EP2788989A1 - Radionuclide generator having first and second atoms of a first element - Google Patents

Radionuclide generator having first and second atoms of a first element

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Publication number
EP2788989A1
EP2788989A1 EP12824875.4A EP12824875A EP2788989A1 EP 2788989 A1 EP2788989 A1 EP 2788989A1 EP 12824875 A EP12824875 A EP 12824875A EP 2788989 A1 EP2788989 A1 EP 2788989A1
Authority
EP
European Patent Office
Prior art keywords
atoms
present
life
radioactive
generator
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP12824875.4A
Other languages
German (de)
French (fr)
Other versions
EP2788989B1 (en
Inventor
Peter Bode
Hubertus Theodoor WOLTERBEEK
Daniel Justin DE VRIES
Marcelis DE BRUIN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Technische Universiteit Delft
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Technische Universiteit Delft
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Publication date
Application filed by Technische Universiteit Delft filed Critical Technische Universiteit Delft
Priority to PL12824875T priority Critical patent/PL2788989T3/en
Publication of EP2788989A1 publication Critical patent/EP2788989A1/en
Application granted granted Critical
Publication of EP2788989B1 publication Critical patent/EP2788989B1/en
Not-in-force legal-status Critical Current
Anticipated expiration legal-status Critical

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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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  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Engineering & Computer Science (AREA)
  • General Engineering & Computer Science (AREA)
  • High Energy & Nuclear Physics (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

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. Radionuclide generators contain a parent isotope that decays to produce a radioisotope. The parent is usually produced in a nuclear reactor.

Description

Radionuclide generator having first and second atoms of a first element
FIELD OF THE INVENTION
The invention is in the field of a radionuclide generator .
BACKGROUND OF THE INVENTION
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.
The generator of US 4,182,231 and similar generators are not relevant to the present invention. US 4,782,231 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.
In nuclear medicine, radioisotopes are used for diagnosis, treatment, and research. 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.
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.
Other uses are e.g. in biochemistry, genetics, and food preservation.
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) .
Various examples of use of radionuclides exist.
For instance, according to current practice, 177Lu (half-life 6.7 d) is produced by a neutron activation of stable 176Yb containing targets according to the nuclear reaction 176Yb (η,γ) 177Yb (β-) 177Lu. Subsequently, the 177Lu is chemically separated from the target 176Yb and parent radionuclide 177Yb, 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 176Lu containing targets takes place, which result by the nuclear reaction 176Lu (η,γ) 177Lu+177mLu in a mixture of the radionuclides 177Lu and 177mLu. The presence of the long-lived (161 d) radionuclide 177mLu - which production can not be prevented- is a strong drawback of this approach for application in nuclear medicine; moreover, the presence of 176Lu atoms of the target material result in a lower specific radioactivity.
In order to emphasize relevance of provision of radi¬ onuclides, currently 500 patients per year are treated in Erasmus Medical Centre (EMC) in The Netherlands alone. The EMC pur¬ chases 2 batches of 1 Ci 177Lu per week.
Some problems with state of the art processes relate amongst others to:
a) Availability of 177Lu On demand' of a medical centre is limited. Therefore there is a need for regular purchase of new amounts of 177Lu. The supply however may be interrupted, e.g. due to break-down of a supplier facility.
b) Production of no-carrier added 177Lu without the need of irradiating isotopically enriched 176Yb and associated chemical separations is not possible.
Medical centers depend e.g. on application of 177Lu- PRRT (peptide receptor radiation therapy) on the market availability and operationally of nuclear production reactors. It is noted that recently, research reactors have broken down unexpectedly, and that reactors have scheduled maintenance times as well.
Up till now, Medical centers have to regularly purchase new amounts of 177Lu and depend in this on the availability at the market and reactor schedules and -operation
c) Irradiation of isotopically enriched 176Yb and chemical separations, is not done 'on demand' of a specific medical centre.
Disadvantages mentioned for specific examples such as 177Lu are in principle also applicable to other radionuclides or isotopes .
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.
SUMMARY OF THE INVENTION
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 177mLu-177Lu generator, as well as production of 44mSc, 127mTe, 129mTe, 137raCe, and 186mRe. The examples below also specifically relate to the aforementioned. It is noted that in principle the example of the 177mLu-177Lu generator is equally well applicable to other examples mentioned, and by no means limited to the 177mLu-177Lu 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. In the case of Lu the period is extended from a multiple of 6.7 days (the half-life of 177Lu) to a multi¬ ple of 160 days (the half-life of 177mLu) , 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.
Further the need for a carrier is reduced or absent. Therefore 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 177mLu and 176Lu where the increase factor is at least 100.
As indicated above 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 177Lu, without a need of irradiating an isotopically enriched target, such as 176Yb, 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.
It is noted that 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
177Lu-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 177mLu-177Lu, radionuclide generator of in the example 177Lu (half-life 6.7 d) from a parent (in the exam¬ ple 177mLu (half-life 160 d) ) during a prolonged period, in the example at least half a year after availability of the generator. Moreover, an eluted radio isotope, e.g. 177Lu, is no- carrier added.
Prior art techniques provide availability of an once- only amount of a radioisotope, such as177Lu, from e.g. a neutron irradiated amount of in the example 176Lu or 176Yb, whereas the present invention enables e.g. a 177mLu-177Lu generator in which at desired intervals, amounts of daughter radioisotope e.g. 177Lu can be removed from a given amount of parent isotope e.g. 177mLu.
Specifically the present generator provides in an example no-carrier added isotopes, having high specific activity. Such is required for various applications.
Under suited experimental conditions, 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 .
Further, there are no disadvantages of the present process apart from the necessary entrance to a neutron source coupled to a radiochemical infrastructure.
DETAILED DESCRIPTION OF THE INVENTION
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.
In an example of the present method 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.
It is noted that various routes starting from a tar- get may lead to the present invention in that first and second atoms of a single element according to the invention are obtained. Typically activating is performed in well protected environments, thereby reducing a risk of contamination of the en¬ vironment with radioisotopes, such as in nuclear reactors. In the present invention there is some preference for using smaller particles, such as indicated above, such as neutrons and protons .
In an example 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.
In an example of the present method target atoms, such as naturally occurring or isotopically enriched atoms, and method of production, are selected from the group comprising 176Lu atoms, 58Co atoms, 80Br atoms, 187Re atoms, 232Th atoms, and 198Hg atoms.
The following are examples of production routes for the first (parent) atoms listed:
4 mSc : 5Sc(2,2n)44mSc and 44Ca (p, n) 4 mSc
80mBr : 79Br (n, γ) 80mBr, 81Br (n, 2n) 80mBr and 80Se (p, n) 80mBr
i2imSn. i20Sn (n^y) i2imSn/ 122S (n, 2n) 121mSn, 121Sb (n, p) 121mSn and
235U(n,f)121mSn
i2imTe. i20Te (ni Y) i2imTe^ 1 Te (n, 2n) 121mTe and 121Sb (p, n) 121mTe
127mTe. 126Te (n^Y) 127mTe^ 128^ ( R ^ 2 R } 127^ ^ 121 χ ( n ^ p ) 127¾η
235U(n,f )127raTe
i29mTe. i28Te (ni Y) i29mTe^ 13°Te (n, 2n) 129mTe, 132Xe (η,α) 129mTe and
235U(n,f)1 9mTe
i37mCe. i36Ce (n? Y) i37mCe/ 138Ce (n, 2n) 137mCe , 138La(p,2n)137mCe and 139La(p,3n)137mCe
177mLu : 176Lu(n,Y)177mLu and 177Hf (n, p) 177mLu 186¾e: 185Re(n,Y)186mRe, 187Re (n, 2n) 186mRe, 186W (p, n) 186mRe and
1860s(n,p)186mRe
192mlr: 191Ir(n,Y)192mIr, 193Ir (n, 2n) 192mIr, 1920S (p, n) 192mIr and
192Pt (n,p)192raIr
198mAu: 197Au(n,Y)198mAu, 198Pt (p, n) 198mAu and 198Hg (n, p) 198nAu
242mAm: 241Am(n,Y) 242nAm.
It is therefore noted that various routes starting from a target may lead to the present invention in that first and second atoms of a single element according to the invention are obtained.
In an example of the present method first atoms are selected from the group comprised of; 44mSc atoms, 80mBr atoms, 121mSn atoms, 121mTe atoms, 127mTe atoms, 1 9mTe atoms, 137mCe atoms, 177mLu atoms, 186mRe atoms, 192mIr atoms, 198mAu atoms, and 242mAm atoms, preferably 177raLu atoms, mSc, 127mTe, 1 9mTe, 137mCe, and 186mRe . The decay characteristics of these parent/daughter atoms are all experimentally found to be useful (e.g. in a medical / research sense) .
In an example of the present method second atoms are selected in accordance with first atoms from the group comprised of; 44Sc atoms, 80Br atoms, 121Sn atoms, 121Te atoms, 127Te atoms, 129Te atoms, 137Ce atoms, 177Lu atoms, 186Re atoms, 192Ir atoms, 198Au atoms, and 24Am atoms, such as 177Lu atoms.
It is noted that the following improvements in terms of increased life (long lived) are obtained. For 44mSc atoms the half-life is about 15 times longer than for 44Sc atoms. For 80mBr atoms the half-life is about 15 times longer than for 80Br atoms atoms. For 121mSn atoms the half-life is about 17800 times longer than for 121Sn atoms. For 121mTe atoms the half-life is about 9 times longer than for 121Te atoms. For 127mTe atoms the half-life is about 280 times longer than for 127Te atoms. For 129mTe atoms the half-life is about 695 times longer than for 129Te atoms. For 137mCe atoms the half-life is about 4 times longer than for 137Ce atoms. For 177mLu atoms the half-life is about 25 times longer than for 177Lu atoms. For 186mRe atoms the half-life is about 2X107 times longer than for 186Re atoms. For 192mIr atoms the half-life is about 1100 times longer than for 192Ir atoms. For 198mAu atoms the half-life is about 0.8 times longer than for 198Au atoms. For 242mAm atoms the half-life is about 7.7X104 times longer than for 242Am atoms. In an example 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. In a further exam pie 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.
Accordingly the present' invention relates to a pro¬ cess for the production of no-carrier added daughter atoms, such as 177Lu atoms, of high specific radioactivity, character¬ ized in that atoms, such as176Lu atoms, are bombarded with neutrons resulting in formation of radioactive atoms, such as 177mLu (half-life 160 d) , and radioactive 177Lu (half-life 6.7 d) ; the latter formed by direct production from 176Lu as well a a decay product of 177mLu) , all incorporated in the target. The radioactive 177Lu atoms separate by bond rupture from the 176Lu and 177mLu atoms contained in the target.
In an example, the radionuclide generator comprises the following; the neutron activated 176Lu plus its reaction products, 177mLu and 177Lu to e.g. a solution. The solution is mixed with another solvent to which only the 177Lu is trans¬ ferred from the mixture of radioisotopes. Similar examples are envisaged for the other examples mentioned.
In an example a generator, such as a 177mLu-177Lu 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 177mLu. Such a generator can in an example provide 7-8 batches of radio isotope, such as 177Lu, 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 177Lu during a period of 7-8 months rather than purchase 80 batches of 177Lu 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
(daughter) atoms from any other chemical impurity. In the case of the 177Lu, this could be the removal of 177Hf.
This bond rupture continues also after completion of the irradiation, as soon as 177Lu is formed by the decay of 177mLu . The separated 177Lu radioactive atoms are removed from the said chemical compound or matrix by a chemical process with high selectivity for 177Lu compared to the chemically identical i75/i76Lu a†-oms anc[ parent radionuclide 177mLu. After this removal, new 177Lu atoms are formed from the decay of 177mLu, and the procedure of removal of 1 7Lu can be repeated after sufficient formation time. A 177mLu-177Lu radionuclide generator is thus created, allowing the regular removal of amounts of 177Lu from a single amount of 177mLu.
It is noted that isotopes of the same chemical ele¬ ment have the same chemical behavior and therefore can not normally be separated by conventional chemical methods.
In an example of the present method 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.
In an example of the present method, 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.
It is noted that dimensions of the generator can be adapted, e.g. increasing or decreasing a size thereof, thereby potentially controlling the amount of radioisotope being released. In this respect also the 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.
In an example of the present product the radioisotope generator :
is present on a surface, and/or
is present in a liquid, and/or
is present in a matrix, and/or
is present in a chemical compound, and/or
is present in a complex, and/or combinations thereof.
In an example 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 μηα, such as 1 nm -2 μκι. Thereby release of daughter atoms is improved.
As such as supporting layer/structure may be provided, such as a chemically inert layer, a zeolite, etc. Even further 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.
In an example of the present product the radioisotope generatoris 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.
In an example of the present product it comprises _„
11
a tube, 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 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 long-lived, high specific activity or carrier-free radioisotope generator inside the tube.
Through the inlet typically a liquid is provided to the generator. The liquid collects the daughter radionuclide.
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. Similar, 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. Therewith 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 177Lu 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.
In an example 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.
The invention is further detailed by the accompanying figures, which are exemplary and explanatory of nature and are not limiting the scope of the invention. To the person skilled in the art it may be clear that many variants, being obvious or not, may be conceivable falling within the scope of protection, defined by the present claims.
FIGURES
The invention although described in detailed explanatory context may be best understood in conjunction with the accompanying figures.
Figure 1-2 show a schematic representation of an example of a generator (such as the product of the claims) .
DETAILED DESCRIPTION OF THE DRAWINGS / FIGURES
Figure 1 shows a schematic representation of a generator. Therein 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. Further 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. Also the inlet is of a chemically inert material. Possibly it may also comprise a protection layer. Further an outlet (3) is shown for releasing the liquid from the tube. The outlet and inlet typically have similar properties. In order to protect the environment from radiation optionally 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.
Figure 2 shows details of a generator.
In Figure 2a a section of a plated tube is shown 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) .
In figure 2b a further example is given, wherein the deposited layer comprises spherical particles or the like, typically particles having a diameter of 0.2-10 nm.
In figure 2c the generator is filled with plated beads, having a similar composition as above.
It should be appreciated that for commercial application it may be preferable to use one or more variations of the present system, which would similar be to the ones disclosed in the present application and are within the spirit of the invention.

Claims

1. Method for production of a long-lived radioisotope generator capable of yielding high specific, and/or carrier- free, radioactivity, comprising the steps of:
(a) providing a target,
(b) activating the target thereby obtaining a radioisotope generator, the radioisotope generator comprising
(i) radioactive first atoms (parent) of a first element having a first half-life, the first atoms being in a metastable state,
(ii) second atoms (daughter) of a first element being radioactive having a second half-life, the second atoms being in a second state, such as the ground state, wherein the second atom is a radioactive daughter of the first parent atom, which radioactive daughter is formed by emission of a highly converted gamma-ray transition, such as by E2, E3, E4, E5, M2, M3, M4, M5, or combination thereof, and
wherein optionally the first half-life is at least 2 times longer than the second half-life, preferably at least 5 times longer, even more preferably at least 10 times longer, such as at least 25 times longer, and
(c) optionally incorporating the activated target, including first atoms, second atoms, and inactive target atoms, by electrochemical or physical deposition onto an inert surface .
2. Method according to claim 1, wherein activating is performed by one or more of the following methods : neutron reaction, proton reaction, photonuclear reactions, such as gamma- or X-ray, alpha particle reaction, and ion beam reaction.
3. Method according to claims 1 or 2, wherein target atoms, such as naturally occurring or isotopically enriched at¬ oms, and method of production, are selected from the group comprising 176Lu atoms, 58Co atoms, 80Br atoms, 187Re atoms, 232Th atoms, and 198Hg atoms.
4. Method according to any of the preceding claims, wherein first atoms are selected from the group comprised of; mSc atoms, 80mBr atoms, 121mSn atoms, 121mTe atoms, 127mTe atoms, 129mTe atoms, 137mCe atoms, 177mLu atoms, 186mRe atoms, 192mIr atoms, 198mAu atoms, and 42mAm atoms, preferably 177mLu, 44mSc, 127mTe, 129mTe, 137mCe, and 186mRe atoms.
5. Method according to any of the preceding claims, wherein second atoms are selected in accordance with first atoms from the group comprised of; 4 Sc atoms, 80Br atoms, 1 1Sn atoms, 121Te atoms, 127Te atoms, 129Te atoms, 137Ce atoms, 177Lu atoms, 186Re atoms, 192Ir atoms, 198Au atoms, and 2 2Am atoms, preferably 177Lu atoms.
6. Method according to any of the preceding claims, further comprising a step of:
separating the first atoms under formation of second atoms, preferably by chemical separation, preferably
wherein the second atoms are separated into a liquid medium, such as a gas, a liquid, and supercritical fluid, or a combination thereof.
7. Method according to claim 6, wherein the liquid medium preferably is water and comprises one or more solutes, such as salts, acids, bases, adjuvants, saccharides, and stabilizers .
8. Long-lived, high specific activity and/or carrier- free radioisotope generator, the radioisotope generator comprising
(i) radioactive first atoms (parent) of a first element having a first half-life, the first atoms being in a metastable state,
(ii) second atoms (daughter) of the first element being radioactive having a second half-life, the second atoms being in a second state, such as the ground state, wherein the second atom is a radioactive daughter of the first atom (parent) , and the radioactive daughter is formed by emission of a highly converted gamma-ray, such as by E2, E3, E4, E5, M2, M3, M4, M5, or combination thereof, and
wherein optionally the first half-life is at least 2 times longer than the second half-life, preferably at least 5 times longer, even more preferably at least 10 times longer, such as at least 25 times longer, obtainable by a method ac- cording to any of claims 1-7.
9. Product comprising the long-lived, high specific activity and/or carrier-free, radioisotope generator according to claim 8.
10. Product according to claim 9, wherein the radioisotope generator:
is present on a surface, and/or
is present in a liquid, and/or
is present in a matrix, and/or
is present in a chemical compound, and/or
is present in a complex, and/or combinations thereof.
11. Product according to claim 10, wherein 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.
12. Product according to claim 11, comprising a tube (1), 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, tan- talum, titanium, metal alloy, or a combination thereof,
an inlet (2) for providing a liquid into the tube, an outlet (3) for releasing the liquid from the tube, optionally a protection (6) surrounding the tube for preventing radiation from effecting the environment, such as a lead comprising protection, and
a long-lived, high specific activity or carrier-free radioisotope generator inside the tube.
13. Single amount of radioactive atoms, such as 177Lu atoms, obtainable by a method according to any of claims 1-7, or provided by a product according to any of claims 9-12 or generator according to claim 8.
14. Kit comprising a product according to any of claims 10-13 and/or a single amount according to claim 13.
15. Product according to any of claims 9-12 and/or a single amount according to claim 13 for the preparation of a medicament, such as for use in radiotherapy or imaging, such as peptide receptor radiation therapy, for the purpose of diagnosis or treatment.
EP12824875.4A 2011-12-06 2012-12-06 Radionuclide generator having first and second atoms of a first element Not-in-force EP2788989B1 (en)

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NL2007925A NL2007925C2 (en) 2011-12-06 2011-12-06 Radionuclide generator.
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US10867710B2 (en) 2015-09-30 2020-12-15 Terrapower, Llc Molten fuel nuclear reactor with neutron reflecting coolant
US10665356B2 (en) 2015-09-30 2020-05-26 Terrapower, Llc Molten fuel nuclear reactor with neutron reflecting coolant
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NL2017628B1 (en) 2016-10-17 2018-04-24 Univ Delft Tech Isomeric Transition Radionuclide Generator, such as a 177mLu/177Lu Generator
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US11286172B2 (en) 2017-02-24 2022-03-29 BWXT Isotope Technology Group, Inc. Metal-molybdate and method for making the same
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WO2013085383A1 (en) 2013-06-13
NL2007925C2 (en) 2013-06-10

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