PRODUCTION OF HIGHLY PURIFIED 212Pb

Abstract

To provide: assemblies and methods for obtaining a container comprising 212Pb on walls obtained from a 212Pb precursor isotope source; and improved systems and methods which can produce 212Pb with high yields and high purity without the need for processing and can safely and efficiently transport it to locations where it is to be used.SOLUTION: The solution is described in the claims.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to 212 On-wall Pb isotope source 212 The present invention relates to a single chamber diffusion generator (assembly), a plurality of assemblies and a method for obtaining a vessel containing Pb, with high yield and high purity, without the need for processing. 212 An improved system and method is provided that allows Pb to be produced and transported safely and efficiently to the location where it is intended to be used. [Background technology]

[0002] 212 The assembly for preparing or manufacturing Pb has been previously described; 220 After Rn diffuses from the first chamber (the source chamber) to the second chamber (the collector chamber) 212 Combined with stearic acid in a chamber with a separate chamber for collecting Pb 228 Based on Th.

[0003] In another system, 228 Th / 224 Ra is extracted from one container by an airflow generated by a pump, 220 Rn / 212 Pb was collected in a separate container. 220 "Air loop" for transporting Rn and 212 It consisted of a "liquid loop" to rinse the Pb and then collect it after rinsing - a fairly complicated system that is not suitable for shipping and handling, and is vulnerable to leakage or improper use, for example in hospitals.

[0004] In another system, the divergent radiation sources are placed inside a chamber and a gas flow passes through them; 220 Rn / 212 In a separate chamber, Pb is collected. 220The Rn is transported through the upper valve to the collection unit. After a while, the carrier gas valve is closed, and the liquid is added to the collection unit through the upper valve and collected through the lower valve. This system is also relatively complicated. Both of these systems require considerable work effort from skilled workers, as well as relatively advanced laboratory equipment and working space.

[0005] Also, 220 Independent of Rn exhalation and diffusion 212 Pb generator systems have existed for some time. In the existing generator systems, 224 Ra binds to the ion exchange material and is eluted with acid. 212 Pb was extracted, but it had to be evaporated before it could be used for radiolabeling; in other existing systems, 224 Following removal of Ra by molecular sieve purification 224 In solution containing Ra 212 Pb is used for labeling. Both methods work but require additional processing time, the first being much longer than the second.

[0006] 212 The half-life of Pb is only 10.6 hours. This half-life gave rise to the idea of ​​radioisotopes for medical applications such as anti-cancer drug treatment. 212 Pb acts on target without long-term side effects due to its long half-life. However, this feature also 212 Pb decays quickly, resulting in low yields over time, making it difficult to use in commercial situations involving intensive production and long distance shipment to end users.

[0007] Therefore, the challenge with current divergence and diffusion systems is to 220 The distance over which Rn decay can significantly reduce efficiency. For example, one system had a 7.05MBq 228 For the Th source, 2.01 MBq was collected over a 3-day run. 212Total Pb yields, i.e., less than 30% yield, were reported. Collection did not increase with increasing run time, and the system was sensitive to air velocity.

[0008] There is a need for alpha-emitter therapeutics for biomedical applications. 212 Pb) is a beta emitter that decays into short-lived progeny that yield alpha particles and can therefore act as an in vivo alpha emitter generator useful for alpha-emitter therapy.

[0009] The industry therefore produces high yields and high purity products without the need for processing. 212 There is a need for improved systems and methods that can produce Pb and transport it safely and efficiently to locations where it will be used. Summary of the Invention

[0010] The object of the present invention is to 212 A method for obtaining a container containing Pb, the method comprising the steps of providing an assembly comprising a first part and a second part, the first part comprising the container and the second part comprising: 212 Providing a Pb precursor isotope source, 212 combining the first portion and the second portion such that the Pb precursor isotope source does not contact an interior wall of the vessel and to provide a single chamber vessel assembly; 212 Progeny of Pb precursor isotope source 220 Rn, 216 Po, or 212 Allow sufficient time for it to decay to Pb, and 220 Rn, 216 Po and / or 212 allowing sufficient time for Pb to settle on the interior walls of the single chamber vessel assembly; 212 The Pb precursor isotope source was not allowed to come into contact with the inner walls of the single-chamber vessel assembly, and the remaining 212 removing or isolating the Pb precursor isotope from the single chamber assembly and depositing the precursor isotope on the interior wall of the vessel. 212Pb is contained in the inner wall of the container. 212 The method includes obtaining a container that is substantially free of a Pb precursor isotope source, the system comprising: 212 It may be called a single-chamber diffusion generator of Pb.

[0011] In the following, precursor isotopes are referred to as: 212 The mother, grandmother, and great-grandmother nuclides of Pb, i.e. 216 Po, 220 Rn, 224 It is defined as Ra etc.

[0012] A further object of the invention is an assembly comprising a first part and a second part, the first part comprising a container and the second part comprising: 212 Pb precursor isotope source, the first portion and the second portion comprising 212 The assembly is bonded such that the Pb precursor isotope source does not contact the interior walls of the vessel and provides a single chamber vessel assembly.

[0013] Yet another object of the present invention is a single chamber container assembly comprising a first portion and a second portion, the first portion comprising a container and the second portion comprising: 212 Pb precursor isotope source, the first portion and the second portion comprising 212 The present invention relates to a single-chamber vessel assembly in which a Pb precursor isotope source is bonded such that it does not come into contact with the interior walls of the vessel.

[0014] In one or more embodiments of the present invention, the single chamber container assembly is airtight.

[0015] In one or more embodiments of the present invention, 212 The Pb precursor isotope source is 232 Th, 228 Ra, 228 Ac, 228 Th and / or 224 Ra is selected from the group consisting of

[0016] In one or more embodiments of the present invention, 212 The Pb precursor isotope source is 232 Th, 228 Ra, 228 Ac, 228 Th and 224 It is a mixture of Ra.

[0017] In one or more embodiments of the present invention, 212 The Pb precursor isotope source is 228 Th and 224 It is a mixture of Ra.

[0018] In one or more embodiments of the present invention, 212 The Pb precursor isotope source is 224 In one or more embodiments of the present invention, 212 The Pb precursor isotope source is 228 Th. This 212 Pb activity typically varies depending on internal growth conditions in the generator. 224 It may vary from 0% to 114% of the Ra precursor radioactivity. 212 Pb radioactivity is 224 It may be at least 90%, such as at least 80%, such as at least 70%, such as at least 60%, such as at least 50%, such as at least 40%, such as at least 30%, such as at least 20%, such as at least 10% of the Ra precursor radioactivity.

[0019] In one or more embodiments of the present invention, 212 The Pb precursor isotope source is 212 At least 90%, such as at least 80%, such as at least 70%, such as at least 60%, such as at least 50%, such as at least 40%, such as at least 30%, such as at least 20%, such as at least 10%, measured as a ratio of radioactivity to Pb. 228 Having Th 228 Th.

[0020] In one or more embodiments of the present invention,212 The Pb precursor isotope source is 212 At least 90%, such as at least 80%, such as at least 70%, such as at least 60%, such as at least 50%, such as at least 40%, such as at least 30%, such as at least 20%, such as at least 10%, measured as a ratio of radioactivity to Pb. 224 Has Ra 224 It's Ra.

[0021] In one or more embodiments of the present invention, the total amount of radioactivity in this single chamber container assembly is between 1 kBq and 100 GBq.

[0022] In one or more embodiments of the present invention, 212 The Pb precursor isotope source is in the form of an inorganic or organic salt, such as RaCl2.

[0023] In one or more embodiments of the present invention, 212 The Pb precursor isotope source is bound to a non-radioactive material, such as a particle or a holding material.

[0024] In one or more embodiments of the present invention, 212 The Pb precursor isotope source may be in dry form or in liquid solution, such as an aqueous solution or dispersion.

[0025] In one or more embodiments of the present invention, 212 The Pb precursor isotope source is a liquid solution that is acidic, neutral or basic pH.

[0026] In one or more embodiments of the present invention, 212 The Pb precursor isotope source is deposited on a strip or sphere made from a material suitable for liquid applications.

[0027] In one or more embodiments of the present invention, 212The Pb precursor isotope source is deposited on a strip or sphere made from a material selected from the group consisting of paper, plastic, metal, ceramic, and natural or synthetic fibers, cellulose.

[0028] In one or more embodiments of the invention, the strip or sphere is attached to the second part, which comprises a means for holding the strip or sphere, such as a rod.

[0029] In one or more embodiments of the invention, the second portion comprises a syringe or the rod is the syringe.

[0030] In one or more embodiments of the invention, the syringe tip extends through a rubber cap.

[0031] In one or more embodiments of the invention, the second portion comprises a bar that is attached to the means for opening and closing the container.

[0032] In one or more embodiments of the invention, the means for opening and closing the container is a cap, cover or lid.

[0033] In one or more embodiments of the invention, the cap, cover or lid is made from a material selected from the group consisting of rubber, glass, paper, plastic, metal, ceramic, and natural or synthetic fibers.

[0034] In one or more embodiments of the present invention, 212 The Pb precursor isotope source is placed on or in a sphere suitable for holding the source but allowing radon diffusion.

[0035] In one or more embodiments of the present invention, the container comprises 212 It is equipped with a gas-permeable barrier that is impermeable to the Pb precursor isotope source.

[0036] In one or more embodiments of the present invention, 212This gas-permeable barrier is impermeable to Pb precursor isotope sources. 212 Contact with Pb precursor isotope source.

[0037] In one or more embodiments of the present invention, the container comprises 212 The Pb precursor isotope source does not have a gas-permeable barrier that is impermeable to the Pb precursor isotope source.

[0038] In one or more embodiments of the invention, the volume of the container is from 1 μl to 10 liters, such as from 1 μl to 1 liter, such as from 100 μl to 10 ml, such as from 100 μl to 100 ml.

[0039] In one or more embodiments of the present invention, the container has an inner wall on which the 212 Substantially free of Pb precursor isotope sources 212 This was measured as a radioactivity ratio to Pb. 212 Less than 3%, such as less than 1%, such as less than 0.5%, of the Pb precursor isotope source 224 It is specified as Ra.

[0040] In one or more embodiments of the present invention, the interior wall of the container is coated, which may be a film of a salt or other suitable material on the interior wall.

[0041] In one or more embodiments of the present invention, the inner wall of the container comprises: 212 It is coated with a compound that contains a chelating agent that can form a complex with Pb.

[0042] In one or more embodiments of the invention, the interior walls of the container are coated with a chelating agent that is TCMC or a derivative thereof.

[0043] In one or more embodiments of the invention, the container contains an aqueous or oily solution. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0044] The present invention is small in size and has a short half-life. 220 Rn and 212 In response to the need for a simpler and safer system for handling Pb with shorter transport distances, an assembly was designed in which the radon producing source is placed inside a collection chamber or container. 228 Instead of using only Th as a source, the present invention uses a versatile, pure 224 Ra or 228 Th and 224 Combinations with Ra can be used as sources or even their precursor isotopes (Figure 1).

[0045] The assembly of the present invention is very compact, very easy to fabricate, shippable, and disposable. 212 In the context of the present invention, the terms assembly, diffusion generator and system are used interchangeably. The assembly or system described therefore: 212 It may be called a single chamber diffusion generator for Pb.

[0046] Therefore, the object of the present invention is to provide a 212 A method for obtaining a container containing Pb, the method comprising the steps of providing an assembly comprising a first part and a second part, the first part comprising the container and the second part comprising: 212 Providing a Pb precursor isotope source, 212 combining the first portion and the second portion such that the Pb precursor isotope source does not contact an interior wall of the vessel and to provide a single chamber vessel assembly; 212 Progeny of Pb precursor isotope source 220 Rn, 216 Po, and / or 212 Allow sufficient time for it to decay to Pb, and 220 Rn, 216 Po and / or 212 allowing sufficient time for Pb to settle on the interior walls of the single chamber vessel assembly; 212The Pb precursor isotope source was not allowed to come into contact with the inner walls of the single-chamber vessel assembly, and the remaining 212 removing or isolating the Pb precursor isotope from the single chamber assembly and depositing the precursor isotope on the interior wall of the vessel. 212 Pb is contained in the inner wall of the container. 212 The method includes obtaining a container that is substantially free of a Pb precursor isotope source. Examples of such containers or assemblies are described in the examples of the present disclosure and can also be seen in Figures 2-5.

[0047] The aspect of the present invention is to 212 Acquiring the above container containing Pb and 212 collecting Pb in solution; 212 Regarding the method of obtaining Pb solution, 212 Pb, this 212 Pb can be collected in solution in this container before it is generated, or 212 After Pb is generated, it can be collected using a solution introduced into the container, for example using a syringe.

[0048] A further object of the invention is an assembly comprising a first part and a second part, the first part comprising a container and the second part comprising: 212 Pb precursor isotope source, the first portion and the second portion comprising 212 The assembly is bonded such that the Pb precursor isotope source does not contact the interior walls of the vessel and provides a single chamber vessel assembly.

[0049] Yet another object of the present invention is a single chamber container assembly comprising a first portion and a second portion, the first portion comprising a container and the second portion comprising: 212 Pb precursor isotope source, the first portion and the second portion comprising 212 The present invention relates to a single-chamber vessel assembly in which a Pb precursor isotope source is bonded such that it does not come into contact with the interior walls of the vessel.

[0050] The major advantages of the described assembly (also defined herein as vessel, system or generator) are: 212 The short half-life of Pb (10.6 hours) does not affect the radioactivity level. 212 The system described allows for the production of diffusion generators in a centralized production facility and shipping these to end users. Portable disposable generators may also be manufactured and shipped from one side or region to another, such as to hospitals. For such disposable units, pure 224 Ra( 228 (not containing 1H) is preferred because it becomes inactive after 40-50 days and the generation of long-lived radioactive waste is largely avoided. 224 In a manner that is influenced by the half-life of Ra, 220 Rn / 212 Pb will be steadily produced (Table 1 and Figure 1). 212 The container containing the Pb precursor isotope source is 212 Will produce Pb. 212 The amount of Pb is 212 It will depend on several factors, including the choice of Pb precursor isotope source and time. Time is a critical factor. The objective of the present invention is to obtain substantially pure 212 A method for preparing a Pb solution, the method comprising obtaining the assembly and container described herein, 212 The Pb precursor isotope source is maintained for a period of time in a sealed assembly and container. 212 The Pb precursor isotope source is separated or removed without contact, and the 212 Pb is then 212 Pb is collected by adding a suitable solution for collection. 212 The time that the Pb precursor isotope source is maintained within the assembly and container of the present invention is: 212 Selection of Pb precursor isotope source and required 212Depending on the amount of Pb, the time period can be from minutes to hours to days to years. The time period can be at least 1 day. The time period can be at least 1 day. The time period can be at least 2 days. The time period can be at least 4 days. The time period can be at least 1 week. The time period can be at least 2 weeks. The time period can be at least 2 weeks. The time period can be at least 1 month. The time period can be at least 1 year.

[0051] 212 Pb is a naturally occurring radionuclide in the thorium series. 232 Th(t 1 / 2 =1.4×10 10 It can be found in substances containing 212 The Pb precursor can therefore be selected based on the intended purpose. 212 To manufacture an assembly or system that serves as a Pb generator, precursors with a longer half-life can be selected. Alternatively, using isotopes with a shorter half-life is an intended purpose, for example in hospitals or similar, where the generation of long-lived radioactive waste may be an issue. Of course, mixtures of different precursors are therefore also suitable, allowing the production of specific amounts of Pb over a specific period of time. 212 A specific assembly is also required to generate Pb.

[0052] Thus, in one or more embodiments of the present invention, 212 The Pb precursor isotope source is 232 Th, 228 Ra, 228 Ac, 228 Th and / or 224 Ra is selected from the group consisting of: 212 The Pb precursor isotopes are 212 The mother, grandmother, and great-grandmother nuclides of Pb, i.e. 216 Po, 220 Rn, 224 Ra, 228 Th, 228 Ac,228 Ra, 232 It is defined as Th.

[0053] The decay of these radioisotopes can be seen in Figure 1, where they have different decay profiles. 212 The feasibility of creating Pb precursor isotope sources was clearly demonstrated, with different combinations of precursor isotopes producing Pb at different rates for different periods of time. 212 Pb could be generated.

[0054] In one or more embodiments of the present invention, 212 The Pb precursor isotope source is 232 Th, 228 Ra, 228 Ac, 228 Th and 224 In one or more embodiments of the present invention, 212 The Pb precursor isotope source is 228 Th and 224 This source is also a mixture of 232 Th, 228 Ra, 228 Ac, 228 Th and 224 It can also be each of Ra, 232 Th 228 The decay of Ra, etc., of course, produces a mixture. The key is the gas 220 The reason for this is that gaseous 220 Rn diffuses from the source and then to the inner wall of the container. 212 This is because it settles as Pb.

[0055] In one or more embodiments of the present invention, 212 The Pb precursor isotope source is 212 At least 90%, such as at least 80%, such as at least 70%, such as at least 60%, such as at least 50%, such as at least 40%, such as at least 30%, such as at least 20%, such as at least 10%, measured as a ratio of radioactivity to Pb. 228 Having Th 228Th.

[0056] In one or more embodiments of the present invention, 212 The Pb precursor isotope source is 224 In one or more embodiments of the present invention, 212 The Pb precursor isotope source is 228 Th. 212 Pb activity typically varies depending on internal growth conditions in the generator. 224 It may vary from 0% to 114% of the Ra precursor radioactivity. 212 Pb radioactivity is 224 It may be at least 90%, such as at least 80%, such as at least 70%, such as at least 60%, such as at least 50%, such as at least 40%, such as at least 30%, such as at least 20%, such as at least 10% of the Ra precursor radioactivity. 212 Pb radioactivity is 224 It may be at least 10% of the Ra precursor radioactivity. 212 Pb radioactivity is 224 It may be at least 10% of the Ra precursor radioactivity. 212 Pb radioactivity is 224 It can be at least 20% of the Ra precursor radioactivity. 212 Pb radioactivity is 224 It can be at least 30% of the Ra precursor radioactivity. 212 Pb radioactivity is 224 It can be at least 40% of the Ra precursor radioactivity. 212 Pb radioactivity is 224 It can be at least 50% of the Ra precursor radioactivity. 212 Pb radioactivity is 224 It can be at least 60% of the Ra precursor radioactivity. 212 Pb radioactivity is 224 It can be at least 70% of the Ra precursor radioactivity. 212 Pb radioactivity is 224 It can be at least 80% of the Ra precursor radioactivity. 212 Pb radioactivity is 224It can be at least 90% of the Ra precursor radioactivity. 212 Pb radioactivity is 224 It can be at least 100% of the Ra precursor radioactivity. 212 Pb radioactivity is 224 It may be at least 110% of the Ra precursor radioactivity. 212 Pb radioactivity is 224 It can be up to 20% of the Ra precursor radioactivity. 212 Pb radioactivity is 224 It can be up to 30% of the Ra precursor radioactivity. 212 Pb radioactivity is 224 It can be up to 40% of the Ra precursor radioactivity. 212 Pb radioactivity is 224 It can be up to 50% of the Ra precursor radioactivity. 212 Pb radioactivity is 224 It can be up to 60% of the Ra precursor radioactivity. 212 Pb radioactivity is 224 It can be up to 70% of the Ra precursor radioactivity. 212 Pb radioactivity is 224 It can be up to 80% of the Ra precursor radioactivity. 212 Pb radioactivity is 224 It can be up to 90% of the Ra precursor radioactivity. 212 Pb radioactivity is 224 It can be up to 100% of the Ra precursor radioactivity.

[0057] In one or more embodiments of the present invention, 212 The Pb precursor isotope source is 224 In one or more embodiments of the present invention, 212 The Pb precursor isotope source is 212 At least 90%, such as at least 80%, such as at least 70%, such as at least 60%, such as at least 50%, such as at least 40%, such as at least 30%, such as at least 20%, such as at least 10%, measured as a ratio of radioactivity to Pb. 224 Has Ra 224 It's Ra.

[0058] 212 Assemblies acting as Pb generator units can be mass-produced in centralized manufacturing facilities and shipped to end users for application in radiopharmaceutical manufacturing. 212 It can also be applied and used for large-scale centralized production of Pb. Thus, the amount of radioactivity in the assembly can be adjusted according to its intended purpose. In one or more embodiments of the present invention, the total amount of radioactivity in the single-chamber container assembly can therefore be 1 kBq to 100 GBq, such as 1 kBq to 10 MBq, such as 100 kBq to 10 MBq, such as 1 MBq to 1 GBq, such as 10 MBq to 10 GBq, such as 1 MBq to 1 GBq, such as 1 GBq to 100 GBq. The total amount of radioactivity in the single-chamber container assembly can be 1 kBq to 100 GBq. The total amount of radioactivity in the single-chamber container assembly can be 1 kBq to 10 MBq. The total amount of radioactivity in the single-chamber container assembly can be 100 kBq to 10 MBq. The total amount of radioactivity in the single-chamber container assembly can be 1 MBq to 1 GBq. The total amount of radioactivity in the single chamber container assembly can be between 10MBq and 10GBq. The total amount of radioactivity in the single chamber container assembly can be between 1MBq and 1GBq. The total amount of radioactivity in the single chamber container assembly can be between 1GBq and 100GBq.

[0059] In one or more embodiments of the present invention, in a single chamber container assembly 212 The amount of Pb radioactivity may thus be between 1 kBq and 10 MBq, such as between 100 kBq and 10 MBq, such as between 1 MBq and 1 GBq, such as between 10 MBq and 10 GBq, such as between 1 MBq and 1 GBq, such as between 1 GBq and 100 GBq. 212The amount of Pb precursor isotope source activity can thus be from 1 kBq to 10 MBq, such as from 100 kBq to 10 MBq, such as from 1 MBq to 1 GBq, such as from 10 MBq to 10 GBq, such as from 1 MBq to 1 GBq, such as from 1 GBq to 100 GBq.

[0060] 212 Pb precursor isotope sources can take different shapes, sizes and configurations depending on the type of application. Thus, in one or more embodiments of the present invention: 212 The Pb precursor isotope source is in the form of an inorganic or organic salt, such as RaCl2. 212 The Pb precursor isotope source can also be in dry form or in liquid solution, such as an aqueous solution or dispersion. 212 The Pb precursor isotope source is a liquid solution that is acidic, neutral or basic pH. The pH can be 1-14, such as pH 1-6, pH 2-6, pH 2-8, pH 4-8, pH 5-7, pH 6-8, pH 7-8, pH 7.2, pH 8-10, pH 8-12, or pH 10-14.

[0061] The solution may be an aqueous solution. The solution may be a 0.1M HCl solution in water. The solution may be applied to the wall of the assembly. 212 It can be used to dissolve Pb.

[0062] The assembly acting as a generator system may be used to prepare single or multiple patient doses, or even for industrial use. The amount of radioisotope can therefore be adjusted depending on the application of the assembly.

[0063] 212 The Pb precursor isotope source, typically in a very small liquid volume, can be placed on the rod, either directly or on a strip attached to the rod. In one or more embodiments of the invention, 212The Pb precursor isotope source is deposited on a strip or sphere made of a material suitable for liquid application, such liquid may be in a volume of 1 μl to 1 ml, such as 1 μl to 10 μl, such as 1 μl to 100 μl.

[0064] The container, which may be a vial, may be empty or contain a small volume of liquid at the bottom, which is not in contact with the source. In one or more embodiments of the invention, the container contains an aqueous or oily solution.

[0065] It is important that the source does not drip or chip in a manner that would cause cross-contamination of the inside surfaces of the collection unit (container) with the source material, and that the source and source holder can be removed or pulled from the collector without causing cross-contamination by touch.

[0066] In one or more embodiments, the source is surrounded by a grid or encapsulated in a porous material to reduce the risk of cross-contamination. 212 The Pb precursor isotope source may be an impermeable gas-permeable barrier.

[0067] Thus, in one or more embodiments of the invention, the container comprises: 212 With or without a gas-permeable barrier that is impermeable to the Pb precursor isotope source.

[0068] In one or more embodiments of the present invention, 212 The Pb precursor isotope source is placed on or in a sphere suitable for holding the source but allowing radon diffusion. 212 Equipped with a gas-permeable barrier that is impermeable to the Pb precursor isotope source; 212 The Pb precursor isotope source impermeable gas-permeable barrier is 212 The single chamber vessel assembly is capable of contacting a Pb precursor isotope source. In one or more embodiments of the present invention, the single chamber vessel assembly is gas tight.

[0069] FIG. 2 shows the case (first part) combined with the cap, and the rod attached to the cap, without the source touching the inner wall of the case during the entire process. 212 An example of a single chamber container assembly that can be used to hold the Pb precursor isotope source (second portion) is shown.

[0070] In one or more embodiments of the present invention, 212 The Pb precursor isotope source can therefore be bound to a non-radioactive material, such as a particle or a retaining material, which can ensure that the source does not contaminate the container. 212 The Pb precursor isotope source can be deposited on a strip, sphere or rod made of a material selected from the group consisting of paper, plastic, metal, ceramic, and natural or synthetic fibers. The strip or sphere can be attached to or contained or included in the second part, which includes a means for holding the strip or sphere. Such a means can be, for example, a rod.

[0071] In one or more embodiments of the invention, the second part optionally comprises a rod that is attached to a means for opening and closing the container. The means for opening and closing the container can be a cap, cover or lid that can be made from a material selected from the group consisting of rubber, glass, paper, plastic, metal, ceramic, and natural or synthetic fibers, cellulose ion exchange resins, natural minerals, polymers. Alternatively, the source is attached to a material that is placed on the cap, both glued and not glued to the cap. When the cap is placed on the bottom, the source material is attached to the material that is placed on the cap. 212 It may simply be placed on the inside of the cap without touching the Pb collector and held in place by gravity. In such a case, the generator unit should be stored and handled in the correct position so that the cap with the source is always kept at the bottom.

[0072] The means for opening and closing the container comprises: 212 A Pb precursor isotope source may be provided.212 The Pb precursor isotope source is attached to a sponge, wool, or a means for opening and closing the container. 212 The wool may be placed on another material capable of holding the Pb precursor isotope source. The wool may be quartz wool. The wool may also be mineral wool. The wool may also be glass wool. The means for opening and closing the container may include a 212 The material capable of holding the Pb precursor isotope source can be attached by adhesive, double-sided mounting tape, or other attachment means.

[0073] In one or more embodiments of the invention, the second portion comprises a syringe or the rod is a syringe. The retention means may be deposited on a strip or sphere made from a material selected from the group consisting of paper, plastic, metal, ceramic, and natural or synthetic fibers, cellulose ion exchange resins, natural minerals, polymers.

[0074] In one or more embodiments of the invention, the syringe tip protrudes through the rubber cap. In another design, the second portion is 212 The means for holding the Pb precursor isotope source is a permeable, preferentially self-sealing, rubber cap, or septum of another material, with a syringe tip, attached to the inside wall of the cap or container. In this case, when the assembly is used, the syringe penetrates the cap, but 212 Pb could be dissolved from the inside wall of the container into the aqueous solution. 212 The Pb-water solution can then be collected by the same syringe, providing the option for operation in a GMP environment that can be directly applied to patient use. Thus, in one embodiment, 212The Pb precursor isotope source can be drawn into a capsule or similar, and the container can be washed without the need to disassemble the two units, for example, by using a solution transferred by syringe through a rubber septum. In another embodiment, the assembly can be autoclaved, and the solution is a physiologically acceptable composition containing a chelating agent for disease targeting, and can be drawn into a syringe with or without a sterile syringe filter and injected directly. In one embodiment, the assembly containing all subunits is heat sterilization resistant, the cap has a syringe-permeable area, and the assembly can be filled with a syringe. 212 Pb can be extracted aseptically.

[0075] A few hours or days after the operation, 212 The assembly with the Pb precursor isotope source is, for example, attached 212 By changing the cap equipped with the Pb precursor isotope source to a new cap that is free of radioactivity, 212 The Pb precursor isotope source was stored, the inner surface was washed with a suitable solution, and the Pb precursor was deposited on the surface. 212 By dissolving Pb and progeny 212 It can be used to produce Pb. 212 Since the Pb solution does not contain any long-lived radionuclides, it can be used directly without further chemical treatment to label carrier molecules, for example for cancer therapy.

[0076] 212 The Pb precursor isotope source is 212 Pb precursor isotope source attached 220 The source can be combined with a needle, rod or strip of material that diffuses Rn. 212 It may or may not include a holder for the radioactive part and a grid or ring or the like surrounding the source to prevent cross-contamination when the Pb precursor isotope source is withdrawn from the container. In one embodiment, 212 The Pb precursor isotope source may be attached to a screw cap that can be used to close the container. By withdrawing the source from the cover, 212The Pb precursor isotope source can be separated from the vessel, which prevents cross-contamination of the source with the vessel walls, while 212 This ensures that Pb is extracted and limits the risk of exposure during use of the assembly. Importantly, after the decay period, the Pb absorbed on the inner surface of the vial is removed. 212 Pb precursor isotope source and 212 Pb, for example, by replacing the screw cap to which the source is attached by a rod or similar with a standard airtight screw cap. 212 The Pb precursor isotope source can be separated by withdrawing it from the container. Thus, in one particular embodiment, the device includes a retractable radioactive source that is withdrawn into a cap similar to a "click pen system" or similar to separate the source from the inside of the generator unit. 212 Pb precursor isotope source, thus eliminating the need for disassembly and replacement of the cap (e.g., Figures 2 and 4). Thus, the second part of the assembly can include a piston capable of assuming open and closed positions. The second part of the assembly can also include a chamber with an airtight O-ring seal. In one or more further embodiments, the assembly includes an airtight and liquidtight lid or valve on the second part.

[0077] The second part of the assembly may optionally include a needle, rod or strip that may be provided with small spheres of material capable of absorbing radium or thorium, including glass wool, quartz wool, mineral wool, metal, paper, cotton, stearic acid or another fatty acid, metal, cellulose, natural minerals, polymers, ion exchange resins, or other fibrous materials. The composition of the precursor isotope holder should be carefully selected according to the known affinity of radon for various materials. 228 Th or 224 Excellent adsorption or absorption of Ra, 220 Materials with a low affinity for Rn are suitable. The container can be made of glass (including quartz), polymers and / or metals, such as a glass vial with a screw cap or similar, whereby the source is attached to the screw cap. The container (or assembly) can be, for example, 224Ra or 228 The cap may be an inverted glass flask with quartz wool containing Th centrally placed inside the cap. 212 The Pb was removed from the cap containing the source by turning the flask upside down and then washing the inside of the flask with a solution. 212 Pb can be made by dissolving it in water. The container can have a volume of 1 μl to 10 liters, such as 1 μl to 1 liter, such as 100 μl to 10 ml, such as 100 μl to 100 ml. The volume will depend on the usage and will generally be small for single use and large for industrial batch containers.

[0078] It is important to minimize the risk of cross-contamination. 212 The assembly must be designed so that the Pb precursor isotope source does not come into contact with the inside walls of the vessel. Thus, in one or more embodiments of the present invention, the vessel is provided with a 212 Substantially free of Pb precursor isotope sources. The definition of substantially free is that the Pb precursor isotope sources 212 In one or more embodiments of the present invention, "substantially free" means 212 Less than 3%, such as less than 1%, such as less than 0.5%, measured as a ratio of radioactivity to Pb 224 Ra 212 In one or more embodiments of the present invention, substantially free of Pb precursor isotope sources includes those in the solution from the walls of the container. 224 Against Ra 212 Refers to the purity of Pb. The purity may be greater than 95%. The purity may be greater than 98%. The purity may be greater than 99%. The purity may be greater than 99.5%. The purity may be greater than 99.8%.

[0079] The container is 212 It surrounds, but does not touch, the Pb precursor isotope source. This can be, for example, glass, plexiglass, metals, ceramics, polymers including polypropylene and Teflon, or 220 Rn and / or 212If Pb can deposit on the inner walls of the container and be washed with a suitable solution for further use in radiolabeling 212 The solution should be made from a suitable material, such as other materials suitable for dissolving Pb. The solution should be used to wash the inside walls of the container to remove the radionuclides, primarily 212 It can be used to extract Pb and progeny. The solution is 212 Pb may be present in the assembly during manufacturing, or 212 It may be applied after removal or withdrawal of the Pb precursor isotope source. In one embodiment, this solution and the acidic or alkaline solution may be decanted and neutralized prior to use for administration to a patient. In one embodiment, the solution may be water of a purity suitable for pharmaceutical use. For single use, solution volumes of 1 ul to 1 liter, e.g., 100 ul to 10 ml, and for multiple uses, 1 ul to 10 liters or more may be used.

[0080] The container may or may not include a surface film or a small amount of liquid on the inside surface to help collect the diffusion products. This surface film may be, for example, a coating. Sizes and volumes may range from microliters to ml for single use devices, and from microliters to tens of liters or more for multiple use. The inside walls of the container may be coated. This coating allows: 212 In one or more embodiments of the present invention, the inner wall of the container is 212 It is coated with a compound that contains a chelating agent capable of forming a complex with Pb. 212 If complexes of Pb are required, the interior walls may be coated with one or more compounds. In one or more embodiments of the present invention, the interior walls of the container are 212 It is coated with a chelating agent capable of chelating Pb. The chelating agent may be TCMC or a derivative thereof. The coating may be a film of salt or other suitable material on the inner wall.

[0081] In certain embodiments, the container is washed directly with the reaction solution containing the complexing agent to yield a radiolabeled solution that can be used directly for therapeutic purposes after a suitable reaction time, hi one embodiment, the final product solution is autoclaved and / or sterile filtered prior to administration to a subject in need.

[0082] In one embodiment, the assembly can be fitted with a flushing and filtering circuit, which allows for, when the source is withdrawn from the chamber, e.g. 99m In a similar manner as for the Tc generator, a tank of solution is connected and fitted with an outlet equipped with a filtration filter and a syringe or vacuum pump to flush the chamber and collect the flush solution.

[0083] In general, the area ratio between the surface of the precursor source holder and the inner surface of the collection chamber should be set to maximize the area of ​​the precursor source. 212 Pb should be optimized to settle on the surface of the collection chamber, which may be flat or porous, or may include structures to extend the surface area compared to the diffusion subunit, container, or assembly.

[0084] The production can be for 5, 10, 20 or more hours of production time. The source can then be withdrawn from the chamber into a tubular holder or similar with an air-tight and liquid-tight lid at the bottom that closes when the source is fully withdrawn. This allows for the addition of a washing solution, e.g., by a syringe, or for the removal of the source from the chamber, e.g., by the addition of a cleaning solution ... 99m A flushing and collecting circuit similar to that of the Tc generator can be activated.

[0085] In certain embodiments, the single chamber diffusion unit is attached to the inner surface of the assembly. 212 The Pb precursor isotope source was inserted into the source coating without contacting it. 2122. It has a Pb collector (container), ie, an inverted configuration to that shown in FIG.

[0086] In another embodiment, the diffusion generator is subjected to temperature manipulation, either above or below 20°C.

[0087] Uses of the present invention include the manufacture of radiopharmaceuticals, medical devices and / or 212 The assembly of the present invention is used as a standard source of Pb for calibration. 212 It can be used to prepare Pb standards.

[0088] In one or more embodiments of the invention, the assembly of the invention comprises: 212 The kit includes a Pb precursor isotope source, a solution containing a chelating agent, and a compound for use in therapy. Such a compound may be a nanoparticle or a microparticle. In one embodiment, such a kit includes: 212 It includes a Pb precursor isotope source, a solution for cleaning the interior walls of the vessel, and a carrier compound, such as a chelating agent, microparticles or nanoparticles, in solution or dry form. [Table 1] [Table 2] [Table 3] [Table 4]

[0089] The following figures and examples are provided below to illustrate the invention, they are intended to be illustrative and are not intended to be construed as limiting in any manner. [Brief description of the drawings]

[0090] [Figure 1]Figure 1 shows the decay of 232Th into its progeny. The type of decay (alpha or beta decay) is shown, as well as the half-lives. These half-lives are important because they define the decay rate and are therefore key to determining the optimal mix of isotopes as a 212Pb precursor isotope source for producing 212Pb. [Figure 2A] 2A shows a diagram of a single chamber vessel assembly comprising a vessel (A) and a 212Pb precursor isotope source (B) which generates 220Rn gas that is released into the single chamber vessel assembly and which, after decay, settles as 212Pb on the inner wall of the vessel (C). The top of the single chamber vessel assembly (D) is the second part and comprises the 212Pb precursor isotope source and a cover / cap with a rod, in this case attached towards the centre of the vessel, thus allowing the 212Pb precursor isotope source to release 220Rn into the vessel. [Figure 2B] Figure 2B shows the Pb precursor isotope source (B) being withdrawn into an airtight seal, ensuring that no Rn is released into the vessel. The Pb precursor isotope source can also be removed from the assembly entirely. [Diagram 3] Figure 3 shows a diagram of the bare variant of the generator system based on a 3 ml vial with an open screw cap into which a membrane pierced by a syringe tip (in a position fixed by tape on the top of the screw cap) is inserted and a strip of bench paper attached to the syringe tip (left photo shows the 212Pb precursor isotope source and container). The 212Pb precursor isotope source is placed on the strip by a pipette (right photo) before carefully attaching the screw cap with the source to the vial. It is very important that the source does not come into contact with the vial when assembling or disassembling the unit to avoid cross contamination. [Figure 4] FIG. 4 shows an example of a single-chamber diffusion generator for 212Pb with a retractable source that simplifies flushing of 212Pb from internal surfaces by providing a septum over the permeable area of ​​a syringe on the lid; a syringe may also be used to wash internal surfaces without cross-contamination of radionuclides when the unit is moved to the closed position. [Diagram 5] Figure 5, top, shows 100, 50 and 10 ml generator units for 212Pb production. The bottom of Figure 5 shows a cap with quartz wool in the center of the inner surface. 212Pb precursor nuclide solution can be placed on the quartz wool and the flask is mounted for inverted storage to produce 212Pb generated by 220Rn diffusion from the precursor source material and deposited on the inner surface of the flask. EXAMPLES

[0091] Example 1 - At various times 212 Calculation of relative levels of Pb daughter nuclides Background: Pure radiopharmaceuticals 212 The development and use of Pb is hindered by the short half-life of the radionuclide (10.6 hours), making it nearly impossible to manufacture the product in a centralized manner and ship it to end users. 224 Ra 212 If used as a short-term generator for Pb, 212 The radioactivity level of Pb was measured at 3.6 days. 224 It can be essentially maintained according to the half-life of Ra. 224 Ra sealed source 212 The variation in Pb levels is shown.

[0092] method: 212 Pb pure 224 The ingrowth from the Ra source was calculated using a general-purpose activity calculator.

[0093] Results: Table 2 shows the pure ( 224 Preparation of the drug solution (not including Ra) and storage in an airtight container at various times 212 The amount of Pb is shown. As shown, pure 212 The Pb source decayed rapidly, losing more than 75% per 24 hours. Table 3 shows the 224 Present in a sealed source of Ra 212 The amount of Pb is shown. As shown, 212 Pb activity remains at high levels (>50%) for at least up to 96 hours.

[0094] Table 4 shows 212 For Pb 224 The effect of "milking" a generator based on a Ra precursor several times over a 96 hour period is shown.

[0095] The data also show that pure 224 Starting with Ra, it is shown that there are significant amounts of daughter nuclides within a relatively short time. 212 Pb 224 The ratio of Ra to 1 after 36 hours and then gradually increases to about 1.1, remaining at this ratio for the remainder of the time until complete decay. 224 Ra 212 When used as a Pb source, it allows for centralized manufacturing and shipping to end users, and the existing 224 From Ra 212 It provides an easy method to extract Pb.

[0096] Example 2 - Preparation of radionuclides and counting of radioactive samples In the following, all work with concentrated radioactive preparations, including evaporation of solutions, was carried out in a glove box. 228 The Th source was obtained from a commercial supplier. Ac resin was obtained in prepackaged cartridges from Eichrom Technologies LLC (Lisle, IL, USA).

[0097] Radium 224 was immobilized 228 The actinide resin containing Th was bound to the actinide resin (Eichrom Technologies, LLC) by eluting the column containing the actinide resin with 1M HCl. 228The eluate was purified on a second Ac resin column and evaporated to dryness using an evaporation vial equipped with a cap equipped with a gas inlet and outlet, placed on a heater block at approximately 110°C, and a gentle stream of nitrogen gas to evaporate the solvent. When the evaporation vial was emptied of solvent, typically 200-400 μl of 0.1 M HCl was added to dissolve the residue. Typically, 228 Th source 224 More than 70% of Ra could be extracted and purified using the described method.

[0098] Radioactive samples were counted in a Cobra II Autogamma counter (Packard Instruments, Downer Grove, IL, USA). 228 From Th source 224 During extraction of Ra, a CRC-25R dose calibrator (Capintec Inc., Ramsey, NJ, USA) was used.

[0099] Example 3 - Before reaching radioactive equilibrium 212 Pb / 224 In the Ra mixture 212 Measurement of net count rate for Pb After 3 days, i.e., the "equilibrium" state of the hermetically-kept sample, for practical purposes, is 1.1 times 212 Pb vs. 224 Has Ra.

[0100] In airtight units 212 Regardless of whether Pb is at or below equilibrium, excess 212 Pb was reduced by up to 99%. 212 Pb 224 It can be assumed that this is achieved after 3 days, as ingrowth from Ra is essentially aligned to the "equilibrium state".

[0101] Using a Cobra II Autogamma counter with a counting window set at 70-80KeV, 224With very little contribution from other radionuclides of the Ra series 212 Pb is mainly obtained. 212 Pb disappears and 224 Ra and 212 Radium-224 must be counted indirectly when equilibrium with Pb is reached (after about 3 days). Otherwise, 220 Rn is flowing out and should be achieved 212 Pb and 224 Because this indirect aggregation can disturb the radionuclide equilibrium state of 1.1 between Ra, samples must be stored in relatively airtight containers.

[0102] Sampling and aggregation can be separated at some point, 212 The net count rate of Pb was calculated by the net 212 It can be adjusted for decay to measure the Pb count rate. 212 By storing the Pb sample for more than a week and then re-measuring it, the radioactivity after approximately 110 hours of storage was 212 It must be derived from a longer-lived precursor isotope rather than Pb. 224 The amount of Ra contaminant can be measured.

[0103] Example 4 - 212 Simplified single chamber (diffusion chamber generator) assembly for Pb production (Figure 3). 3ml v-vials with open top caps. The open top caps were provided with a membrane permeable by a syringe tip. The syringe tip was pierced through the membrane and taped to the top to fix the position of the tip with respect to the open top cap. A strip of absorbent paper approximately 0.5 x 3 cm was placed on the syringe tip by inserting the syringe tip into the two holes in the strip. 2-40ul of absorbent paper was placed on the paper strip. 224 The Ra solution was then added. The cap was then carefully placed onto the v-vial while ensuring that the syringe tip and the radioactive strip did not come into contact with the inside of the v-vial. The assembly was then left for various periods of time to allow the radioactive material to escape from the strip into the space surrounding it. 220 Via Rn diffusion212 Pb was prepared. 212 Pb tended to settle on the inner surface of the v-vial. 224 Depending on the liquid volume used to apply the Ra source onto the strip, there may be some condensation of liquid due to evaporation / condensation of the applied liquid. Alternatively, the source may be dried before assembling the unit to avoid condensation of any solvent on the v-vial inner surface.

[0104] Example 5A: Absorbed onto paper strips 212 Uses Pb precursor isotope source 212 Production of Pb Method: Assemble the parts according to Figure 3. 224 Assemble Ra by placing it on a strip of diffusion subunit inserted into a v-vial; 220 Rn and 212 The product was left to stand for more than 17.5 hours to produce Pb. 212 Production Pb Assessment. At the end of the production period, all units were measured in a Capintec dose calibrator. The product was assessed by separating the source from the container and cap with an airtight screw top and immediately measuring in a Capintec dose calibrator. The purity of the product was evaluated in all 212 Pb has decayed, but the longer-lived earlier nuclides 224 Ra and 228 The presence of Th was determined by repeating the assay of the collector subunits several days later. Results: Highly purified 212 Pb was collected in the collector subunits with a relative yield of 65.6% (range 62.7-69.9%, n=4) and without measurable longer-lived prenuclear species (<0.5%). In conclusion: the assembly was easily purified without the need for further purification. 212 It was effective in producing and collecting Pb.

[0105] Example 5B: Absorbed onto Parafilm Strips 212 Pb precursor isotope source 212Preparation of Pb. The experiment in 5A was repeated except that a strip of parafilm was used instead of a strip of paper to carry the precursor isotope source.

[0106] Results: On the inner surface of the collector subunit (vial or container) 212 The yield of Pb was found to be only 19.3%. In contrast, a unit with paper strips run in parallel with exactly the same configuration and exposure period gave a yield of 63.9%. 212 The material used to absorb and hold the Pb precursor isotope source is a collector subunit or a container. 212 It could have a great effect on the yield of Pb.

[0107] Example 6: From a container using a solution 212 Pb dissolution Methods: Collection vials were added with 0.3-0.5 ml of 0.1 M HCl, gently swirled so that the inner surface was in contact with the liquid, and counted in a Capintec dose calibrator. The liquid was then transferred to an Eppendorf tube and measured in a Capintec dose calibrator. When the collector subunit (3 ml v-vial) was washed only once with 0.3 ml 0.1 M HCl, the extraction yield was 74.0% (range 70.0-76.9%, n=3). In conclusion, the amount of HCl absorbed on the vessel surface was 100%. 212 Pb was dissolved rapidly and in good yield, making the solution useful for radiopharmaceutical processing.

[0108] Example 7: Thin-layer chromatographic analysis Thin layer chromatography (TLC) was performed using chromatography strips (model #150-772, Biodex Medical Systems Inc, Shirley, NY, USA). A small beaker containing approximately 0.5 ml of 0.9% NaCl was used to place the sample-spotted strips. Typically, 1-4 μl of sample was added to the strips approximately 10% above the bottom of the strip. After the solvent front had migrated approximately 20% from the top of the strip, the strips were cut in half and each half was placed in a 5 ml test tube for counting. In this system, radiolabeled antibodies and free radionuclides do not migrate from the bottom half, whereas EDTA-complexed radionuclides migrate to the top half. Formulation buffer (FB), consisting of 7.5% human serum albumin and 1 mM EDTA in DPBS and adjusted to approximately pH 7 with NaOH, was mixed with the radioconjugate in a 2:1 ratio for at least 5 minutes before application to the strips for measuring free radionuclide. 212 Radionuclides in the Pb-containing test solutions were found to be completely complexed (>99%) by EDTA when mixed with FB and migrated to the top half of the TLC strip.

[0109] Example 8: In solution 212 In situ chelation of Pb Background: Extracted from container with 0.1M HCl 212 The labeling properties of Pb were evaluated. Method: In 0.1 M HCl and 5 M ammonium acetate in a ratio of 10:1, 212 Pb was used prior to the addition of the chelator to bring the pH range of 5-6 for the reaction. Reaction times of 15-30 minutes at 37°C were tested. A 5 μg PSMA-617 solution per 100 μl was labeled with a good yield of 96.6% as determined by TLC. A TCMC-conjugated Herceptin antibody solution of approximately 1.0 mg / ml was also labeled with pure Herceptin antibody. 212 The labeling with Pb was achieved with a good yield of 98.9%. In conclusion: the lead-212 produced by the assembly can be easily complexed with small and large molecular conjugates. 212 It was found to be suitable for use in the production of Pb-based radiopharmaceuticals.

[0110] Example 9 - Unit sealed and emptied at one time only 224 Ra source 212 Production of Pb The bottom row of Table 3 shows the 100MBq capacity in the unit. 224 Examples of the output from a diffusion generator that was emptied at various times after the Ra source was inserted are shown. As shown, the generator remained relatively stable for up to 96 hours. 212 This results in an output of Pb.

[0111] Example 10 - For example, when used for fractionated radionuclide therapy, emptying the unit once a day for four days 224 Ra source 212 Production of Pb Table 4 shows the power output when the assembly is milked once every 24 hours. Starting with a 100MBq source, the total power output is 151.5MBq. 212 In conclusion, this one chamber assembly is suitable for single-dose as well as split-dose production.

[0112] Example 11 - Example of an assembly with a retractable source (FIGS. 2 and 4) Materials used may be glass (including quartz), polymer, metal, ceramic, or other materials suitable for pharmaceutical containers. The rod in Figure 2 (piston in Figure 4) slides into a tube with an O-ring or similar on top to ensure an air-tight seal. A valve at the bottom of the rod is air-tight and liquid-tight in the closed position for the unit.

[0113] In the open position, the source is exposed inside the container; 220 Rn is radiated to the inner surface. 212 In the closed position, the source is sealed off from the vessel (Figure 2B) and the vessel surface is in contact with a suitable solution. 212 Pb can be dissolved.

[0114] In embodiments where the cap has a syringe-permeable membrane, the syringe may be inserted without removing the cap. 212To extract the Pb, use a sterile syringe with a sterile solution. 212 When such a unit is autoclaved prior to extraction of Pb, the entire procedure can be performed in an aseptic / sterile fashion.

[0115] Example 12. 212 Precursor nuclides arranged on quartz wool for Pb single-chamber generator Method: A flask as shown in Figure 5 was used. Flask size may vary, typically 10-100 ml flasks were used. When used as a generator, the flask was inverted. The cap was removed and quartz or glass wool was placed inside the center of the cap. Radium-224 in solution was placed on the quartz wool and the flask was attached to the cap without the quartz wool touching the flask. The unit was then clamped down and stored in an inverted position for a period of time to remove any internal growth. 212 After typically one to several days, the flask was held upside down and unscrewed from the cap, carefully removing it from the cap without touching the quartz wool. The cap with the source was then combined with another flask, and 212 It was stored upside down to produce Pb. 212 Add 0.5 to 2 ml of 0.1 M HCl solution to the flask containing Pb and wash the inside surface. 212 The Pb was extracted from the flask and collected for use.

[0116] Results: Typically, 212 50-70% of the Pb radioactivity was found in the flask and by careful washing 212 More than 90% of the Pb radioactivity was collected in the washing solution. 212 Pb was extracted in the fresh solution. 224 Ra is 212 Pb 10 -4 The product was highly suitable for use in labeling chelator-containing proteins and small molecules, resulting in very high labeling yields, typically greater than 97%.

[0117] In conclusion, from the data, quartz wool 224 It has been shown to be very suitable for holding Ra sources, and quartz / glass / mineral wool, metal wool, etc. have been found to be suitable for this purpose. It is also possible to use the flask / quartz wool system in an upright position, and the quartz wool can be glued to the capsule, for example by glue, double-sided mounting tape, etc. In this example, the flask was used upside down, and the quartz wool was not glued, but simply placed and held in place by gravity in the cap.

[0118] Example 13. Inverted flask system version of a single chamber generator 212 A flask-based diffusion generator for labeling with Pb

[0119] Lead-212 decays via short-lived alpha-emitting daughters, 212 It produces an average of one alpha particle per Pb decay, producing therapeutically high-LET radiation. 212 The half-life of Pb, 10.6 hours, limits its use, necessitating rapid and safe manufacturing and purification procedures. If a ready-to-use product were produced in a centralized manufacturing facility and shipped to the end user, the radioactivity level would drop to less than 25% in a day. Lead-212-based radioimmunoconjugates were purified by cation exchange columns. 224 Separated from Ra and dissolved in mineral acid 212 It is currently undergoing clinical trials for peritoneal cancer using Pb, which must be reverted before radiolabeling. 224 From Ra generator materials 212 It requires considerable work effort, equipment and suitable apparatus for the evaporation of mineral acids to produce Pb. It is absorbed on quartz wool and placed inside a ring in the center of the removable cap of the generator chamber (generator cap). 224 An alternative generator method based on Ra was developed and tested. The chamber consisted of an inverted glass bottle with a removable cap. 224Support Ra-labeled quartz wool (Figure 5). 224 When Ra decays, a short-lived 220 Rn is released from the quartz wool and the long-lived decay products 212 This causes Pb to be absorbed onto the inside surface of the flask. The flask can be removed from the cap without contacting the glass with the quartz wool. After removing the flask from the generator cap, 212 The inside of the flask can be rinsed with 0.1M HCl to dissolve the Pb deposits, resulting in a highly purified 212 Prepare the Pb solution. The generator flask is operated and flushed prior to radiolabeling of NG001. 212 Pb 224 The purity for Ra is greater than 99.8% when the generator is operated correctly (i.e., the source does not come into contact with the walls). The generator can be reused by fitting a new glass bottle to the generator cap, and a new 212 It can typically be stored for 1-2 days to generate Pb.

[0120] In summary, this generator method is easier and less time consuming to use compared to ion exchange based generators, and the generator may be reused several times (although its capacity decreases due to radioactive decay depending on the half-life of the source).

[0121] Example 14: Collector flask size Flask sizes of 10, 50, and 100 ml were tested (Table 5, top). 224 Ra was added to quartz wool placed in the cap of an inverted flask. 212 The Pb yield varied from about 40% to 60%. To obtain higher yields, it seemed advantageous to use a larger flask to cover the inner volume. In conclusion, although flasks of various sizes can be used for generator applications, a relatively large flask relative to the cap is preferred, since there is relatively less loss due to absorption on the cap and source material. 212It seemed to improve the yield of Pb.

[0122] Example 15: Materials for holding radiation sources To hold the source material in the correct position inside the generator, for example in the center of the inner cap, use steel wool, glass wool, or quartz wool. 224 The material was tested with a Ra source. The material is porous, fluffy, and diffusible. It was dissolved in 0.1M HCl at a volume of 100-150 microliters. 224 Ra was deposited on the material placed inside the cap of a 100 ml flask. After standing for 2-3 days or more, 224 52-64% compared to Ra 212 As Pb settles on the glass surface, all three materials work, i.e. 224 The Ra activity averaged over five tests each for quartz wool was 59.9% (range 52.1-64.4%), for one test for glass wool 54.9% and for one test for steel wool 64.1%. In conclusion, several different materials could be used to hold the source in a single-chamber diffusion generator.

[0123] Example 16: Radiation Source Radionuclides 224 Ra and 228 Th was used as the source inside the generator. The glass flask was replaced with an unused one, and the first flask was washed and 212 By simply preparing the Pb solution, 224 Ra-based generators could typically be used repeatedly for up to several weeks, 228 The Th-based unit could be used repeatedly for several months. The yield did not decrease significantly with repeated use, except for the decay of the radionuclides in the generator. Cross-contamination from the source to the glass flask was minimal, as long as the source was centered inside the cap to avoid contact with the glass bottle, and the flask and cap were kept dry. In conclusion, 228 Th and 224 Both Ra and 212The single chamber diffusion unit could be used repeatedly to produce Pb. 228 Lead-212 radioactivity on the inner glass surface originating from Th was found to be 49.3% (range 40.9%–66.7%), averaging across four tests.

[0124] Example 17: Preparation involving heating: Heating the flask before mounting it on the cap containing the source material can be a way to create a reduced pressure in the generator. The flask is heated in a heating chamber at 90°C for at least 15 minutes, and then the flask and cap are tightly screwed together to form an airtight seal. The generator unit is then stored at room temperature to allow the internal pressure to decrease. After 1-4 days, the chamber is opened and the flask on the glass flask is heated to 90°C for at least 15 minutes, and the flask and cap are tightly screwed together to form an airtight seal. The generator unit is then stored at room temperature to allow the internal pressure to decrease. After 1-4 days, the chamber is opened and the flask is cooled to 100°C. 212 Pb radioactivity was measured. 224 The yield from four trials with Ra averaged 68.1% (range 60.5%-75.9%, showing an improvement in yield compared to previous data for normal pressure flasks (average 59.9%)). In conclusion, the reduction in chamber pressure leads to a higher yield in single chamber diffusion generators. 212 The yield of Pb can be improved.

[0125] Example 18: In the rinse solution 212 Pb yield Trapped on the inner glass surface of a 100 ml flask 212 A standard solution of 0.1M HCl was used to extract the Pb. The wash solution was carefully shaken and swirled to cover the inside of the flask for approximately 2 minutes, then 80% of the volume was removed, measured, and compared to the total count in the flask before the wash procedure. It was assumed that the 80% volume should be divided by 0.8 to determine the total radioactivity in the liquid. Similar wash efforts extracted approximately 85% with 0.6 ml and 93% with 1 ml. 224 The Ra-based generator extracted 86.1% (range 79.4%–93.4%) of the sample from the vial, averaging eight trials. 228The Th-based generator extracted 86.5% (range 84.5%-88.5%) of the uranium from the glass vial on average over two trials. In conclusion, the uranium trapped on the inner glass surface of the generator 212 Pb is easily extracted with 0.1M HCl.

[0126] Example 19. Radiolabel reactivity in solution Extracted from the generator 212 Pb 212 To test Pb labeling, we used the TCMC chelator-based molecule NG001 (Stenberg et al. 2020). Pb-212 in 0.1 M HCl was added to adjust the pH to approximately 5.5. NG001 was then added at 10–20 micrograms per ml. After 30 min of reaction at 37 °C using a Thermomixer (Eppendorf, Germany), samples were pulled and thin-layer chromatography (TLC) was performed by mixing the sample 1:2 with 1 mM EDTMP in 7.5% bovine serum albumin solution and allowed to stand for 5 min. 1–5 microliters were then applied to a chromatography strip (model #150-772, Biodex) and eluted with 0.9% NaCl solution in a beaker. When the liquid front reached the top of the strip, the strip was cut in half, each half was placed in a tube, and counted separately in a Packard Cobra II gamma counter (Packard Instruments Co Inc, USA). The data showed that after 3 hours, activity in the bottom half was typically 99%, indicating nearly quantitative yields. Blind tests without NG001 but with all other compounds yielded 3% in the bottom half of the strip, indicating excellent selectivity on TLC. In conclusion, the extracts from the generator flasks yielded 10% of the desired activity, indicating that the activity was not quantitatively correlated with the TLC yield. 212 Pb has been shown to exhibit excellent reactivity and is suitable for radiopharmaceutical applications.

[0127] Example 20. Radiochemical purity of extracted solutions Lead-212 solution was stored for more than 10 days. 224 Counting was repeated to determine Ra. 224Ra activity was decay-corrected back to time 0. 212 Pb 224 The Ra was determined to be, on average, 0.045% (range 0.01%-0.13%). In conclusion, 212 The Pb had high radiochemical purity suitable for pharmaceutical use.

Claims

1. On the wall ２１２ A method for obtaining a container containing Pb, the method comprising the steps of: providing an assembly comprising a first portion and a second portion, wherein the first portion comprises a container and the second portion comprises: ２１２ A Pb precursor isotope source is provided; The above ２１２ combining the first and second parts such that a Pb precursor isotope source does not contact an interior wall of the vessel and to provide a single-chamber vessel assembly; The above ２１２ Progeny of Pb precursor isotope source ２２０ Rn, ２１６ Po, and / or ２１２ Pb for sufficient time to decay, and ２２０ Rn, ２１６ Po and / or ２１２ allowing sufficient time for Pb to settle onto the interior walls of the single chamber vessel assembly; The above ２１２ The Pb precursor isotope source is not in contact with the inner wall of the single chamber vessel assembly, and the remaining ２１２ removing or separating the Pb precursor isotope from the single chamber assembly; and On the inner wall of the container ２１２ Pb, and the inner wall of the container is ２１２ obtaining a container substantially free of a Pb precursor isotope source; method.

2. An assembly comprising a first portion and a second portion, the first portion comprising a container and the second portion comprising: ２１２ a Pb precursor isotope source, the first portion and the second portion comprising ２１２ The assembly is bonded such that the Pb precursor isotope source does not contact the interior walls of the vessel and provides a single chamber vessel assembly.

3. 1. A single chamber container assembly comprising a first portion and a second portion, the first portion comprising a container and the second portion comprising: ２１２ a Pb precursor isotope source, the first portion and the second portion comprising ２１２ A single-chamber vessel assembly, wherein a Pb precursor isotope source is bonded such that it does not contact the interior walls of said vessel.

4. The method of claim 1 and the assembly of claims 2-3, wherein the single-chamber container assembly is airtight.

5. The above ２１２ The Pb precursor isotope source is ２３２ Th, ２２８ Ra, ２２８ A c, ２２８ Th and / or ２２４ The method and assembly of any one of claims 1 to 4, wherein said first metal is selected from the group consisting of Ra.

6. The above ２１２ The Pb precursor isotope source is ２３２ Th, ２２８ Ra, ２２８ A c, ２２８ Th and ２２４ The method and assembly of any one of claims 1 to 5, wherein the material is a mixture of Ra.

7. The above ２１２ The Pb precursor isotope source is ２２８ Th and ２２４ The method and assembly of any one of claims 1 to 6, wherein the material is a mixture of Ra.

8. The above ２１２ Pb radioactivity is as described above. ２２４ The method and assembly of any one of claims 1 to 7, wherein the activity of the Ra precursor is between 0% and 114%.

9. The above ２１２ Pb radioactivity is as described above. ２２８ The method and assembly of any one of claims 1 to 8, wherein the Th precursor activity is between 0% and 103%.

10. A method and assembly according to any one of claims 1 to 9, wherein the total amount of radioactivity in said single chamber container assembly is between 1 kBq and 100 GBq.

11. The above ２１２ The Pb precursor isotope source is RaCl ２ The method and assembly of any one of claims 1 to 10, wherein the compound is in the form of an inorganic or organic salt such as:

12. The above ２１２ The method and assembly of any one of claims 1 to 11, wherein the Pb precursor isotope source is bound to a non-radioactive substance, such as a particle or a retaining material.

13. The above ２１２ The method and assembly of any one of claims 1 to 12, wherein the Pb precursor isotope source is in dry form or in liquid solution, such as an aqueous solution or dispersion.

14. The above ２１２ The method and assembly of any one of claims 1 to 13, wherein the Pb precursor isotope source is a liquid solution that is at an acidic, neutral or basic pH.

15. The above ２１２ A method and assembly according to any one of claims 1 to 14, wherein the Pb precursor isotope source is deposited on a sponge, wool, strips or spheres made of a material suitable for liquid application.

16. The above ２１２ 16. The method and assembly of any one of claims 1 to 15, wherein the Pb precursor isotope source is deposited on a sponge, wool, strips or spheres made from a material selected from the group consisting of quartz, glass, mineral, paper, plastic, metal, ceramic, and natural or synthetic fibers.

17. 17. A method and assembly according to any one of claims 15 to 16, wherein strips or spheres are attached to the second part, the second part comprising a means for holding the sponge, wool, strips or spheres, such as a stick.

18. 18. The method and assembly of claim 17, wherein the second portion comprises a syringe or the rod is the syringe.

19. 20. The method and assembly of claim 18, wherein the syringe tip extends through a rubber cap.

20. A method and assembly according to any one of the preceding claims, wherein the second part comprises a bar attached to a means for opening and closing the container.

21. 21. The method and assembly of claim 20, wherein the means for opening and closing the container is a cap, cover or lid.

22. 22. The method and assembly of claim 21, wherein the cap, cover or lid is made from a material selected from the group consisting of quartz, glass, mineral, rubber, glass, paper, plastic, metal, ceramic, and natural or synthetic fibers.

23. The above ２１２ 23. A method and assembly according to any one of claims 1 to 22, wherein the Pb precursor isotope source is disposed on or in a sphere suitable for holding said source but allowing radon diffusion.

24. The container is ２１２ 24. The method and assembly of any one of claims 1 to 23, comprising a gas permeable barrier impermeable to the Pb precursor isotope source.

25. The above ２１２ The gas-permeable barrier that is impermeable to the Pb precursor isotope source is ２１２ 25. The method and assembly of claim 24, wherein the Pb precursor is contacted with a source of isotope.

26. The container is ２１２ The method and assembly of any preceding claim, wherein the method and assembly does not include a gas-permeable barrier that is impermeable to the Pb precursor isotope source.

27. 27. A method and assembly according to any preceding claim, wherein the volume of the container is between 1 μl and 10 litres, such as between 1 μl and 1 litre, such as between 100 μl and 10 ml, such as between 100 μl and 100 ml.

28. On the inner wall of the container ２１２ The substantial absence of Pb precursor isotope sources, as measured by the relative radioactivity ratio, is ２１２ Less than 3%, such as less than 1%, such as less than 0.5%, of the Pb precursor isotope source. ２２４ 28. The method and assembly of any one of claims 1 to 27, wherein said thickness is defined as Ra.

29. A method and assembly according to any one of the preceding claims, wherein the inner wall of the container is coated.

30. The inner wall of the container is ２１２ The method and assembly of any one of claims 1 to 29, which is coated with a compound containing a chelating agent capable of forming a complex with Pb.

31. A method and assembly according to any one of claims 1 to 30, wherein the inner wall of the container is coated with a chelating agent which is TCMC or a derivative thereof.

32. A method and assembly according to any preceding claim, wherein the container contains an aqueous or oily solution.

33. A method and assembly as claimed in any preceding claim, wherein the second part of the assembly comprises a piston capable of assuming an open position and a closed position.

34. A method and assembly according to any preceding claim, wherein the second part of the assembly comprises a chamber having an airtight O-ring seal.

35. A method and assembly according to any preceding claim, wherein the second part of the assembly comprises an air-tight and liquid-tight lid or valve.

36. The assembly comprises: ２２４ Ra or ２２８ 36. The method and assembly of any one of claims 1 to 35, wherein quartz wool containing Th is centrally placed inside the cap, produced by an inverted glass flask.

37. On the wall according to any one of claims 1 to 36 ２１２ Obtaining a container or assembly containing Pb, and then ２１２ collecting the Pb in solution; ２１２ How to obtain Pb solution.

38. Obtaining the glass flask assembly of claim 37, unscrewing the flask upside down from the cap containing the radiation source, and thereafter rinsing the interior of the flask with a solution. ２１２ Dissolving Pb. ２１２ How to obtain Pb solution.

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