NL2007925C2

NL2007925C2 - Radionuclide generator.

Info

Publication number: NL2007925C2
Application number: NL2007925A
Authority: NL
Inventors: Peter Bode; Hubertus Theodoor Wolterbeek; Daniel Justin Vries; Marcelis Bruin
Original assignee: Univ Delft Tech
Priority date: 2011-12-06
Filing date: 2011-12-06
Publication date: 2013-06-10
Also published as: EP2788989A1; WO2013085383A1; RU2014127513A; PL2788989T3; RU2630475C2; EP2788989B1

Description

Radionuclide Generator

FIELD OF THE INVENTION

The invention is in the field of a radionuclide gen- 5 erator.

BACKGROUND OF THE INVENTION

A radionuclide is an atom with an unstable nucleus, which is a nucleus characterized by excess energy available to 10 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 15 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 20 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 25 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 contain a parent isotope that 30 decays to produce a (daughter) radioisotope. 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.

35 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 non-radioactive nuclides, so almost all chemical, biological, and 2 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 5 about a person's internal anatomy and the functioning of specific 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 he-10 mopoietic 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.

15 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.

20 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 (n, y) 177Yb (|3- ) 177Lu. Subsequently, the 177Lu is chemically separated from the target 176Yb and parent radionuclide 177Yb, 25 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 (n,y) 177Lu+177mLu in a mixture of the radionuclides 177Lu and 30 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.

35 In order to emphasize relevance of provision of ra dionuclides, currently 500 patients per year are treated in Erasmus Medical Centre (EMC) in The Netherlands alone. The EMC purchases 2 batches of 1 Ci 177Lu per week.

3

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 5 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.

10 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 15 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 20 separations, is not done 'on demand' of a specific medical centre.

The present invention therefore relates to a method of providing a radionuclide generator, the generator, products comprising said generator, and use thereof, which overcomes 25 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 30 a method for production of a long-lived radioisotope generator capable of yielding high specific, and/or carrier-free, radioactivity according to claim 1, a long-lived radioisotope generator, a product comprising said radioisotope generator, a single amount, a kit, and use thereof.

35 The present invention is particularly suited for pro duction of a 177mLu-177Lu generator, as well as production of 44mSc, 127mTe, 129mTe, 137mCe, 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 4 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 5 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) 10 to a multiple of 160 days (the half-life of 177mLu) , in other words an increase 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. 15 Therefore the present invention provides a generator with high specific activity. The specific activity is significantly increased, typically by at least a factor of 10, compared to chemically identical atoms, such as in an example 177mLu and 176Lu where the increase factor is at least 100.

20 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 25 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 30 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 isotopes of the same chemical element have in prin-35 ciple the same chemical behavior and therefore can not normally be separated by conventional chemical methods.

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 5 availability and operational schedule of nuclear reactors.

The present invention provides continuous production of a, in an example 177raLu-177Lu, radionuclide generator of in the example 177Lu (half-life 6.7 d) from a parent (in the exam-5 pie 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 nocarrier added.

Prior art techniques provide availability of an once-10 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 15 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-20 dionuclide generator results in an assured availability of radionuclides of high specific radioactivity for an extended period of time e.g. dependent on the half-life of the parent radionuclide instead of the half-life of the daughter radionuclide .

25 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 30 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 35 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.

6

It is 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. Typically activating is performed in well protected 5 environments, thereby reducing a risk of contamination of the environment 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 .

10 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, 15 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 20 (parent) atoms listed: 44mSc: 45Sc (2,2n) 44mSc and 44Ca (p, n) 44mSc 80mBr: 79Br (n, y) 8°mBr, 81Br (n, 2n) 80mBr and 80Se (p, n) 80mBr 121mSn: 120Sn (n, y) 121mSn, 122Sn (n, 2n) 121mSn, 121Sb (n, p) 121mSn and 235U (n, f) 121mSn 25 121mTe: 120Te (n, y) 121mTe, 122Te (n, 2n) 121mTe and 121Sb (p, n) 121mTe 127mTe: 126Te (n, y) 127mTe, 128Te (n, 2n) 127mTe, 127I (n,p)127mSn and 235U (n, f) 127mTe 129mTe: 128Te (n, y) 129mTe, 130Te (n, 2n) 129mTe, 132Xe (n, a) 129mTe and 235U (n, f) 129mTe 30 137mCe: 136Ce (n, y) 137mCe, 138Ce (n, 2n) 137mCe, 138La (p, 2n) 137mCe and 139La (p, 3n) 137mCe 177mLu: 176Lu(n, y) 177mLu and 177Hf (n, p) 177mLu 186mRe: 185Re (n, y) 186mRe, 187Re (n, 2n) 186mRe, 186W (p, n) 186mRe and 1860s (n,p) 186mRe 35 192mIr: 191Ir (n, y) 192mIr, 193Ir (n, 2n) 192mIr, 1920s (p, n) 192mIr and 192Pt (n,p) 192mIr 198mAu: 197Au(n, y) 198mAu, 198Pt (p, n) 198mAu and 198Hg (n,p) 198mAu 242mAm: 241Am(n, Y) 242mAm.

It is therefore noted that various routes starting 7 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 5 selected from the group comprised of; 44mSc atoms, 80mBr atoms, 121mSn atoms, 121mTe atoms, 127mTe atoms, 129mTe atoms, 137mCe atoms, 177mLu atoms, 186mRe atoms, 192mIr atoms, 198mAu atoms, and 242mArn atoms, preferably 177mLu atoms, 44mSc, 127mTe, 129mTe, 137mCe, and 186mRe. The decay characteristics of these parent/daughter atoms 10 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 15 atoms, 129Te atoms, 137Ce atoms, 177Lu atoms, 186Re atoms, 192Ir atoms, 198Au atoms, and 242Am 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 20 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 25 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 30 i92mjr a-j-oms 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 242mArn atoms the half-life is about 7.7X104 times longer than for 242Am atoms.

In an example the present method further comprises a 35 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 gamma-ray in the decay of parent atoms. It is believed that this 8 emission results in an Auger cascade in which the orbital electrons are ejected from their shells. Consequently, a variety of highly positively charged daughter atoms are formed.

The Coulomb repulsion between these atomic fragments may, in 5 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 example a similar mechanism may occur when target, parent and 10 daughter atoms are present as a solid, e.g. a solid layer. The present invention results in a specific radioactivity of daughter 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 proc-15 ess 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 20 d) ; the latter formed by direct production from 176Lu as well as 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 25 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 transferred from the mixture of radioisotopes. Similar examples are envisaged for the other examples mentioned.

30 In an example a generator, such as a 177mLu-177Lu gen erator, 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 activi-35 ties 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 177mLu-177Lu 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 9 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 5 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 10 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 175/176Lu atoms and parent radionuclide 177mLu. After 15 this removal, new 177Lu atoms are formed from the decay of 177mLu, and the procedure of removal of 177Lu 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.

20 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, 25 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.

30 In an example of the present method, the liquid me dium 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 35 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.

10

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 5 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.

10 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 15 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 (am, such as 1 nm -2 |lm. Thereby release of 20 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 25 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 30 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, 35 such as in a complex with one or more organic molecules, in a complex with one or more inorganic molecules, and combinations thereof.

11

In an example of the present product it comprises 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, 5 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 com-10 prising 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. 15 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 com-20 prising 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, ob-25 tainable 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 30 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 com-35 prises 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 12 example 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 me-5 dicament, 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 per-10 son 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

15 The invention although described in detailed ex planatory context may be best understood in conjunction with the accompanying figures.

Figure 1-2 show a schematic representation of a generator.

20 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 25 such as copper, tantalum, titanium, metal alloy, or a combination 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 protec-30 tion 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 35 further comprises a long-lived, high specific activity or carrier-free radioisotope generator inside the tube. The generator can be in any suitable form, such as described above.

13

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-5 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 10 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 15 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

Method for producing a long-lived radioisotope generator capable of providing highly specific and / or carrier-free radioactivity, comprising the steps of: (a) providing a target, (b) activating the target under the obtaining a radioisotope generator, wherein the radioisotope generator, comprises (i) radioactive first atoms (parent) of a first element with a first half value, the first atoms being in a metastable state, ( ii) second atoms (daughter) of a first element that is radioactive with a second half value, wherein the second atoms are 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-radiation transition, such as by E2, E3, E4, E5, M2, M3, M4, M5, or combination thereof, and optionally with the first half value being at least two the time is longer than the second half value, preferably at least 5 times longer, more preferably at least 10 times longer, such as at least 25 times longer and 25 (c) in which optionally the activated target, including the first atoms, second atoms , and inactive target atoms, have been introduced into an inert surface by electrochemical or physical deposition.

2. A method according to claim 1, wherein the activation is performed by one or more of the following methods: neutron reaction, proton reaction, photonuclear reactions, such as gamma or X-radiation, alpha particle reaction, and ion beam reaction.

3. A method according to claim 1 or 2, wherein target atoms, such as naturally occurring or isotope-enriched atoms, and the production method, are selected from the group comprising 176 Lu atoms, 58 Co atoms, 80 Br atoms, 187 Re atoms, 232 Th atoms, -IQO and Hg atoms.

The method of any one of the preceding claims, wherein first atoms are selected from the group consisting of; 44mSc atoms, 80mBr atoms, 121mSn atoms, 121mTe atoms, 129mTe atoms, 137mCe atoms, 177mLu atoms, 186mRe atoms, 192mir 5 atoms, 198mAu atoms, and 242mArn atoms, preferably 177mLu, 44mSc, 137mC, 129, 127mC, and 186mRe atoms.

A method according to any one of the preceding claims, wherein second atoms are selected in accordance with the first atoms from the group consisting of; 44 Sc atoms, 80 Br 10 atoms, 121 Sn atoms, 121 Te atoms, 127 Te atoms, 129 Te atoms, 137 Ce atoms, Lu atoms, Re atoms, Ir atoms, Au atoms, and 242 Am atoms, preferably 177 Lu atoms.

6. A method according to any one of the preceding claims, further comprising a step of: separating the first atoms to form second atoms, preferably by chemical separation.

7. A method according to claim 6, wherein the second atoms are separated in a liquid medium, such as a gas, a liquid, and supercritical liquid, or a combination thereof.

The method of claim 7, wherein the liquid medium is preferably water and comprises one or more solutes, such as salts, acids, bases, excipients, saccharides, and stabilizers.

9. A long-lived, high specific activity and / or carrier-free radioisotope generator, the radioisotope generator, comprising (i) radioactive first atoms (parent) of a first element with a first half-value, the first atoms in a metastable state, (ii) are second atoms (daughter) of a first element that is radioactive with a second half-value, 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-radiation transition, such as by E2, E3, E4, E5, M2, M3, M4, M5, or combination thereof, and optionally the first half value is at least two times longer than the second half value, preferably at least 5 times longer, more preferably at least 10 times longer, such as at least 25 times longer, obtainable by a method according to any of the claims loops 1-8.

A product comprising a high specific activity and / or carrier-free radioisotope generator according to claim 9.

The product of claim 10, 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.

The product of claim 11, wherein the radioisotope generator is present on a chemically inert surface, such as an interior surface of a tube-like structure, a surface of a particle, present dissolved in a liquid, 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.

13. Product according to claim 12, consisting of a tube (1), the tube consisting of an inner surface 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 (2) for providing a liquid in the tube, an outlet (3) for releasing the liquid from the tube, optionally a protection (6) around the tube for preventing radiation from reaching the environment, such as a lead-containing protection and a long service life, high specific activity and / or carrier-free radioisotope generator in the tube.

A single amount of radioactive atoms, such as 40 177 Lu atoms, obtainable by a method according to any of claims 1-8, or provided by a product according to any of claims 10-13 or generator according to claim 9.

15. Kit consisting of a product according to any of claims 10-13 and / or a single amount according to claim 14.

16. Product according to any of claims 10-13 and / or a single amount according to claim 14 for the preparation of a medicament, for example for use in radiotherapy or imaging, such as peptide receptor irradiation, for diagnosis or treatment.