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, 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 (η,γ) ¹⁷⁷ Yb (β-) 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 (η,γ) ¹⁷⁷ Lu+ ^177m Lu in a mixture of the radionuclides ¹⁷⁷ Lu and ^177m Lu. The presence of the long-lived (161 d) radionuclide ^177m Lu - which production can not be prevented- is a strong drawback of this approach for application in nuclear medicine; moreover, the presence of ¹⁷⁶ Lu 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 ¹⁷⁷ Lu per week.

Some problems with state of the art processes relate amongst others to:

a) Availability of ¹⁷⁷ Lu On demand' of a medical centre is limited. Therefore there is a need for regular purchase of new amounts of ¹⁷⁷ Lu. The supply however may be interrupted, e.g. due to break-down of a supplier facility.

b) Production of no-carrier added ¹⁷⁷ Lu without the need of irradiating isotopically enriched ¹⁷⁶ Yb and associated chemical separations is not possible.

Medical centers depend e.g. on application of ¹⁷⁷ Lu- 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 ¹⁷⁷ Lu and depend in this on the availability at the market and reactor schedules and -operation

c) Irradiation of isotopically enriched ¹⁷⁶ Yb and chemical separations, is not done 'on demand' of a specific medical centre.

Disadvantages mentioned for specific examples such as ¹⁷⁷ Lu 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 ^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. In the case of Lu 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.

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 ^177m Lu and ¹⁷⁶ Lu 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 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.

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

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. Moreover, 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.

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 ¹⁷⁶ Lu atoms, ⁵⁸ Co atoms, ⁸⁰ Br atoms, ¹⁸⁷ Re atoms, ²³² Th atoms, and ¹⁹⁸ Hg atoms.

The following are examples of production routes for the first (parent) atoms listed:

4 ^m Sc : ⁵ Sc(2,2n) ^44m Sc and ⁴⁴ Ca (p, n) ^{4 m} Sc

8 ^0m Br : ⁷⁹ Br (n, γ) ^80m Br, ⁸¹ Br (n, 2n) ^80m Br and ⁸⁰ Se (p, n) ^80m Br

i2im _Sn . i20 _{Sn (n} ^ _y) i2im _Sn/ ¹²² S (n, 2n) ^121m Sn, ¹²¹ Sb (n, p) ^121m Sn and

²³⁵ U(n,f) ^121m Sn

i2im _Te . i20 _{Te (ni Y)} i2im _Te ^ ¹ Te (n, 2n) ^121m Te and ¹²¹ Sb (p, n) ^121m Te

127m _Te . 126 _{Te (n} ^ _Y) 127m _Te ^ 128^ _{( R} ^ _{2 R }} 127^ ^ 121 _{χ ( n} ^ _{p )} 127 _¾η

2 ³⁵ U(n,f ) ^127ra Te

i29m _Te . i28 _{Te (ni Y)} i29m _Te ^ ¹³ °Te (n, 2n) ^129m Te, ¹³² Xe (η,α) ^129m Te and

²³⁵ U(n,f) ^{1 9m} Te

i37m _Ce . i36 _{Ce (n? Y)} i37m _Ce/ ¹³⁸ Ce (n, 2n) ^137m Ce , ¹³⁸ La(p,2n) ^137m Ce and ¹³⁹ La(p,3n) ^137m Ce

1 ^77m Lu : ¹⁷⁶ Lu(n,Y) ^177m Lu and ¹⁷⁷ Hf (n, p) ^177m Lu ¹⁸⁶ ¾e: ¹⁸⁵ Re(n, _Y ) ^186m Re, ¹⁸⁷ Re (n, 2n) ^186m Re, ¹⁸⁶ W (p, n) ^186m Re and

1 ⁸⁶ 0s(n,p) ^186m Re

^192m lr: ¹⁹¹ Ir(n, _Y ) ^192m Ir, ¹⁹³ Ir (n, 2n) ^192m Ir, ¹⁹² 0S (p, n) ^192m Ir and

1 ⁹² Pt (n,p) ^192ra Ir

^198m Au: ¹⁹⁷ Au(n, _Y ) ^198m Au, ¹⁹⁸ Pt (p, n) ^198m Au and ¹⁹⁸ Hg (n, p) ¹⁹⁸ⁿ Au

2 ^42m Am: ²⁴¹ Am(n, _Y ) ²⁴²ⁿ Am.

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; ^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) .

In an example of the present method 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.

It is noted that the following improvements in terms of increased life (long lived) are obtained. For ^44m Sc atoms the half-life is about 15 times longer than for ⁴⁴ Sc atoms. For ^80m Br atoms the half-life is about 15 times longer than for ⁸⁰ Br atoms atoms. For ^121m Sn atoms the half-life is about 17800 times longer than for ¹²¹ Sn atoms. For ^121m Te atoms the half-life is about 9 times longer than for ¹²¹ Te atoms. For ^127m Te atoms the half-life is about 280 times longer than for ¹²⁷ Te atoms. For ^129m Te atoms the half-life is about 695 times longer than for ¹²⁹ Te atoms. For ^137m Ce atoms the half-life is about 4 times longer than for ¹³⁷ Ce atoms. For ^177m Lu atoms the half-life is about 25 times longer than for ¹⁷⁷ Lu atoms. For ^186m Re atoms the half-life is about 2X10 ⁷ times longer than for ¹⁸⁶ Re atoms. For ^192m Ir atoms the half-life is about 1100 times longer than for ¹⁹² Ir atoms. For ^198m Au atoms the half-life is about 0.8 times longer than for ¹⁹⁸ Au atoms. For ^242m Am atoms the half-life is about 7.7X10 ⁴ times longer than for ²⁴² Am 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 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.

In an example, 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.

In an example 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. 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

(daughter) atoms from any other chemical impurity. In the case of the ¹⁷⁷ Lu, this could be the removal of ¹⁷⁷ Hf.

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.

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 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.

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.