Classifications

• • G—PHYSICS
  • G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
  • G21G—CONVERSION OF CHEMICAL ELEMENTS; RADIOACTIVE SOURCES
  • G21G1/00—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes
  • G21G1/0005—Isotope delivery systems
• • G—PHYSICS
  • G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
  • G21G—CONVERSION OF CHEMICAL ELEMENTS; RADIOACTIVE SOURCES
  • G21G1/00—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes
• • G—PHYSICS
  • G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
  • G21G—CONVERSION OF CHEMICAL ELEMENTS; RADIOACTIVE SOURCES
  • G21G1/00—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes
  • G21G1/001—Recovery of specific isotopes from irradiated targets
  • G21G2001/0094—Other isotopes not provided for in the groups listed above

Definitions

• Radionuclide generator having first and second atoms of a first element
• the invention is in the field of a radionuclide generator .
• a radionuclide is an atom with an unstable nucleus, which is a nucleus characterized by excess energy available to be imparted either to a newly created radiation particle within the nucleus or to an atomic electron.
• the radionuclide in this process, undergoes radioactive decay, and emits one or more of the following; photons, negatron, positron, or alpha particles, directly or indirectly. These particles constitute ionizing radiation. Radionuclides occur naturally, and can also be artificially produced.
• the number of radionuclides is uncertain. Some nuclides are stable and some decay. The decay is characterized by a half-life. Including artificially produced nuclides, more than 3300 nuclides are known (including ⁇ 3000 radionuclides), including many more (> ⁇ 2400) that have decay half-lives shorter than 60 minutes. This list expands as new radionuclides with very short half-lives are identified.
• Radionuclides are often referred to by chemists and physicists as radioactive isotopes or radioisotopes. Radioisotopes with suitable half-lives play an important part in a number of constructive technologies (for example, nuclear medicine) .
• Radionuclide generators are devices in which a (daughter) radionuclide is generated from its parent precursor radionuclide and is optionally separated therefrom .
• the parent is usually produced in a nuclear reactor, which is a complex and expensive system.
• a typical example is the technetium-99m generator used in nuclear medicine.
• the parent produced in the reactor is molybdenum-99.
• US 4,782,231 recites a standard component 99mTC elu- tion generator useful for medical purposes .
• the invention further provides for efficient generation of 99mTC radionuclides from medium neutron flux irradiation of molybdenum in a natural isotopic mixture.
• US 4,182,231 recites standard chemical separation of two radionuclides of chemically different elements .
• Radionuclides are used in two major ways: for their chemical properties and as sources of radiation. Radionuclides of familiar elements such as carbon can serve as tracers because they are assumed to be chemically identical to the nonradioactive nuclides, so almost all chemical, biological, and ecological processes treat them in the same way.
• Radioactive tracers emitting gamma rays or positrons can provide diagnostic information about a person's internal anatomy and the functioning of spe ⁇ cific organs. This is used in some forms of tomography: single- photon emission computed tomography (SPECT) and positron emission tomography (PET) scanning.
• SPECT single- photon emission computed tomography
• PET positron emission tomography
• Radioisotopes are also a method of treatment in hemopoietic forms of tumors; the success for treatment of solid tumors has been limited. More powerful gamma sources sterilize syringes and other medical equipment.
• a nucleus In gamma de-excitation, a nucleus gives off excess energy, by emitting a gamma ray. The element is not changed to another element in the process (no nuclear transmutation is involved) .
• radionuclides Various examples of use of radionuclides exist.
• 177 Lu (half-life 6.7 d) is produced by a neutron activation of stable 176 Yb containing targets according to the nuclear reaction 176 Yb ( ⁇ , ⁇ ) 177 Yb ( ⁇ -) 177 Lu. Subsequently, the 177 Lu is chemically separated from the target 176 Yb and parent radionuclide 177 Yb, and a no-carrier added product of high specific activity is obtained.
• This approach exists next to a previously employed production route wherein activation of stable 176 Lu containing targets takes place, which result by the nuclear reaction 176 Lu ( ⁇ , ⁇ ) 177 Lu+ 177m Lu in a mixture of the radionuclides 177 Lu and 177m Lu.
• the present invention therefore relates to a method of providing a radionuclide generator, the generator, products comprising said generator, and use thereof, which overcomes one or more of the above disadvantages, without jeopardizing functionality and advantages.
• the present invention relates in a first aspect to a method for production of a long-lived radioisotope generator capable of yielding high specific, and/or carrier-free, radio ⁇ activity according to claim 1, a long-lived radioisotope gener ⁇ ator, a product comprising said radioisotope generator, a single amount, a kit, and use thereof.
• the present invention is particularly suited for production of a 177m Lu- 177 Lu generator, as well as production of 44m Sc, 127m Te, 129m Te, 137ra Ce, and 186m Re.
• the examples below also specifically relate to the aforementioned. It is noted that in principle the example of the 177m Lu- 177 Lu generator is equally well applicable to other examples mentioned, and by no means limited to the 177m Lu- 177 Lu example.
• the present invention solves one or more of the above mentioned problems.
• the risk of lack of market availability and operational disruption of nuclear reactors is limited to a large extent; the present invention provides for on demand delivery of radio isotopes in a required amount for a significant longer period of time.
• the period is extended from a multiple of 6.7 days (the half-life of 177 Lu) to a multi ⁇ ple of 160 days (the half-life of 177m Lu) , in other words an in- crease by a factor of about 25.
• a similar improvement is obtained for other atoms, specifically the ones mentioned above.
• the present invention provides a generator with high specific activity.
• the specific activity is signifi- cantly increased, typically by at least a factor of 10, com ⁇ pared to chemically identical atoms, such as in an example 177m Lu and 176 Lu where the increase factor is at least 100.
• the present invention provides a long-lived radioisotope generator.
• Long-lived is relative to the half-life of a daughter nuclide.
• the increase in generator life time is typically at least a factor 2, i.e. being useful two times longer, although a factor of more than 1000 is also achievable .
• the present invention provides for production of high specific activity no-carrier added isotopes, such as 177 Lu, without a need of irradiating an isotopically enriched target, such as 176 Yb, and depending on the isotope without a need of associated chemical separations thereof.
• the present invention is therefore amongst others easier, e.g. in terms of process steps, and as a consequence is available on-demand, contrary to most prior art isotopes, which have to be purchased.
• the invention relates to a generator comprising first and second radionuclides of the same chemical element: isotopes of the same chemical element have in princi ⁇ ple the same chemical behavior and therefore can not normally be separated by conventional chemical methods; in an aspect, the invention provides separation .
• the present invention provides medical centers with an easy option to apply the present isotopes, such as
• Lu-PRRT 1 77 Lu-PRRT, largely without being dependent on e.g. the market availability and operational schedule of nuclear reactors.
• the present invention provides continuous production of a, in an example 177m Lu- 177 Lu, radionuclide generator of in the example 177 Lu (half-life 6.7 d) from a parent (in the exam ⁇ ple 177m Lu (half-life 160 d) ) during a prolonged period, in the example at least half a year after availability of the generator.
• an eluted radio isotope e.g. 177 Lu, is no- carrier added.
• Prior art techniques provide availability of an once- only amount of a radioisotope, such as 177 Lu, from e.g. a neutron irradiated amount of in the example 176 Lu or 176 Yb, whereas the present invention enables e.g. a 177m Lu- 177 Lu generator in which at desired intervals, amounts of daughter radioisotope e.g. 177 Lu can be removed from a given amount of parent isotope e.g. 177m Lu.
• the present generator provides in an example no-carrier added isotopes, having high specific activity. Such is required for various applications.
• the present ra ⁇ dionuclide generator results in an assured availability of ra ⁇ dionuclides of high specific radioactivity for an extended pe ⁇ riod of time e.g. dependent on the half-life of the parent ra ⁇ dionuclide instead of the half-life of the daughter radionuclide .
• the present invention relates in a first aspect to a method for production of a long-lived radioisotope, optionally incorporated into a generator, and capable of yielding no carrier added high specific activity according to claim 1.
• activating is performed by one or more of the following methods: neutron reaction, such as by bombarding by neutrons, proton reaction, photonuclear reactions, such as gamma- or X-ray, alpha particle reaction, and ion beam reaction.
• first and second atoms of a single element according to the invention are obtained.
• activating is performed in well protected environments, thereby reducing a risk of contamination of the en ⁇ vironment with radioisotopes, such as in nuclear reactors.
• radioisotopes such as in nuclear reactors.
• smaller particles such as indicated above, such as neutrons and protons .
• the bombardment of the target compound with neutrons occurs in a reactor, whereas according to another example the bombardment occurs outside the reactor in a neutron beam or in a proton beam from e.g. a cyclotron.
• target atoms such as naturally occurring or isotopically enriched atoms, and method of production, are selected from the group comprising 176 Lu atoms, 58 Co atoms, 80 Br atoms, 187 Re atoms, 232 Th atoms, and 198 Hg atoms.
• first atoms are selected from the group comprised of; 44m Sc atoms, 80m Br atoms, 121m Sn atoms, 121m Te atoms, 127m Te atoms, 1 9m Te atoms, 137m Ce atoms, 177m Lu atoms, 186m Re atoms, 192m Ir atoms, 198m Au atoms, and 242m Am atoms, preferably 177ra Lu atoms, m Sc, 127m Te, 1 9m Te, 137m Ce, and 186m Re .
• the decay characteristics of these parent/daughter atoms are all experimentally found to be useful (e.g. in a medical / research sense) .
• second atoms are selected in accordance with first atoms from the group comprised of; 44 Sc atoms, 80 Br atoms, 121 Sn atoms, 121 Te atoms, 127 Te atoms, 129 Te atoms, 137 Ce atoms, 177 Lu atoms, 186 Re atoms, 192 Ir atoms, 198 Au atoms, and 24 Am atoms, such as 177 Lu atoms.
• the half-life is about 15 times longer than for 44 Sc atoms.
• the half-life is about 15 times longer than for 80 Br atoms atoms.
• the half-life is about 17800 times longer than for 121 Sn atoms.
• the half-life is about 9 times longer than for 121 Te atoms.
• the half-life is about 280 times longer than for 127 Te atoms.
• the half-life is about 695 times longer than for 129 Te atoms.
• the present method further comprises- a step of separating the first atoms under formation of second atoms, preferably by chemical separation.
• the separation is obtained according to the invention by taking advantage of the emission of a highly converted gam ⁇ ma-ray in the decay of parent atoms. It is believed that this emission results in an Auger cascade in which the orbital elec trons are ejected from their shells. Consequently, a variety o highly positively charged daughter atoms are formed.
• the Cou ⁇ lomb repulsion between these atomic fragments may, in the case of a chemical compound, result in the rupturing of chemical bonds between compound and daughter atoms, and as a consequence these daughter atoms will be separated from both the target compound and the parent radionuclide.
• a similar mechanism may occur when target, parent and daughter atoms are present as a solid, e.g. a solid layer.
• the present invention results in a specific radioactivity of daugh ter which is typically at least a factor of 100 higher than if the daughter is not separated from the target.
• the present' invention relates to a pro ⁇ cess for the production of no-carrier added daughter atoms, such as 177 Lu atoms, of high specific radioactivity, character ⁇ ized in that atoms, such as 176 Lu atoms, are bombarded with neutrons resulting in formation of radioactive atoms, such as 177m Lu (half-life 160 d) , and radioactive 177 Lu (half-life 6.7 d) ; the latter formed by direct production from 176 Lu as well a a decay product of 177m Lu) , all incorporated in the target.
• the radioactive 177 Lu atoms separate by bond rupture from the 176 Lu and 177m Lu atoms contained in the target.
• the radionuclide generator comprises the following; the neutron activated 176 Lu plus its reaction products, 177m Lu and 177 Lu to e.g. a solution.
• the solution is mixed with another solvent to which only the 177 Lu is trans ⁇ ferred from the mixture of radioisotopes. Similar examples are envisaged for the other examples mentioned.
• a generator such as a 177m Lu- 177 Lu gener ⁇ ator, is provided loaded with 0.02-500 Ci radio isotope, such as from 0.5-250 Ci, such as from 1-100 Ci, such as 2-50 Ci, such as with 177m Lu.
• Ci radio isotope such as from 0.5-250 Ci, such as from 1-100 Ci, such as 2-50 Ci, such as with 177m Lu.
• Such a generator can in an example provide 7-8 batches of radio isotope, such as 177 Lu, with activities varying from 175 - 0.001 Ci during a period of 7-8 months. For a weekly consumption as described above, the EMC would need 2-4
• Lu- Lu generators (procured sequentially over 2-4 weeks) for having a continuous weekly availability of 177 Lu during a period of 7-8 months rather than purchase 80 batches of 177 Lu over the same period, which is a clear advantage.
• the liquid used may be of an oxidizing nature and or have some ionic strength in order to facilitate ⁇ the collection of the second (daughter) atoms.
• This liquid may be selected such that it can be used in chemical separation of second
• This bond rupture continues also after completion of the irradiation, as soon as 177 Lu is formed by the decay of 177m Lu .
• the separated 177 Lu radioactive atoms are removed from the said chemical compound or matrix by a chemical process with high selectivity for 177 Lu compared to the chemically identical i75/i76 Lu a ⁇ - oms anc [ p ar ent radionuclide 177m Lu. After this removal, new 177 Lu atoms are formed from the decay of 177m Lu, and the procedure of removal of 1 7 Lu can be repeated after sufficient formation time.
• a 177m Lu- 177 Lu radionuclide generator is thus created, allowing the regular removal of amounts of 177 Lu from a single amount of 177m Lu.
• isotopes of the same chemical ele ⁇ ment have the same chemical behavior and therefore can not normally be separated by conventional chemical methods.
• the second atoms are separated into a liquid medium, such as a gas, a liquid, and supercritical fluid, or a combination thereof.
• the liquid medium should be capable of receiving daughter atoms. If used directly in a subsequent application, the liquid medium should be acceptable within that application as well, e.g. non-toxic, resembling body fluid, etc.
• the liquid medium preferably is water and comprises one or more solutes, such as salts, acids, bases, adjuvants, saccharides, and stabilizers .
• Such liquid medium may be adapted to mimic e.g. a body fluid, e.g. in terms of typical concentrations of solutes therein .
• the present invention relates in a second aspect to a long-lived, high specific activity and/or carrier-free radioisotope generator according to claim -9-8.
• dimensions of the generator can be adapted, e.g. increasing or decreasing a size thereof, thereby potentially controlling the amount of radioisotope being released.
• amount of liquid provided to the generator, surface of the generator, etc. can be adapted.
• the present invention relates in a third aspect to a product comprising the long-lived, high specific activity and/or carrier-free radioisotope generator according to the invention.
• the radioisotope generator In an example of the present product the radioisotope generator :
• the generator is present having a large surface area and a small volume, e.g. as a layer of 1 atom thick ( ⁇ 100 pm) -10 ⁇ , such as 1 nm -2 ⁇ . Thereby release of daughter atoms is improved.
• the generator may be present in a compound, such as a chemical compound capable of forming (chemical) bonds with the daughter and parent atoms, and optionally with the target atoms, or likewise in a complex.
• the generator may also be present in a liquid, such as water, a gas, such as nitrogen, and the like.
• the radioisotope generator is present on a chemically inert surface, such as an inner surface of a tube like structure, a surface of a particle, is present dissolved in a liquid, is present in a 3D- and/or 2D-matrix, such as a zeolite, is in a chemical compound, such as in an organometallic compound, is in a complex, such as in a complex with one or more organic molecules, in a complex with one or more inorganic molecules, and combinations thereof.
• a chemically inert surface such as an inner surface of a tube like structure, a surface of a particle, is present dissolved in a liquid, is present in a 3D- and/or 2D-matrix, such as a zeolite, is in a chemical compound, such as in an organometallic compound, is in a complex, such as in a complex with one or more organic molecules, in a complex with one or more inorganic molecules, and combinations thereof.
• a tube comprising an inner surface, being formed of a chemically inert material, such as glass, Teflon, a suitable polymer, silicon, a metal such as copper, tantalum, titanium, metal alloy, or a combination thereof,
• a chemically inert material such as glass, Teflon, a suitable polymer, silicon, a metal such as copper, tantalum, titanium, metal alloy, or a combination thereof,
• an inlet for providing a liquid into the tube an outlet for releasing the liquid from the tube, a protection surrounding the tube for preventing radiation from effecting the environment, such as a lead comprising protection, and
• a liquid is provided to the generator.
• the liquid collects the daughter radionuclide.
• the liquid After collecting a sufficient amount of radioisotope the liquid is released through the outlet.
• the amount released per unit time can be calculated, e.g. in order to determine residence time.
• a continuous flow of liquid may be provided, typically at a low flow rate, providing liquid comprising the daughter radionuclide.
• the flow rate may be from 0.1 ml/h-50 ml/h.
• a controllable amount of radioisotope can be provided.
• the present invention relates in a fourth aspect to a single amount of radioactive atoms, such as 177 Lu atoms, obtainable by a method according to the invention, or provided by a product according to the invention or generator according to the invention.
• the single amount is from 0.02-5 Ci, such as from 0.02-1.6 Ci, such as from 0.1-1.0 Ci .
• the present invention relates in a fifth aspect to a kit comprising a product according to the invention and/or a single amount according to the invention.
• the kit comprises the above generator. Further the kit may comprise a liquid, such as 0.1 - 1000 mL per single amount to be obtained. Preferably the liquid comprises further components, such as the above solutes. As such the obtained single amount may be directly used for its intended (final) purpose.
• the kit may further comprise a syringe, such as a 10-250 ml syringe. Typically also gloves are supplied.
• the kit may further comprise a storage kit. In an exam ⁇ ple the kit is substantially free of microorganisms.
• the present invention relates in a sixth aspect to a use of a product according to the invention and/or a single amount according to the invention for the preparation of a medicament, such as for use in therapy, such as peptide receptor radiation therapy.
• Figure 1-2 show a schematic representation of an example of a generator (such as the product of the claims) .
• FIG. 1 shows a schematic representation of a generator.
• a tube (1) is shown, the tube comprising an inner surface, being formed of a chemically inert material, such as glass, Teflon, a suitable polymer, silicon, a metal such as copper, tantalum, titanium, metal alloy, or a combina- tion thereof.
• an inlet (2) is shown for providing a liquid into the tube.
• a typical inner dimension of the inlet is .01-10 mm, such as 0.3-5 mm.
• the inlet is of a chemically inert material. Possibly it may also comprise a protection layer.
• an outlet (3) is shown for releasing the liquid from the tube.
• the outlet and inlet typically have similar properties.
• a protection (6) surrounding the tube is present, such as a lead comprising protection.
• the product further comprises a long-lived, high specific activity or carrier-free ra- dioisotope generator inside the tube.
• the generator can be in any suitable form, such as described above.
• FIG. 2 shows details of a generator.
• a section of a plated tube comprising element A: a deposited layer of first atoms (monoatomic or multiple layers); the layer may include non- radioactive atoms of the same element); element B: a chemically inert surface (e.g. glass, tantalum, silicon, etc.), and element C: a structural material; this material may include a shielding material (e.g. lead) .
• the deposited layer comprises spherical particles or the like, typically particles having a diameter of 0.2-10 nm.

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• 2011
  • 2011-12-06 NL NL2007925A patent/NL2007925C2/en not_active IP Right Cessation
• 2012
  • 2012-12-06 WO PCT/NL2012/050856 patent/WO2013085383A1/en active Application Filing
  • 2012-12-06 EP EP12824875.4A patent/EP2788989B1/en not_active Not-in-force
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