WO2018074918A1 - Générateur de radionucléides à transition isomérique, tel qu'un générateur 177m lu/ 177 lu - Google Patents

Générateur de radionucléides à transition isomérique, tel qu'un générateur 177m lu/ 177 lu Download PDF

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Publication number
WO2018074918A1
WO2018074918A1 PCT/NL2017/050674 NL2017050674W WO2018074918A1 WO 2018074918 A1 WO2018074918 A1 WO 2018074918A1 NL 2017050674 W NL2017050674 W NL 2017050674W WO 2018074918 A1 WO2018074918 A1 WO 2018074918A1
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atoms
parent
daughter
radionuclide
acid
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PCT/NL2017/050674
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English (en)
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Rupali BHARDWAJ
Antonia Georgieva DENKOVA
Pablo Serra CRESPO
Hubert Theodoor Wolterbeek
Jorge Gascon SABATE
Marcel DE BRUIN
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Technische Universiteit Delft
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Publication of WO2018074918A1 publication Critical patent/WO2018074918A1/fr

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    • G—PHYSICS
    • G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
    • G21G—CONVERSION OF CHEMICAL ELEMENTS; RADIOACTIVE SOURCES
    • G21G1/00—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes
    • G21G1/0005—Isotope delivery systems
    • G—PHYSICS
    • G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
    • G21G—CONVERSION OF CHEMICAL ELEMENTS; RADIOACTIVE SOURCES
    • G21G1/00—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes
    • G21G1/04—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes outside nuclear reactors or particle accelerators
    • G21G1/06—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes outside nuclear reactors or particle accelerators by neutron irradiation

Definitions

  • the invention is in the field of a radionuclide generator.
  • a radionuclide is an atom with an unstable nucleus, which is a nucleus characterized by excess energy available to be imparted either to a newly created radiation particle within the nucleus or to an atomic electron.
  • the radionuclide in this process, undergoes radioactive decay, and emits one or more of the following; photons, 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 pro- prised.
  • 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.
  • 177m Lu is a high-energy nuclear isomer with a half-life of 160.44 days. It has been found that 19.3% of 177in Lu decays by beta emission to their chemical species (i77m Hf and i 7 H f) anc ⁇ 21.4% decays to 177 Lu via so-called isomeric transition. An isomeric transition is found to occur either via internal conversion or ⁇ rays emission (see figure 1 (a) ) .
  • 177 Lu may be produced as decay product of short-lived 17 Yb, which is produced by neutron capture of enriched 176 Yb.
  • the direct produc- tion route produces 177 Lu by neutron capture of enriched 176 Lu with clinically required specific activity at a lower cost.
  • both routes depend on the constant availability of nuclear reactors since weekly irradiations are needed for the production of 177 Lu.
  • 177 Lu may be produced by a neutron activation of stable 176 Yb containing targets according to the nu- clear reaction 176 Yb (n, ⁇ ) 177 Yb ( ⁇ -) 177 Lu . Subsequently, the 17 Lu is chemically separated from the target 176 Yb and parent radionuclide 177 Yb, and a no-carrier added product of high specific activity is obtained.
  • This approach exists next to a previously employed production route wherein activation of stable 176 Lu containing targets takes place, which result by the nuclear reaction 176 Lu ( ⁇ , ⁇ ) 177 Lu+ 177m Lu in a mixture of the radionuclides 177 Lu and 177m Lu.
  • 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 be- cause 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.
  • 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 sy ⁇ ringes and other medical equipment.
  • SPECT single-photon emission computed tomography
  • PET positron emission tomography
  • Lutetium-177 ( 177 Lu) is considered a promising radionuclide for targeted therapy.
  • Low energy ⁇ - emissions, a half-life of 6.4 days, and emission of low energy and low abundance ⁇ -rays has made 177 Lu a good candidate for therapy.
  • the low energy ⁇ - particles having a tissue pene ⁇ tration of less than 3 mm make 177 Lu suitable for treatment of prostate, breast, melanoma, lung and pancreatic tumors, bone palliation therapy and other chronic diseases.
  • the low energy ⁇ rays (208.37 and 112.98 keV) allow simultaneous imaging and quantification of the tumor treatment process in vivo.
  • 177 Lu is used for treating neuroendocrine tumors with 177 Lu-labeled peptides.
  • 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.
  • 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
  • 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
  • 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
  • the compound A comprises a coordination complex, 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, and wherein the genera ⁇ tor is comprised in a holder having at least one first access opening for providing the generator and at least one second access opening
  • 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 metasta- ble it continuously produces decay products, in casu daughter atoms.
  • the de- cay in an internal conversion process.
  • the internal conversion causes bonds of chemical compound A and/or of the Lu-compound to disrupt (or break) .
  • the Lu-atom, decayed into its daughter is no longer bonded and can e.g. be eluted.
  • a holder is provided in order to store the daughter atoms until e.g. being used in a further application.
  • 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.
  • 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 incorpo- rated into the present specification by reference.
  • the present separation method provides adequate separation of nuclear isomers.
  • 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.
  • a flow rate applied during elution of the radionuclide can be limited such as by the retention of a Lu-1, 4 , , 10-tetraazacyclododecane- 1, 4, 7, 10-tetraacetic acid- (Tyr3) -octreotate ( DOTA A) complex.
  • a Lu-1, 4 , , 10-tetraazacyclododecane- 1, 4, 7, 10-tetraacetic acid- (Tyr3) -octreotate ( DOTA A) 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 radio- nuclide, such as 177m Lu, in the mobile phase thereby decreasing the activity ratio and the quality of the elution.
  • rate of production of an isomer by internal conversion, such as 177 Lu is typically independent of temperature, and is time dependent.
  • 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.
  • 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) .
  • the present invention is particularly suited for production of a 177m Lu- 177 Lu generator, as well as production of 44m Sc, 127m Te, i29mTe, 137m Ce, and 186m Re.
  • the examples below also specifically relate to the aforementioned. It is noted that in principle the example of the 177lI1 Lu- 177 Lu generator is equally well applicable to other examples mentioned, and by no means limited to the 177rtl Lu- 1 7 Lu example.
  • the present invention solves one or more of the above- mentioned problems.
  • the risk of lack of market availability and operational disruption of nuclear reactors is limited to a large extent; the present invention provides for on demand delivery of radio isotopes in a required amount for a significant longer period of time.
  • the period is extended from a multiple of 6.7 days (the half-life of 177 Lu) to a multiple of 160 days (the half-life of 177m Lu) , 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 ab- sent.
  • the prior art route of producing e.g. 177 Lu provides users thereof with a maximum relative activity of 177m Lu 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 de ⁇ vice and method reduce the high dependency on nuclear reactors to produce radionuclides as 177 Lu.
  • the present invention provides a method of separating at least two isomeric radionuclide/iso- topes 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.
  • 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.
  • the present invention relates to a kit according to claim 21.
  • the present invention relates to a device according to claim 22.
  • the present invention provides a solution to one or more of the above-mentioned problems.
  • the present invention relates in a first aspect to a device according to claim 1.
  • parent atoms are selected from the group comprised of; 44m Sc atoms, 58m Co atoms, eo m Br atoms, 121m Sn atoms, i si ⁇ Te atoms, 127 Sn atoms, i27m Te atoms, i29ra Te atoms, 137m Ce atoms, 177ltl Lu atoms, 186m Re atoms, 192m Ir atoms, 19Sm Au atoms, 229 Ra atoms, and 242m Am atoms, preferably 177m Lu, ⁇ Sc, 127 TMTe, 123 ⁇ 4n Te, m*Ce, and i86m Re atoms, more preferably 1 7m Lu, and/or wherein daughter atoms are selected in accordance with parent atoms from the group comprised of 44 Sc atoms, 58 Co atoms, 80 Br atoms, 121 Sn atoms, 121
  • the compound A comprises a coordination complex, such as a chelate or chelator, preferably a bidentate, a tetradentate, or a pol- ydentate, wherein the dentate is independently selected from a carboxylate, preferably a Ci-Ce carboxylate, such as formate, acetate, lactate, and citrate, a phosphate, and a primary or secondary amine, preferably a Ci-Ce amine, preferably a steri- cally hindered molecule, for example aminopolycarboxylic acid, such as DOTA 1, 4, 7, 10-tetraazacyclododecane-l, 4, 7, 10- tetraacetic acid, e.g.
  • a coordination complex such as a chelate or chelator, preferably a bidentate, a tetradentate, or a pol- ydentate
  • the dentate is independently selected from a carboxylate, preferably a Ci-Ce carboxylate
  • the compound A has a binding affinity to Ca 2+ of > 2 meq/g Ca, preferably > 5 meq/g Ca, more preferably > 8 meg/g Ca.
  • Ca 2+ 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.
  • 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.
  • the holder is selected from a column, preferably a chromatographic column, more preferably a reversed phase chromatographic col ⁇ umn, an ion exchange chromatographic column, an affinity chro ⁇ matographic column, an expanded bed adsorption chromatographic column, preferably a HPLC column, and an electrophoretic de ⁇ vice, such as a capillary electrophoretic device.
  • a column preferably a chromatographic column, more preferably a reversed phase chromatographic col ⁇ umn, an ion exchange chromatographic column, an affinity chro ⁇ matographic column, an expanded bed adsorption chromatographic column, preferably a HPLC column, and an electrophoretic de ⁇ vice, such as a capillary electrophoretic device.
  • the holder comprises a filler, such as a silica filler, such as an amino alkyl, such as amino propyl, an alumina filler, a poly- mer, such as polystyrene, and celluloses, e.g. a tC-18 silica filler .
  • a silica filler such as an amino alkyl, such as amino propyl, an alumina filler, a poly- mer, such as polystyrene, and celluloses, e.g. a tC-18 silica filler .
  • the above constant may vary, typically increase, with increasing pH.
  • the constant may be obtained by spectrometry, by potentiometry, etc.
  • the parent atoms are present in the form of cations. As such good binding properties versus compound A are obtained.
  • 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.
  • the internal conversion energy is 100-750 keV, preferably 150-500 keV, more preferably 200-400 keV, such as 250-300 keV. Therewith enough energy is provided in order to disrupt chemical bonds.
  • 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.
  • the device is portable. As such the device can be moved from one lo ⁇ cation, such as a production site, to a place of intended use.
  • the complex such as Lu-DOTA
  • 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 extrac ⁇ tion. This is found to work surprisingly well.
  • the ra- dionuclide e.g. in the form of a DOTA-complex
  • a solid such as silica and polymeric resins.
  • the solid may relate to a micro-particle or nano-particle, e.g. having a particle size of 10-1000 ym, such as 20 um, 125 ⁇ , and 500 ⁇ . Such also provides good results. Separation of the freed radionuclide is favored and separation is easier.
  • the present invention relates to a method of separating at least two isomeric radionuclide/ isotopes according to claim 14.
  • the mo- bile 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.
  • polar liquids such as alcohols
  • phosphoric acids such as di-2-ethyl hexyl phosphoric acid (DEHPA)
  • MEHPA mono-2-ethyl hexyl phosphoric acid
  • 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.
  • 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.-lOO hours, such as 1-60 hours.
  • the flow rate may depend on an amount required and on a size of the de- vice.
  • the temperature may depend on storage temperature, temperature of intended use, etc.
  • the 177m Lu is produced by neutron capture of enriched 176 Lu.
  • the mo ⁇ bile phase is buffered to a pH of 3-7, preferably 4-6, such as 4.5-5. As such an improved stability is obtained.
  • the mo- bile phase comprises 1-20 vol.% of an alcohol, preferably a Ci- C 5 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- .
  • Figure la-b Schematic representation of the decay process.
  • Figure 2a-d Separation of nuclear isomers 177 Lu and 177m Lu.
  • Figure 3a-b Effect of temperature and flow rate on effi- ciency.
  • Figure 4a-b Effect of 177 Lu activity accumulation on ratio and efficiency.
  • Figure 5a-h Efficiency of accumulation at different temperature and flow rates (average along with the standard devia- tion) .
  • FIG. 1 Schematic representation of the decay process, (a) Decay scheme of 177m Lu to 177 Lu. (ii) Process of bond rupture.
  • the metastable isomer 177m Lu is coordinated to a very sta- ble complex ⁇ left side) .
  • the nucleus excess of energy is transferred to an inner electron causing an auger electron cascade (center) .
  • the atom is in a highly charge state, the chemical bonds are broken and the freed 177 Lu 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 ( 177 Lu) from the metastable state ( 177m Lu) .
  • the present nuclear isomer separation method is based on the combination of three elements ⁇ see fig ⁇ ure 1 ) : (i) a very inert complex with slow association-disso ⁇ ciation 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 sepa ⁇ ration step capable to set apart the complexed element and the freed one.
  • This present separation method provides separating nu ⁇ clear isomers, as well as novel radionuclide generators such as with a longer half-life ( 177m Lu 160.4 days, compared to the 6.7 days half-life of its daughter radionuclide 177 Lu) .
  • a reversed phase chromatographic system was provided.
  • the tC-18 silica filler is found to lack affinity toward polar metal ions, and thus the bond ruptured 177 Lu ions can be eluted off the column using a mobile phase flow.
  • the 177m Lu-DOTATATE complex has a very long reten- tion 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 1 7 Lu and 177m Lu.
  • Exemplary experiments with a continuous flow of a mobile phase were performed at different temperatures and mobile phase fluxes.
  • the initial 177 Lu/ 177m Lu activity ratio in the 177m Lu-complex was measured to be 0.24 ⁇ 0.03.
  • Figure 2(b) displays obtained 177 Lu/ 177m Lu activity ratio after different elution times.
  • the 177 Lu/ 177m Lu activity ra- tio is found to change in the eluted fractions from the equi ⁇ librium value, being about 0.24, to an average ratio of
  • the efficiency of the separation may be defined as the ratio of the collected 177 Lu activity (eluted) divided by the theoretical activity of 177 Lu produced from the decay of the parent 177m Lu in a specific time. An average of 64 ⁇ 2% efficiency is obtained for the continuous elution experiments at 20 °C and 0.05 ml/min as shown in figure 2(b).
  • Figure 3 Effect of temperature and flow rate on efficiency, (a) Effect of temperature on the 177 Lu/ 177m Lu 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 devia- tion.
  • 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 218 ⁇ 10 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 stud ⁇ ied; with increasing temperature a decrease in their values is observed, reaching a minimum value of 25+3 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 65+3% at 10 °C. Only eluting at 0 °C with a flux of 0.012 ml/min gave a lower efficiency, with a value of 47 ⁇ 4%.
  • 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 sepa ⁇ ration v/s the accumulation time at different temperatures
  • 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.
  • big- ger ratios than in continuous elution experiments are obtained, reaching a maximum value of 252+12 at 10 °C after 5 days of accumulation, leading to an enrichment factor of around 1000.
  • 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 devi- ation) for an exemplary embodiment of the present device having an isomeric transition radionuclide generator with a
  • the 1 7m Lu activity source was provided by IDB Holland. It contained approximately ImM LuCl 3 in a 1M HCl solu- tion with a specific activity of 7.2 MBq/g of L11CI3.
  • L11CI3 was neutron activated in the HOR reactor at Delft.
  • DOTATATE Biosynthema
  • 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.
  • 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 W ) 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.
  • the complex was loaded on the column using a Rheodyne injector, with a mobile phase flow of
  • Y 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 measure- ment were performed with a fixed 0.4 ml aliquot for a time period of 4 hours. The gamma ray spectra were analyzed using in- house 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.

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Abstract

L'invention concerne le domaine d'un générateur de radionucléides. Un radionucléide est un atome présentant un noyau instable qui est un noyau caractérisé par un excès d'énergie disponible à être transmise soit à une particule de rayonnement nouvellement créée dans le noyau, soit à un électron atomique. Le dispositif selon l'invention comprend un générateur parent/fille métastable, et est capable de produire des radionucléides avec une activité élevée d'une manière fiable et constante.
PCT/NL2017/050674 2016-10-17 2017-10-16 Générateur de radionucléides à transition isomérique, tel qu'un générateur 177m lu/ 177 lu WO2018074918A1 (fr)

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NL2017628 2016-10-17
NL2017628A NL2017628B1 (en) 2016-10-17 2016-10-17 Isomeric Transition Radionuclide Generator, such as a 177mLu/177Lu Generator

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2704005C1 (ru) * 2019-04-26 2019-10-23 Федеральное государственное бюджетное учреждение "Петербургский институт ядерной физики им. Б.П. Константинова Национального исследовательского центра "Курчатовский институт" (НИЦ "Курчатовский институт-ПИЯФ) Способ получения радионуклида Lu-177
US10596276B2 (en) 2018-07-25 2020-03-24 Advanced Accelerator Applications (Italy) S.R.L. Stable, concentrated radionuclide complex solutions
US10596278B2 (en) 2018-07-25 2020-03-24 Advanced Accelerator Applications (Italy) S.R.L. Stable, concentrated radionuclide complex solutions

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US10596276B2 (en) 2018-07-25 2020-03-24 Advanced Accelerator Applications (Italy) S.R.L. Stable, concentrated radionuclide complex solutions
US10596278B2 (en) 2018-07-25 2020-03-24 Advanced Accelerator Applications (Italy) S.R.L. Stable, concentrated radionuclide complex solutions
US11904027B2 (en) 2018-07-25 2024-02-20 Advanced Accelerator Applications Stable, concentrated radionuclide complex solutions
RU2704005C1 (ru) * 2019-04-26 2019-10-23 Федеральное государственное бюджетное учреждение "Петербургский институт ядерной физики им. Б.П. Константинова Национального исследовательского центра "Курчатовский институт" (НИЦ "Курчатовский институт-ПИЯФ) Способ получения радионуклида Lu-177

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