NL2017628B1 - Isomeric Transition Radionuclide Generator, such as a 177mLu/177Lu Generator - Google Patents

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 with- in the nucleus or to an atomic electron. The present device comprises a metastable parent/daughter generator, and is capable of producing radionuclides with a high activity in a reliable and constant manner.

Description

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, beta particle, positron, or alpha particles, directly or indirectly; and/or captures an electron. 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. Radionuclide generators are often used as on demand in-house production devices that provide a specific radionuclide generated by parent radionuclide decay without a need for access to an accelerator or research reactor. As such a dependency on irradiation is eliminated and a constant and continuous availability of the radionuclide of interest is warranted.

A nuclear isomer is considered as a metastable state of an atomic nucleus caused by the excitation of one or more of its nucleons. For example, ^177mLu is a high-energy nuclear isomer with a half-life of 160.44 days. It has been found that 7 9.3% of ^177mLu decays by beta emission to their chemical species (^177mHf and ¹⁷⁷Hf) and 21.4% decays to ¹⁷⁷Lu via so-called isomeric transition. An isomeric transition is found to occur either via internal conversion or γ rays emission (see figure 1(a)). During internal conversion, considered as a radiationless decay, an excess of nucleus energy is transferred to an electron in a respective inner shell (or energy level). Other nuclear isomers, such as of Te, Co, and Se, have been separated in the past using internal conversion. In case of other isomers, such as ^177mLu, chemically and physically alike atoms are formed during transition that as a consequence thereof cannot be separate with the chemical and physical techniques available .

When the parent and daughter are of the same chemical element the process of generation is also referred to as isomeric transition. In this process in principle two competing events may be possible, namely internal conversion and the emission of gamma rays; hence a chance to the occurrence of both alternatives can be attributed. Internal conversion is considered to be the process wherein an excess of energy is transferred directly from the nucleus to one electron from an inner shell. That electron leaves the atom with an amount of kinetic energy. For instance, about 20% of ^177mLu decays to ¹⁷⁷Lu via internal conversion (IC). 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).

A good example of a radionuclide generator is provided in WO2013/085383 Al of the same applicant, which document and its contents are incorporated by reference into the present application. The document recites use of metastable ^177mLu as the parent radionuclide for ¹⁷⁷Lu production. It unfortunately does not provide a suitable and practical method to separate the two Lu-isomers.

In an indirect production route ¹⁷⁷Lu may be produced as decay product of short-lived ¹⁷⁷Yb, which is produced by neutron capture of enriched ¹⁷⁶Yb. Despite the fact that nocarrier added ¹⁷⁷Lu is produced in this process, the high cost of enriched ¹⁷⁶Yb and the radiochemical separation of 177Lu from the ¹⁷⁶Yb target are limiting its application. The direct production route produces ¹⁷⁷Lu by neutron capture of enriched ¹⁷⁶Lu with clinically required specific activity at a lower cost. However, during the neutron irradiation the long-lived metastable ^177mLu (Τχ/2= 160.44 days) is co-produced, causing a problem in the waste management of medical centres. On top of these issues, both routes depend on the constant availability of nuclear reactors since weekly irradiations are needed for the production of ¹⁷⁷Lu.

In an alternative ¹⁷⁷Lu may be 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 (160 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.

Radionuclides can be 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 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 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 hemopoietic forms of tumors. More powerful gamma sources sterilize syringes and other medical equipment.

Other uses are e.g. in biochemistry, genetics, and food preservation.

Various examples of use of specific radionuclides exist. For instance, Lutetium-177 (¹⁷⁷Lu) is considered a promising radionuclide for targeted therapy. Low energy β- emissions, a half-life of 6.4 days, and emission of low energy and low abundance γ-rays has made ¹⁷⁷Lu a good candidate for therapy. In view of the low energy β- particles having a tissue penetration of less than 3 mm make ¹⁷⁷Lu suitable for treatment of prostate, breast, melanoma, lung and pancreatic tumours, bone palliation therapy and other chronic diseases. In addition, the low energy γ-rays (208.37 and 112.98 keV) allow simultaneous imaging and quantification of the tumour treatment process in vivo. In an example ¹⁷⁷Lu is used for treating neuroendocrine tumours with ¹⁷⁷Lu-labeled peptides.

In order to emphasize relevance of provision of radionuclides, 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.

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 breakdown 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 ¹⁷⁷LuPRRT (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 device comprising a metastable parent/daughter generator which provides a suitable and practical method to separate the isomers, a method for separating said isomers, a kit, and use of the device, which overcome 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 device with a long-lived radioisotope generator capable of yielding high specific, and/or carrier-free, radioactivity according to claim 1. The device comprises a metastable parent/daughter generator, the generator comprising (i) radioactive parent atoms of the first chemical element, the parent atoms being in a metastable state, (ii) daughter atoms of a first chemical element being radioactive, the daughter atoms being in a second state, such as the ground state, which radioactive daughter is formed by isomeric transition, wherein the parent continuously generates the daughter, (iii) a chemical compound A capable of binding the parent atom, such as in a network which may comprise a solvent, on a solid, incorporated in a solid, and in a fluid, the compound A comprising chemical bonds, which bonds are capable of disruption upon decay of the parent into the daughter, thereby freeing the daughter from the network, and wherein the generator is comprised in a holder having at least one first access opening for providing the generator and at least one second access opening for eluting. In a test example the holder had an inner volume of 0.01-10 ml. The parent and daughter atoms are from the same chemical element. As the parent is metastable it continuously produces decay products, in casu daughter atoms. In view of the present invention advantageously the decay in an internal conversion process. The internal conversion causes bonds of chemical compound A and/or of the Lu-compound to disrupt (or break). As a consequence the Lu-atom, decayed into its daughter, is no longer bonded and can e.g. be eluted. In order to store the daughter atoms until e.g. being used in a further application a holder is provided. The holder has a first access opening (inlet) for providing the generator and optionally an eluting fluid, and at least one second access opening (outlet) for eluting. Typically also a valve or the like may be provided.

The present invention is also subject of a scientific publication by Bhardwaj et al., entitled Separation of nuclear isomers for cancer therapeutic radionuclides based on nuclear decay after-effects, which is submitted for publication in Nat. Comm., 2016, which document and its contents are incorporated into the present specification by reference.

The present separation method provides adequate separation of nuclear isomers. In an example, such as in a reversed phase chromatographic column, the present device may be operated in a variety of conditions, wherein temperature, mobile phase flux and operation mode can be modified. The present generator is found to operate in a reliable and constant fashion; for instance after 168 hours of continuous operation the measured activity ratio values differed only slightly (1.1%) from the average (@ 20°C); typical results achieved are a ratio of about 125; after accumulation a ratio of 250 is typically obtained. Efficiency is found to be about 60%, being independent of temperature. Such provides a proper and constant functioning during the long operative life of the present generator. It is noted that for some exemplary embodiments a flow rate applied during elution of the radionuclide can be limited such as by the retention of a Lu-1,4,7,10tetraazacyclododecane-1,4,7, 10-tetraacetic acid-(Tyr3)octreotate (DOTATA) complex. In an example higher fluxes than

0.1 ml/min may to lead to a displacement of the complex. Temperature displays may play a role on the generator separation performance. For instance association-dissociation kinetics of the present complex may be highly influenced by temperature. A higher dissociation rate is found to provide higher concentration of dissociated radionuclide, such as ^177mLu, in the mobile phase thereby decreasing the activity ratio and the quality of the elution. It is noted that the rate of production of an isomer by internal conversion, such as ¹⁷⁷Lu, is typically independent of temperature, and is time dependent. In an exemplary embodiment an optimal elution temperature is found to be 10 °C. It is noted that an experimental temperature of 0 °C may be close to a freezing point of the mobile phase used; the mass transfer of the freed radionuclide may therefore be hindered, limiting the amount of eluted radionuclide and decreasing the values of the activity ratio and the efficiency. However, in an example the temperature is lowered to below the freezing point and raised only when elution of the radionuclide is required; an even better quality is obtained. Such may e.g. be achieved by lowering to a liquid nitrogen temperature (77 K).

It has been found that good separation of the daughter nuclei (177Lu) from the mother (177mLu) can be achieved if 177mLu is bonded, such as in a stable (thermodynamically and kinetically) complex. To achieve this inventors have used different systems, such as based on DOTA (1,4,7,10tetraazacyclododecane-1,4,7, 10-tetraacetic acid) molecules.

The complex 177mLu-DOTA is for instance retained in a column either by direct chemical bond to the column filler or by polarity. The polar 177Lu+ ions released due to internal conversion can be eluted from the column, while the 177mLu-DOTA complex stays on the column. Because of the very low dissociation constant of Lu-DOTA complexes, the fractions collected at different time are rich in 177Lu produced by the decay of 177mLu, and only traces of the later are found.

It is found that the temperature does not affect the efficiency of the collected radionuclide in any of the operation modes (see figure 3(a) and 4 (a)) .

For some embodiments some care has to be taken. A low flow might not be enough to provide good mass transfer to the freed ¹⁷⁷Lu ions and some of them may re-associate back to the ligand, decreasing in this way slightly the efficiency of the elution (see figure 3 (a)) . Something similar may be occurring to some extend when the flux of 0.05 ml/min is compared with 0.012 ml/min, and small amounts of the complex might elute through the column, decreasing the activity ratio (see figure 3(b) ) .

For the above embodiment some decrease in efficiency may be observed when the accumulation time is extended (figure 4(a) ) .

The present radionuclide (^177mLu/¹⁷⁷Lu) generator is considered to complement prior art production routes.

The present invention is particularly suited for production 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 well applicable to other examples mentioned, and by no means limited to the ^177mLu-¹⁷⁷Lu example.

So 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 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.

The prior art route of producing e.g. ¹⁷⁷Lu provides users thereof with a maximum relative activity of ^177mLu of 0.01-0.02% at the end of bombardment. The maximum activity ratio obtained with the present method/device is now already about 250, which relates to a relative activity of about 0.4%.

The present device and method reduce the high dependency on nuclear reactors to produce radionuclides as ¹⁷⁷Lu.

In a second aspect the present invention provides a method of separating at least two isomeric radionuclide/isotopes comprising the steps of providing a parent, the parent continuously generating a daughter, wherein the parent is bonded to an inert chemical compound A, comprising chemical bonds which are disrupted upon decay of the parent into the daughter, continuously eluting the daughter by a mobile phase, and collecting the daughter. For the present method the present device according to claim 1 can be used. It is noted that some of the steps may be performed in a different sequence, and/or at a later or earlier stage.

In a third aspect the present invention relates to a kit according to claim 21.

In a fourth aspect the present invention relates to a device according to claim 22.

Thereby the present invention provides a solution to one or more of the above-mentioned problems.

Advantages of the present invention are detailed throughout the description.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates in a first aspect to a device according to claim 1.

In an exemplary embodiment of the present device parent atoms are selected from the group comprised of; ^44mSc atoms, atoms, atoms, ^58mCo atoms,

127m_n

192m

Te atoms, Ir atoms, preferably ^177mLu,

0m44m

Br atoms, ^129mTe atoms ^198mAu atoms

127m,

121m

Sn atoms, ^137mCe atoms, ^121mTe atoms, ¹²⁷Sn

7mLu atoms, βπι·

Re

229

Ra atoms, and

242m

Am atoms,

Sc, ^1LTe,

9m,

Te,

7m,

Ce, and βπι·

Re atoms, more preferably Lu, and/or wherein daughter atoms are selected in accordance with parent atoms from the group comprised of ? 7 atoms, atoms,

Sc atoms,

127

Sn atoms, Re atoms,

192

Co atoms Te atoms,

58.

129

Br atoms, Te atoms,

121

137

Sn atoms,

121

Te

Ir atoms, ¹⁹⁸Au atoms,

224

7-r

Ce atoms, Ra atoms,

Lu ²²⁸Ra 129_r and ²⁴²Am atoms, preferably ¹⁷⁷Lu atoms,

44.

Sc, ¹²⁷Te, Te, s. Some atoms/atom pairs are preferred e.g. in terms of half live, eneratoms

137 i Q r Ί V V

Ce, and Re atoms, more preferably Lu atoms. Some at186 gy released upon internal conversion, valence status (es) of the parent atom, as well as in view of intended further uses, etc .

In an exemplary embodiment of the present device the compound A comprises a coordination complex, such as a chelate or chelator, preferably a bidentate, a tetradentate, or a polydentate, wherein the dentate is independently selected from a carboxylate, preferably a C1-C6 carboxylate, such as formate, acetate, lactate, and citrate, a phosphate, and a primary or secondary amine, preferably a C1-C6 amine, preferably a sterically hindered molecule, for example aminopolycarboxylic acid, such as DOTA 1,4,7,10-tetraazacyclododecane1,4,7,10-tetraacetic acid, e.g. (DOTA-(Tyr³)-octreotate DOTATATE), 1,4,7,10-tetraazacyclododecane-l,4,7, 10-tetrakis(methylene phosphonic acid) (DOTP), DOTAGA, EDTA, Acetylacetonate compounds, polyaspartic acid, alginate, ALE, imono disuccinic acid (IDS), L-glutamic acid Ν,Ν-diacetic acid(GLDA), methylglycinediacetic acid (MGDA), ethylene diamineN,N'-disuccinic acid (EDDS) , a derivative thereof, a conjugate thereof, an acid thereof, a base thereof, a salt thereof, or wherein the radionuclide, optionally in the form of a complex, is immobilized or grafted on a solid, or is in a fluid, and combinations thereof. In view of stability often a polydentate compound is preferred.

In an exemplary embodiment of the present device the compound A has a binding affinity to Ca²⁺ of > 2 meq/g Ca, preferably > 5 meq/g Ca, more preferably > 8 meg/g Ca. In view of the variation of chemical atoms Ca²⁺ is taken as a reference for binding affinity towards compound A. Affinity values for specific atoms, such as Lu, are in similar ranges; it is noted that compensation in terms of affinity in view of valence state might be appropriate.

In an exemplary embodiment of the present device the metastable parent and compound A are provided in a molar ratio of 0.2-5, preferably 0.5-2.5, such as 1-2. There is a balance between an amount of radionuclide provided and being available after disruption and binding the radionuclide sufficiently to the compound A in order to obtain a time stable status .

In an exemplary embodiment of the present device the holder is selected from a column, preferably a chromatographic column, more preferably a reversed phase chromatographic column, an ion exchange chromatographic column , an affinity chromatographic column , an expanded bed adsorption chromatographic column, preferably a HPLC column, and an electrophoretic device, such as a capillary electrophoretic device .

In an exemplary embodiment of the present device the holder comprises a filler, such as a silica filler, such as an amino alkyl, such as amino propyl, an alumina filler, a polymer, such as polystyrene, and celluloses, e.g. a tC-18 silica filler.

In an exemplary embodiment of the present device a parent atom-compound A complex has a dissociation constant k_d < 10~⁵ s’¹ at 20 °C, pH=4, and 100 kPa, preferably kd < 10~⁶ s’¹, more preferably kd < 10~⁷ s”¹, such as k_d < 3-10”⁸ s’¹, and/or wherein the compound has an equilibrium constant (radionuclide + A θ Radionuclide-A) of > 10 1/mole (@ 25 °C). It is noted that the above constant may vary, typically increase, with increasing pH. The constant may be obtained by spectrometry, by potentiometry, etc.

In an exemplary embodiment of the present device the parent atoms are present in the form of cations. As such good binding properties versus compound A are obtained.

In an exemplary embodiment of the present device the chemical bonds of the complex have an energy of 200-600 kJ/mole, preferably 250-500 kJ/mole, more preferably 270-450 kJ/mole, such as 300-400 kJ/mole. Therewith at the one hand a stable complex is provided and at the other hand energy released by the internal conversion is capable of breaking said bonds .

In an exemplary embodiment of the present device the internal conversion energy is 100-750 keV, preferably 150500 keV, more preferably 200-400 keV, such as 250-300 keV. Therewith enough energy is provided in order to disrupt chemical bonds .

In an exemplary embodiment of the present device the parent atoms form a strong bond with the compound A, which bond may be considered as a covalent bond, in certain cases in a coordination complex.

In an exemplary embodiment of the present device the device is portable. As such the device can be moved from one location, such as a production site, to a place of intended use.

In an exemplary embodiment of the present device the complex, such as Lu-DOTA, is in a liquid phase. It is put at a low temperature, to have lower kinetics, and then a liquid-liquid extraction is performed, typically a two phase extraction. This is found to work surprisingly well.

In an exemplary embodiment of the present device the radionuclide, e.g. in the form of a DOTA-complex, is immobilized or grafted on a solid, such as silica and polymeric resins. The solid may relate to a micro-particle or nanoparticle, e.g. having a particle size of 10-1000 pm, such as 20 pm, 125 pm, and 500 pm. Such also provides good results. Separation of the freed radionuclide is favoured and separation is easier.

In a second aspect the present invention relates to a method of separating at least two isomeric radionuclide/ isotopes according to claim 14.

In an exemplary embodiment of the present method the mobile phase is selected from polar liquids, such as alcohols, phosphoric acids, such as di-2-ethyl hexyl phosphoric acid (DEHPA), and mono-2-ethyl hexyl phosphoric acid (MEHPA), ketones, aldehydes, aromatics, and ring structured organic molecules, and combinations thereof.

In an exemplary embodiment of the present method the mobile phase is provided at a flow rate of 0.005-10 ml/min, preferably 0.01-5 ml/min, more preferably 0.02-1 ml/min, such as 0.05-0.5 ml/min, and/or at a temperature of 050 °C, preferably 10-37 °C, more preferably 15-30 °C, such as 20-25 °C.

In an exemplary embodiment of the present method eluting is performed during a period of 10 sec-1000 hours, preferably 1 min.-250 hours, more preferably 10 min.-168 hours, even more preferably 30 min.-100 hours, such as 1-60 hours. The flow rate may depend on an amount required and on a size of the device. The temperature may depend on storage temperature, temperature of intended use, etc.

In an exemplary embodiment of the present method the ^177mLu is produced by neutron capture of enriched ¹⁷⁶Lu.

In an exemplary embodiment of the present method the mobile phase is buffered to a pH of 3-7, preferably 4-6, such as 4.55. As such an improved stability is obtained.

In an exemplary embodiment of the present method the mobile phase comprises 1-20 vol.% of an alcohol, preferably a C1-C5 alcohol, 10-1000 mM of a monovalent salt, such as NaCl, and 1-1000 mM of a buffer, such as NaAc/HAc, and wherein the mobile phase has a pH of 3-7.

The invention is further detailed by the accompanying figures and examples, 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

Figure la-b: Schematic representation of the decay process. Figure 2a-d: Separation of nuclear isomers ¹⁷⁷Lu and ^177mLu. Figure 3a-b: Effect of temperature and flow rate on efficiency .

Figure 4a-b: Effect of 177Lu activity accumulation on ratio and efficiency.

Figure 5a-h: Efficiency of accumulation at different temperature and flow rates (average along with the standard deviation).

DETAILED DESCRIPTION OF THE FIGURES

Figure 1. Schematic representation of the decay process. (a) Decay scheme of ^177mLu to ¹⁷⁷Lu. (ii) Process of bond rupture. The metastable isomer ^177mLu is coordinated to a very stable complex (left side). During the decay via internal conversion the nucleus excess of energy is transferred to an inner electron causing an auger electron cascade (center). After the cascade the atom is in a highly charge state, the chemical bonds are broken and the freed ¹⁷⁷Lu can be separated (right side). The present method makes use of nuclear after-effects caused by the internal conversion to separate the newly formed ground state (¹⁷⁷Lu) from the metastable state (^177mLu) .

In an example the present nuclear isomer separation method is based on the combination of three elements (see figure 1): (i) a very inert complex with slow associationdissociation kinetics, (ii) a mechanism that makes use of effects of the internal conversion process that is found to break chemical bonds being present in the complex and (iii) a separation step capable to set apart the complexed element and the freed one.

This present separation method provides separating nuclear isomers, as well as novel radionuclide generators such as with a longer half-life (^177mLu 160.4 days, compared to the

6.7 days half-life of its daughter radionuclide ¹⁷⁷Lu).

As an example of the present method and radionuclide generator a reversed phase chromatographic system was provided. Therein a ^177mLu-DOTA- (Tyr3) -octreotate (DOTATATE) complex (with a dissociation constant k_d = 2 -10”⁸ s”¹ at 20 °C) is retained in a tC-18 silica column. The tC-18 silica filler is found to lack affinity toward polar metal ions, and thus the bond ruptured ¹⁷⁷Lu ions can be eluted off the column using a mobile phase flow. The ^177mLu-DOTATATE complex has a very long retention time with the mobile phase chosen, and remains immobilized on the column during the experiments (shown schematically in figure 2 (a)) .

Figure 2: Separation of nuclear isomers ¹⁷⁷Lu and ^177mLu. (a) Schematic representation of the experimental setup (b) ^177mLu/ ¹⁷⁷Lu activity ratio at continuous elution with a flux of 0.05 ml/min and a temperature of 20 °C. (c) γ ray spectra of the mixture injected in the column with photopeaks having contribution from both ¹⁷⁷Lu(*) and ^177mLu(#) . (d) γ ray spectra of eluted fraction after separation with major photopeaks from ¹⁷⁷Lu(*), less than 0.5% contribution from ^177mLu.

Exemplary experiments with a continuous flow of a mobile phase (also referred to as continuous elution) were performed at different temperatures and mobile phase fluxes. The initial ¹⁷⁷Lu/^177mLu activity ratio in the ^177mLu-cornplex was measured to be 0.24 ± 0.03. After loading the complex on the column, it was eluted with a continuous mobile phase flow at

0.05 ml/min at 20 °C. Figure 2(b) displays obtained ¹⁷⁷Lu/^177mLu activity ratio after different elution times. The ¹⁷⁷Lu/^177mLu activity ratio is found to change in the eluted fractions from the equilibrium value, being about 0.24, to an average ratio of 127114; the enrichment in ¹⁷⁷Lu is increased more than 500 times. The ratio is found to remain stable within a small range up to 60 hours of continuous elution. The gamma spectra before and after separation of the nuclear isomers are displayed in figures 2(c)&(d) respectively. The rather complex decay scheme of the initial mixture as injected in the column,

i.e. that contains ^177mLu, ¹⁷⁷Lu and ^177mHf (figure 2c), is in clear contrast with the gamma spectrum of the eluted sample obtained after separation where only the peaks at 113, 208 and 321 keV, being specific for ¹⁷⁷Lu are present: this results proves the excellent isomer separation provided by the present method.

The efficiency of the separation may be defined as the ratio of the collected ¹⁷⁷Lu activity (eluted) divided by the theoretical activity of ¹⁷⁷Lu produced from the decay of the parent ^177mLu in a specific time. An average of 6412% efficiency is obtained for the continuous elution experiments at 20 °C and 0.05 ml/min as shown in figure 2(b).

Inventors further studied the effect of temperature and elution flux on the activity ratios and efficiency. A range of temperatures from 0 to 30 °C was applied at two different mobile phase fluxes, 0.012 and 0.05 ml/min, respectively. Figure 3 shows the activity ratio and the efficiency at different temperatures for both fluxes.

Figure 3: Effect of temperature and flow rate on efficiency. (a) Effect of temperature on the¹⁷⁷Lu/^177mLu activity ratio at different flow rates ((top)· 0.012 ml/min and (bottom)· 0.05 ml/min). (b) Effect of temperature on the efficiency of separation at different flow rate ((bottom)· 0.012 ml/min and (top)· 0.05 ml/min).

The data shown in figure 3 is a result of averaging six to eight fractions and data is shown with its standard deviation. The activity ratio is found to be remarkably higher at a lower flux for all the temperatures apart form 0 °C. It is found to reach an optimum value of 218110 at a temperature of 10 °C and a flux of 0.012 ml/min. The activity ratio values from 10°C to 30°C show a clear trend for the two fluxes studied; with increasing temperature a decrease in their values is observed, reaching a minimum value of 2513 at 0.05 ml/min and 30 °C. The efficiency exhibits a constant trend for both fluxes in the whole temperature range with slightly higher values for a flux of 0.05 ml/min, reaching a maximum value of 6513% at 10 °C. Only eluting at 0 °C with a flux of 0.012 ml/min gave a lower efficiency, with a value of 4714%.

Figure 4: Effect of 177Lu activity accumulation on ratio and efficiency. Accumulation period is the total time between elutions while there is not mobile phase flux.

(a)177Lu/177mLu activity ratio obtained after accumulation period at different temperatures (·10 °C, ·20 °C, A30 °C). (b)

Efficiency of separation v/s the accumulation time at different temperatures (·10 °C, ·20 °C, A30 °C).

The accumulation period is considered to relate to a total time during which the flux of mobile phase through the column was stopped, such as between elution. Different accumulation periods up to 5 days were checked at 10, 20 and 30 °C respectively. Figure 4 shows the activity ratio and efficiency as a function of accumulation time. The activity ratio follows the same trend as in the above experiments in terms of temperature dependency. Higher activity ratios are observed at low temperatures for different accumulation times. Moreover, bigger ratios than in continuous elution experiments are obtained, reaching a maximum value of 252112 at 10 °C after 5 days of accumulation, leading to an enrichment factor of around 1000. In contrast, efficiency values are lower than in the above continuous elution experiments. No clear trend with temperature is observed. However, in all the cases there is a decrease in efficiency when extending the accumulation period, reaching a minimum around 40%.

Figure 5a-h: Efficiency of accumulation at different temperature and flow rates (average along with the standard deviation) for an exemplary embodiment of the present device having an isomeric transition radionuclide generator with a ^177mLu/¹⁷⁷Lu Generator.

The figures are further detailed in the description and examples below.

EXAMPLES/EXPERIMENTS Methods and materials

Materials: The ^177mLu activity source was provided by IDB Holland. It contained approximately ImM LUCI3 in a 1M HC1 solution with a specific activity of 7.2 MBq/g of LUCI3. In preliminary experiments LUCI3 was neutron activated in the HOR reactor at Delft. DOTATATE (Biosynthema) was provided by the Erasmus medical center, Rotterdam. The reversed phase material used, tC-18 silica, was purchased in the form of ready to use sep-pak cartridges (Sep-Pak Plus tC18, usable for pH 2-8), from Waters .

Synthesis of ^177mLu-DOTA-(Tyr3)-octreotate complex: The ^177mLu solution was adjusted to a pH 4 using a 1M NaOH solution; 20pL of 1M NaAc-HAc buffer was also added to keep the pH around 4 during the reaction. Lu-DOTA-(Tyr3)-octreotate, also referred as Lu-DOTATATE, was synthesized using 0.150 pmoles Lu (150 pL of ImM LUCI3 solution, app. 1 MBq ^177mLu) and 0.278 pmoles DOTATATE leading to a total reaction mixture volume about 1 ml.

The reaction mixture was then incubated at 80 °C for 1 hour. The completion of the reaction was checked using instant thin layer chromatography with 1:1 acetonitrile: water as the mobile phase, and silica as the stationary phase. The reaction conditions resulted in a >99% complexation yield.

Experimental setup description: The experimental set up consists of an HPLC-system consisting of a pump (Shimadzu LClOAi), PEEK tubing and a fraction collector for 20 ml vials. The pump was connected to a column made of peek (ID 2.1 mm*100 mm). The column was manually filled with the tC-18 reversed phase silica (waters). A slurry of tC-18 silica in MeOH was added from one end of the column and the other end was connected with a vacuum pipe. The column was then equilibrated with the mobile phase overnight before injecting the complex. The mobile phase and column were both temperature controlled at the desired temperature by a thermostatic circulation water bath (Colora WK4) and a column water jacket (Alltech). The studied temperatures were 0, 10, 20, and 30 °C.

Mobile phase composition: The mobile phase consists of 5% methanol, 150 mM NaCl solution (ionic strength of 0.148 M), and 10 mM NaAc-HAc buffer (pH-4.3). Mobile phase fluxes of 0.012 ml/min and 0.05 ml/min, respectively, were used during continuous elution, and a flux of 0.1 ml/min is used during accumulation experiments. The whole experimental setup was equilibrated for at least two hours with the mobile phase prior to loading of the complex.

Loading of the complex: The complex was loaded on the column using a Rheodyne injector, with a mobile phase flow of 0.1 ml/min. Prior to injection, a 2 μΐ aliquot was kept aside and measured to establish the exact activity loaded on the column. During the first 30 minutes the flow was set to 1 ml/min to remove free metal and impurities or side-products. It was then used to measure the amount of activity lost in loading, as impurities/ side products. The total activity retained on the column was 1.02 ± 0.02 MBq.

γ ray spectroscopy analysis: All fractions were measured on a well-type HPGe detector. The efficiency calibration for different peaks was performed using a known activity of Lu-177 source supplied by IDB Holland. The fraction with volumes up to 18 ml were collected during the experiments; all measurement were performed with a fixed 0.4 ml aliquot for a time period of 4 hours. The gamma ray spectra were analyzed using inhouse software to calculate the activity in (Bq/g) of each fraction. The activity concentration obtained in Bq/g was then multiplied with the total mass of the fraction to establish an absolute activity coming out in each fraction. To minimize the error, all the vials were weighed before and after the fraction collection.

Continuous elution: In the continuous elution mode two flow rates were studied, 0.012 and 0.05 ml/min respectively, at 10, 20, and 30 °C. For each flow rate and temperature six to eight fractions were collected for 6 hour each. Each fraction was measured on the above mentioned well type germanium detector. The 116KeV transition involved in the decay of ^177mLu to ¹⁷⁷Lu has a theoretical internal conversion coefficient value, a=

30.7. Thus the P.I.C value is calculated to be 96.8%.

Accumulation followed by elution: For accumulation experiments the flow of mobile phase was stopped in the column for 1, 2,

3, 4, 5 days and at 10, 20, and 30 °C respectively. For flush10 ing the accumulated activity a flow rate of 0.1 ml/min was used and the fraction collected in the first 60 minutes was used to measure the efficiency (¹⁷⁷Lu/^177mLu) activity ratios.

Fraction number	Activity Ratio (177Lu/ 177mLu)
at (	)°C	at10°C	at 2	o°c	at 30°C
0.05 mL/min	0.012 mL/min	0.05 mL/min	0.012 mL/min	0.05 mL/min	0.012 mL/min	0.05 mL/min	0.012 mL/min
1	160	134	174	213	147	198	21	56
2	147	131	184	211	141	206	23	51
3	132	135	166	216	145	181	24	55
4	168	136	168	209	126	198	30	52
5	140	146	183	223	139	190	26	58
6	171	158	187	238	106	185	23	59
7	194	161	179		111	190	25	58
8	160				111		26	51
9	178				126
10	170				128
AvgtSTD	162±12	143±12	177±8	218±11	126±14	192±8	25±3	55±3

Table 1: ratios obtained at different temperatures, and flow rates.

For the purpose of search the following section is added, which represents a translation of the last section into

English.

1. Device comprising a metastable parent/daughter generator, the generator comprising (i) radioactive parent atoms of a first chemical element, the parent atoms being in a metastable state, (ii) daughter atoms of the first chemical element being radioactive, the daughter atoms being in a second state, such as the ground state, which radioactive daughter is formed by isomeric transition, wherein the parent continuously generates the daughter, (iii) a chemical compound A capable of binding the parent atom, such as in a network, on a solid, incorporated in a solid, and in a fluid, the compound A comprising chemical bonds, which bonds are capable of disruption upon decay of the parent into the daughter, thereby freeing the daughter from the compound A, and wherein the generator is comprised in a holder having at least one first access opening for providing the generator and at least one second access opening for eluting.

2. Device according to embodiment 1, wherein parent atoms are selected from the group comprised of; 44mSc atoms, 58mCo atoms, 80mBr atoms, 121mSn atoms, 121mTe atoms, 127Sn atoms, 127mTe atoms, 129mTe atoms, 137mCe atoms, 177mLu atoms, 186mRe atoms, 192mlr atoms, 198mAu atoms, 229Ra atoms, and 242mAm atoms, preferably 177mLu, 44mSc, 127mTe, 129mTe, 137mCe, and 186mRe atoms, more preferably 177mLu, and/or wherein daughter atoms are selected in accordance with parent atoms from the group comprised of 44Sc atoms, 58Co atoms, 80Br atoms, 121Sn atoms, 121Te atoms, 127Sn atoms, 127Te atoms, 129Te atoms, 137Ce atoms, 177Lu atoms, 186Re atoms, 192Ir atoms, 198Au atoms, 224Ra atoms, 228Ra atoms, and 242Am atoms, preferably 177Lu atoms, 44Sc,

127Te, 129Te, 137Ce, and 186Re atoms, more preferably 177Lu atoms.

3. Device according to any of the preceding embodiments, wherein the compound A comprises coordination complex, such as a chelate or chelator, preferably a bidentate, a tetradentate, or a polydentate, wherein the dentate is independently selected from a carboxylate, preferably a ClC6 carboxylate, such as formate, acetate, lactate, and citrate, a phosphate, and a primary or secondary amine, preferably a C1-C6 amine, preferably a sterically hindered molecule, for example aminopolycarboxylic acid, such as

DOTA 1,4,7,10-tetraazacyclododecane-l, 4,7, 10-tetraacetic acid, e.g. (DOTA-(Tyr3)-octreotate DOTATATE), 1,4,7,10tetraazacyclododecane-l , 4,7,10-tetrakis(methylene phosphonic acid) (DOTP), EDTA, Acetylacetonate compounds, polyaspartic acid, alginate, ALE, imono disuccinic acid (IDS), L-glutamic acid Ν,Ν-diacetic acid(GLDA), methylglycinediacetic acid (MGDA), ethylene diamine-N,N'-disuccinic acid (EDDS), a derivative thereof, a conjugate thereof, an acid thereof, a base thereof, a salt thereof, or wherein the radionuclide, optionally in the form of a complex, is immobilized or grafted on a solid, or is in a fluid, and combinations thereof.

4. Device according to any of the preceding embodiments, wherein the compound A has a binding affinity to Ca²⁺ of >

meq/g Ca, preferably > 5 meq/g Ca, more preferably > 8 meg/g Ca.

5. Device according to any of the preceding embodiments, wherein the metastable parent and compound A are provided in a molar ratio of 0.2-5, preferably 0.5-2.5, such as 12 .

6. Device according to any of the preceding embodiments, wherein the holder is selected from a column, preferably a chromatographic column, more preferably a reversed phase chromatographic column, an ion exchange chromatographic column, an affinity chromatographic column, an expanded bed adsorption chromatographic column, preferably a HPLC column, and an electrophoretic device, such as a capillary electrophoretic device.

7. Device according to any of the preceding embodiments, wherein the holder comprises a filler, such as a silica filler, an alumina filler, and celluloses, e.g. a tC-18 silica filler.

8. Device according to any of the preceding embodiments, wherein a parent atom-compound A complex has a dissociation constant k_d < 10~⁵ s”¹ at 20 °C, pH=4, and 100 kPa, preferably kd < 10~⁶ s”¹, more preferably kd < 10~⁷ s”¹, such as k_d < 3-10”⁸ s’¹, and/or wherein the compound has an equilibrium constant (radionuclide + A θ Radionuclide-A)of > 10 1/mole (@ 25 °C).

9. Device according to any of the preceding embodiments, wherein the parent atoms are present in the form of cations .

10. Device according to any of the preceding embodiments, wherein the chemical bonds of the complex have an energy of 200-600 kJ/mole, preferably 250-500 kJ/mole, more preferably 270-450 kJ/mole, such as 300-400 kJ/mole.

11. Device according to any of the preceding embodiments, wherein the internal conversion energy is 100-750 keV, preferably 150-500 keV, more preferably 200-400 keV, such as 250-300 keV.

12. Device according to any of the preceding embodiments, wherein the parent atoms form a covalent bond with the complex .

13. Device according to any of the preceding embodiments, wherein the device is portable.

14. Method of separating at least two isomeric radionuclide/ isotopes comprising the steps of providing a parent, the parent continuously generating a daughter, wherein the parent is bonded to an inert chemical compound A, comprising chemical bonds which are disrupted upon decay of the parent into the daughter, continuously eluting the daughter by a mobile phase, and collecting the daughter.

15. Method according to embodiment 14, wherein the mobile phase is selected from polar liquids, such as alcohols, phosphoric acids, such as di-2-ethyl hexyl phosphoric acid (DEHPA), and mono-2-ethyl hexyl phosphoric acid (MEHPA), ketones, aldehydes, aromatics, and ring structured organic molecules, and combinations thereof.

16. Method according to embodiment 14 or 15, wherein the mobile phase is provided at a flow rate of 0.005-10 ml/min, preferably 0.01-5 ml/min, more preferably 0.02-1 ml/min, such as 0.05-0.5 ml/min, and/or at a temperature of 0-50 °C, preferably 10-37 °C, more preferably 15-30 °C, such as 20-25 °C.

17. Method according to any of embodiments 14-16, wherein eluting is performed during a period of 10 sec-1000 hours, preferably 1 min.-250 hours, more preferably 10 min.-168 hours, even more preferably 30 min.-100 hours, such as 15 60 hours.

18. Method according to any of embodiments 14-17, wherein the 177mLu is produced by neutron capture of enriched 176Lu.

19. Method according to any of embodiments 14-18, wherein the mobile phase is buffered to a pH of 3-7, preferably 4-6, such as 4.5-5.

20. Method according to any of embodiments 14-19, wherein the mobile phase comprises 1-20 vol.% of an alcohol, preferably a C1-C5 alcohol, 10-1000 mM of a monovalent salt, such as NaCl, and 1-1000 mM of a buffer, such as NaAc/HAc, and wherein the mobile phase has a pH of 3-7.

21. Kit comprising a product according to any of embodiments

1-13 and/or a single amount obtained by a method according to any of embodiments 14-20.

22. Device according to any of embodiments 1-13 and/or a kit according to embodiment 21 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.

Claims (22)

CONCLUSIONS An apparatus comprising a metastable parent / daughter generator, the generator comprising (i) radioactive parent atoms of a first chemical element, wherein the parent atoms are in a metastable state, (ii) wherein daughter atoms of the first chemical element are radioactive, the daughter atoms in a second state, such as the ground state, where radioactive daughter is formed by isomeric transition, where the parent continuously generates the daughter, (iii) a chemical A that can bind to the parent atom, such as in a network, on a solid , contained in a solid, and in a liquid, wherein the substance A comprises chemical bonds, which bonds can be broken in the daughter after the parent's decay, thereby releasing the daughter from the substance A, and the generator being contained in a holder with at least one first access opening for providing the generator and at least one second access opening for elution. Device according to claim 1, selected from the group comprising 1, where parentato ^44m Sc atoms, ^58m Co atoms, ^80m Br atoms, ^121m Sn atoms, ^121m Atoms, ¹²⁷ Sn atoms, ^127m Atoms, l ^29m Atoms, ^137m Ce atoms, ^177m Lu atoms, ^186m Re atoms, ^192m Ir atoms, ^198m Au atoms, ²²⁹ Ra atoms and ^242m Arn atoms, with atoms, more preferably ^177m Lu, and / or the daughter atoms are chosen according to parent atoms from the group consisting of ⁴⁴ Sc atoms, ⁵⁸ Co atoms, ⁸⁰ Br atoms, ¹²¹ Sn atoms, ¹²¹ Atoms, atoms, ¹²⁷ Atoms, ¹²⁹ Atoms, ¹³⁷ Ce atoms, ¹⁷⁷ Lu atoms, ¹⁸⁶ Re atoms, ¹⁹² Ir atoms, ¹⁹⁸ Au atoms, ²²⁴ Rath atoms, ²²⁸ Rathoms, and ²⁴² Am atoms, preferably ¹⁷⁷ Lu atoms, ⁴⁴ Sc, ¹²⁷ Te, ¹²⁹ Te, ¹³⁷ Ce, and ¹⁸⁶ Re atoms, more preferably ¹⁷⁷ Lu atoms. Device according to any one of the preceding claims, wherein the compound A comprises a coordination complex, such as a chelate or a chelator, preferably a bidentate, a tetradentate, or polydentate, wherein the dentate is independently selected from a carboxylate, preferably a C1 -C6 carboxylate, for example formate, acetate, lactate, and citrate, a phosphate, and a primary or secondary amine, preferably a C1 -C6 amine, preferably a sterically hindered molecule, for example aminopolycarboxylic acid, such as DOTA 1,4,7, 10-tetraazacyclododecane-1, 4,7,10-tetraacetic acid, such as (DOTA (Tyr ³ ) -Octreotate DOTATATE), 1,4,7, 10-tetraazacyclododecane-1,4,7,10-tetrakis (methylene phosphonic acid) (DOTP ), EDTA, acetylacetonate compounds, polyaspartic acid, alginate, ALE, imonodisuccinic acid (IDS), L-glutamic acid N, N-diacetic acid (GLDA), methylglycine diacetic acid (MGDA), ethylenediamine N, N'-disuccinic acid (EDDS), a derivative thereof, a conjugate thereof, an acid thereof, a base thereof , a salt thereof, or wherein the radionuclide, optionally in the form of a complex, is immobilized or grafted onto a solid or fluid, and combinations thereof. Device according to any of the preceding claims, wherein the compound A has a binding affinity with Ca ²⁺ of> 2 meq / g Ca, preferably> 5 meq / g Ca, preferably> 8 meq / g Ca. A device according to any one of the preceding claims, wherein the metastable parent and compound A are provided in a molar ratio of 0.2-5, preferably 0.5-2.5, such as 1-2. The device according to any of the preceding claims, wherein the container is selected from a column, preferably a chromatographic column, preferably a reverse phase chromatographic column, an ion exchange chromatography column, an affinity chromatographic column, an expanded bed adsorption chromatography column, at preferably an HPLC column, and an electrophoretic device, such as a capillary electrophoretic device. The device of any preceding claim, wherein the container comprises a filler, such as a silica filler, an alumina filler, and cellulose, such as a tC-18 silica filler. The device according to any of the preceding claims, wherein a parent atom-compound A complex has a dissociation constant k _d <10 ~ ⁵ s " ¹ at 20 ° C, pH = 4, and 100 kPa, preferably k _d <10 ~ ⁶ s " ¹ , more preferably kd <10 ~ ⁷ s" ¹ , such as kd <3-10 ~ ⁸ s " ¹ , and / or wherein the compound has an equilibrium constant (radionuclide + A · θ · Radionuclide-A) of> 10 1 / mol (@ 25 ° C). Device according to any one of the preceding claims, wherein the parent atoms are present in the form of cations. Device according to any one of the preceding claims, wherein the chemical bonds of the complex have an energy of 200-600 kJ / mol, preferably 250-500 kJ / mol, more preferably 270-450 kJ / mol, such as 300-400 kJ / mol. Device according to any of the preceding claims, wherein the internal energy conversion is 100-750 keV, preferably 150-500 keV, more preferably 200-400 keV, such as 250-300 keV. The device of any one of the preceding claims, wherein the parent atoms form a covalent bond with the complex. Device as claimed in any of the foregoing claims, wherein the device is portable. A method for separating at least two isomeric radionuclide / isotopes comprising the steps of providing a parent, the parent continuously generating a daughter, the parent being bound to an inert chemical compound A, including chemical bonds that decay from the parent to the daughter being broken, continuous elution of the daughter through a mobile phase, and collecting the daughter. The method of claim 14, wherein the mobile phase is selected from polar liquids, such as alcohols, phosphoric acids, such as di-2-ethyl-hexyl phosphoric acid (DEHPA), and mono-2-ethyl hexyl phosphoric acid (MEHPA), ketones, aldehydes , aromatics, and ring structured organic molecules, and combinations thereof. A method according to claim 14 or 15, wherein the mobile phase is provided at a flow rate of 0.00510 ml / min, preferably 0.01-5 ml / min, more preferably 0.02-1 ml / min, for example 0.05-0.5 ml / min and / or at a temperature of 050 ° C, preferably 10-37 ° C, more preferably 15-30 ° C, such as 20-25 ° C. A method according to any of claims 14-16, wherein the eluting is carried out for a period of 10 seconds-1000 hours, preferably 1 minute-250 hours, more preferably 10 minutes -68 hours, more preferably 30 minutes-100 hours, for example 1-60 hours. 5 The method of any one of claims 14-17, wherein the ^177m Lu is produced by neutron ^capture of enriched ¹⁷⁶ Lu. The method of any one of claims 14-18, wherein the mobile phase is buffered to a pH of 3-7, at Preferably 4-6, for example 4.5-5. The method of any one of claims 14-19, wherein the mobile phase comprises 1-20% by volume of an alcohol, preferably a C1-C5 alcohol, 10-1000 mM of a monovalent salt, such as NaCl, and 1- 1000 mM of a buffer, such as NaAc / HAc, and Wherein the mobile phase has a pH of 3-7. A kit comprising a product according to any of claims 1-13 and / or a single amount obtained by a method according to any of claims 14-20. Device according to any of claims 1-13 and / or a kit according to claim 21 for the preparation of a medicament, for example for use in radiotherapy or imaging, such as peptide receptor radiation therapy, for diagnosis or treatment. 1/3 ^Fn Lu FIG. la (ί, / 2 = 160.44 days) FIG. lb isomeric transition (21.4%) _t Internal conversion electron ⁱ⁷⁷ Lu (t _lft = 6.64 days) iniemai conversion fesöing to bona raptors 4. Auger Reckon cascade FIG. 3b 1000 J 100 -J o • 5 « FIG. 3a Hi70as fiatie in epeiilibncfn Ö14-r 1 --- J ---; -'- 1 ---! --- Γ5 10 15 20 25 30 Temperature fC) 0 5 to 20 20S 30 Temperature (“C) 302/3 3/3 Temp-O ^V C; Egg rate G.G32mL'fnin; Average Efficiency4?; Sl% Temp 0 * C; Ftow-raw? O.OSmUmm; Aw «$ s Efficiency .6Sfc $% Temp ll / C; Fkwraie ikOSmLW Average Efficiency 55 :: 3% TempWv; Flow rate 0 OigiBL / mic. Average Efficiency 53> 5T < Time incurs) Temp 20 * 0, Flow rate O.OamUmm; Average: βίβρί «ρργ. & Ί · ί2% Temp20 * C: Rwvrate0 0t2mt.7min: Average Ei & sancy 00 *>% Ternc30 ^'s C; FiPVsQate O OSmLTnin; Average Efficiency 67 :: 4%: T ^ p / 30 * G: iRöwT8i0 0.03 KmLffnin; .Average E ^ cfeccy 01a3% Time (tote)