2 *1016 protons / second, a fast neutron flux of 3*1014 neutrons / second can be produced which will be slowed down in the mini-activator and will adiabatically cross the specific resonances of the radionuclides to be activated.

[0012] This high proton intensity is required to obtain batches of suitable dimensions for the production of approximately 50 daily doses. 1. Accelerated particles: For the production of alpha emitters, ions with the same charge-to-mass ratio, Z / A, can be accelerated by the cyclotron. This choice takes into account the ionization potentials in electron volts (see table below) in order to obtain the required intensity performance. The following table indicates in red the 4He+ and 12C3+ ions to be produced by ion sources installed on the external injection platform of the cyclotron. Element Z eVl eV2 eV3 eV4 eV5 eV6 He(A=4) 2 24.68 54.4 C(A=12) 6 11.26 24.38 47.86 64.48 392 489.8 4He+ and 12C3+(Z / A=l / 4) will be accelerated on the same harmonic of the HF frequency • For the production of [3-] emitters, the accelerated particle will be molecular hydrogen H2+ (Z / A=l / 2) in order to produce two protons / H2+ by stripping. 1. Cyclotron geometry For an ion of mass A, charge Z and energy W = 8 MeV / nucleon, the magnetic stiffness is:

[0014] c = speed of light and U0 = mass unit = 931.5 MeV

[0015] Given the low energy W and in order to realize an isochronous cyclotron Compact and economical, the following three concepts were selected: • a magnetic structure with 3 sectors • a fixed frequency HF accelerator system with 3 delta (dees) galvanically connected to the center, thus defining 6 accelerating spaces per revolution. • a very efficient extraction (yield close to 100%) by ion stripping, therefore without the beam losses of a bulky electrostatic channel. Figure 3:

[0016] 3D view of the median plane with the 3 magnetic sectors and the 3 HF cavities

[0017] The 3 delta-shaped HF elements are galvanically connected at the center and form A unique HF cavity allows the use of a single HF amplifier and avoids phase regulation between the three deltas. These cavity configurations permit acceleration on harmonics that are multiples of 3. Given the charge-to-mass ratio Z / A = 1 / 4 for 4He+ and 12C3+ ions, these ions will be accelerated on the 6th harmonic. H2+ ions, with Z / A = 1 / 2, will therefore be accelerated on the 3rd harmonic.

[0018] Fig.4

[0019] The set of 3 Dees forming the HF cavity and the coupling of the Amplifier

[0020] Fig.5

[0021] Central harmonic region 6 with the galvanic connection of the 3 Dees

[0022] Calculations of this cavity with the CST software (Dassault Systems) give the following law of the HF peak voltage along the accelerating gaps for a voltage of 50 KV in the central region 1.

[0023] Fig. 6 V (kVj radius (cm)

[0024] AIMA Développement possesses the know-how (HF amplifier and low-level control electronics) for HF systems operating at a frequency of F=70.4 MHz. The choice of this particular frequency is well suited to the proposed cavity structure.

[0025] The choice of frequency allows the magnetic field induction B to be defined:

[0026] B =

[0027] Where A / Z characterizes the accelerated ion, F the HF frequency, h the harmonic and U0 and c

[0028] the unit of mass and the speed of light.

[0029] This gives us an induction B= 3.06 Tesla, easily achievable with a superconducting coil, which determines the average extraction radius for the magnetic stiffness of 1.63 T*m, i.e. a radius of 0.53 m.

[0030] The geometry of the magnet 3 is thus fixed, see Figure below:

[0031] Fig. 7

[0032] For the fabrication of the superconducting coil, the choice of Magnesium diboride (MgB2) technology allows operation at 20 K, therefore without helium, using cryogenerators. This technological choice was also made by our Company for a higher energy Cyclotron design. 1. Ion injection 1. Ion Sources They are external, installed in dedicated high-voltage platforms. Two ion sources followed by their low-energy beam transport optics (LEBT) are placed in the same horizontal plane, on either side of the cyclotron's vertical injection axis. A magnetic dipole deflects the beams by 90° and selects the desired charge states for axial injection.

[0033] For the production of Z / A=l / 4 ions, ECR sources produced by industrial companies capable of continuously delivering 2.5 mA 4He+ and at least 500 qAe of 12C3+ will be adopted.

[0034] For the production of Z / A=l / 2 ions, the multi-cusp H2+ source developed by the Company, shown in the following figures with its measured performance, will be used. The maximum extracted intensity is 15 mA, more than sufficient to accelerate a 2.5 mA beam and thus to extract 3 mA of protons after stripping.

[0035] Fig. 8 Hy 86% 75V 8A discharoo 1. The axial injection line It includes focusing elements (Glaser lenses), two HF groupers to increase the phase acceptance of the cyclotron, measurement devices (Faraday cage), and control / monitoring of the injected intensity. The injection energies differ depending on the type of ion accelerated: for CyTHER-a, the injection energy is approximately 20 keV / nucleon, while for CyTHER-[3], H2+ ions are injected at approximately 50 keV.

[0036] This axial line terminates in a spiral-type electrostatic inflector for injecting particles into the median plane of the cyclotron. Vertical and median-plane views of the CyTHER-[3 H2+] inflector are shown below.

[0037] Fig.9

[0038]

[0039] The injection energies differ depending on the type of ion being accelerated. Fig. 10 Deflection magnet Multicusp source HAS Source ECR E CM Glaser lens Beam diagnostics ...... ï : » w irl;:! ;l ; * O Harmonic Buncher 2 Harmonic Buncher 1 Glaser lens

[0040]

[0041] Vertical cross-section of the injection line 1. The central regions One aspect of the plan is that the cyclotron is configured so that its central part is interchangeable. Each central part is configured to accelerate a specific type of particle. Therefore, there can be two or more interchangeable central parts. For example, 2 central regions are interchangeable and compatible with a single HF accelerator system common to the 2 harmonics 3 and 6.

[0042] According to this example, two different central regions adapted to the choice of the harmonic, i.e. to the acceleration of the Z / A=l / 4 ions (alpha emitters) on the 6th harmonic and the acceleration of the Z / A=l / 2 ions on the 3rd harmonic, are necessary in order to optimize the intensity performance of the beams.

[0043] The following figures are simulations of the beam trajectories on the first 2 turns, obtained with the proprietary software AGORA-6D.

[0044] The two figures are shown at the same scale. The colors of the trajectories correspond to the phases of passage of the 200 accelerated particles.

[0045] Fig-11: Central region CyTHER-a: 6th harmonic

[0046] Fig. 12: Central region CyTHER-[3# Harmonic 3

[0047] These two central regions, interchangeable according to the desired harmonic mode, are mechanically compatible and are connected to the dees 9 and antidees 10 of the HF cavity, at a radius of 13 cm, by the fixing system shown in the figure below. The colors of the electrodes represent the two superimposed central regions (red: 6th harmonic, green: 3rd harmonic).

[0048] Fig. 13 1. Ion extraction It is carried out by stripping the ions into: - Doubling the state of charge for 4He+ and 12C3+ ions, i.e. 4He++ and 12C36+ - Breaking the molecular ion into H2+ into 2 protons, thus allowing the 1' to be doubled intensity. These six dedicated strippers for a, 12C, and H2+ are inserted through three vertical holes in the yoke and pole 2 of magnet 3. The beam outputs are therefore in three different azimuths at 120° intervals, feeding three beam lines. These six strippers are mounted on a rod 7 which carries spare strippers to allow for quick replacement of any damaged stripper.

[0049] Reading the intensity on the stripper 6 allows monitoring of the current extracted from the cyclotron.

[0050] Fig. 14

[0051] Vertical section of the magnet (lower half) showing the stripper rod arriving in the median plane

[0052] The following figure represents the extraction of beam a. It can be seen that the stripped beam, which rotates inside a sector 4 where the magnetic field is higher, and whose spiral has been adjusted for this purpose, thus avoids the central region 1. The extraction efficiency will therefore be very close to 99%.

[0053] A magneto-static gradient corrector 5, placed at the output of pole 2 under the coil, ensures the horizontal focusing of the extracted beam.

[0054] The trajectories in harmonic 3 (accelerated H2+, stripped protons), are substantially identical to the harmonic 6 trajectories, requiring a single extraction channel 8 in the cylinder head.

[0055] Fig. 15

[0056] ***

[0057] According to a first aspect, the cyclotron is configured so that its central part is interchangeable. Each central part is configured to accelerate a given type of particle. Thus, there can be two or more interchangeable central parts.

[0058] For example, 2 central regions are interchangeable and compatible with a single HF accelerator system common to the 2 harmonics 3 and 6. In another aspect, it is anticipated that for CyTHER Alpha, the two accelerated ions (He+ and C3+, with the same charge-to-mass ratio) are produced in two separate ECR sources. For CyTHER Beta, a single multi-cusp source (manufactured by our company) is used for the production of molecular hydrogen (H2+). In another aspect, the CyTHER concept is configured to allow the use of a single stripping extraction system for both the CyTHER Alpha and CyTHER beta options.

[0059] ***

[0060] Securing supplies of innovative molecules for European theranostics using Minicyc™ and CyTHER™ cyclotrons

[0061] The nuclear medicine (NM) sector faces recurring difficulties in its supply of radiopharmaceuticals (RPs). These complex molecules containing radionuclides play a crucial role in the management of cancer patients, enabling a more precise diagnosis of the disease with [3+ emitting radionuclides for PET (Positron Emission Tomography) and delivering a# or [3] emitting radionuclides that selectively target cancer cells, thus limiting damage to surrounding healthy organs responsible for the usual side effects of radiotherapy.

[0062] This personalized medical approach combining diagnosis (in particular with Gallium-68) and therapy (in particular with Lutetium 177) is known today under the term theranostics.

[0063] Recently, global supply difficulties have affected Nuclear Medicine services to varying degrees by limiting the availability of these essential diagnostic and therapeutic molecules. Even Fluoride-18 labeled molecules for diagnostic purposes, such as FDG, also encounter disruptions in their production and distribution, which can cause significant delays in cancer treatment due to the inability to perform essential PET scans.

[0064] By their physical and economic dimensions, the new compact Minicyc™ cyclotrons under construction (for [3+] isotopes) and CyTHER™ under development (for a# and [3-] isotopes) offered by the French company AIMA développement represent important innovations in the field of medical cyclotrons, offering the possibility of local production of these essential radionuclides to meet a growing demand for these theranostic drugs.

[0065] These innovations not only improve access to more effective innovative treatments, but also reduce production times and secure the supply subsidiary, thus guaranteeing rapid and effective care for patients requiring these advanced modalities, without risk of interruption in the patient care chain.

[0066] The logistical vulnerabilities of the supply chains for these radiopharmaceuticals have considerable repercussions on public health, compromising rapid access to treatments that offer the best chances of recovery. It is therefore imperative that policymakers in the European Union take these issues into account to ensure a stable and secure supply of radiopharmaceuticals.

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