Method for purifying radiolabeled human serum albumin large aggregates

Abstract

The present invention relates to a method for purifying radiolabeled human serum albumin macroaggregates (MAA) in a solution that can be injected into a patient using a syringe filter, characterized in that the syringe filter used has the property of trapping and releasing the radiolabeled MAA while not retaining impurities from the entire solution.

Description

Technical Field

[0001] Field of the Invention The present invention relates to a simplified method for the purification of radiolabeled macroaggregated human serum albumin (MAA), which is more simply referred to hereinafter in this specification as a radiolabel. This purification enables easier automation of such radiotracer synthesis.

Background Art

[0002] Background Art Positron Emission Tomography Positron emission tomography (PET) is a medical imaging method for obtaining quantitative molecular and biochemical information on physiological processes in the body. The most commonly used PET radiopharmaceuticals currently in use are [18F]-fluorodeoxyglucose ([18F]-FDG), a radiolabeled glucose molecule. PET imaging using [18F]-FDG enables visualization of glucose metabolism and has a wide range of clinical applications. Among positron emitters, 18F is currently the most widely used in clinical settings. Due to increasing regulatory pressure, radiopharmaceuticals are currently usually prepared from disposable components assembled in a ready-to-use cassette.

[0003] In addition to 18F, radiometals (e.g., 64Cu, 89Zr, 67Ga, 68Ga, 86Y, 90Y, 177Lu, and 99mTc) play extremely important roles in nuclear medicine as therapeutic agents and imaging agents for radiotherapy and the labeling of biologically important low molecular weight molecules and macromolecules such as proteins, peptides, and antibodies.

[0004] Recently, the rapid increase in both clinical and preclinical studies using 68Ga-labeled radiopharmaceuticals has attracted attention (Velikyan I., Prospective of 68Ga-radiopharmaceutical development. Theranostics 2014; 4:47~80; Banerjee SR, Pomper MG, Clinical applications of Gallium-68. Appl. Radiat. Isot. 2013; 76:2~13; Zimmerman BE, Current status and future needs for standards of radionuclides used in positron emission tomography. Appl. Radiat. Isot. 2013; 76:31~37; Smith DL, Breeman WAP, Sims-Mourtada J., The untapped potential of Gallium-68 PET: The next wave of 68Ga-agents. Appl. Radiat. Isot. 2013; 76:14~23). This increase in physical characteristics of 68Ga (Eβ) is advantageous for imaging various rapidly changing processes (proliferation, apoptosis, angiogenesis) and targets (growth hormone, myocardial and pulmonary perfusion, inflammation, and infection). max 1.8 MeV, β+89%, T 1 / 2This can be attributed to newer and more reliable generation and labeling methods, to some extent, as well as to newer and more reliable generation and labeling methods. For example, gallium-68 labeled somatostatin analogs have already demonstrated their superiority over the existing activator 111In-DTPA-octreotide due to enhanced sensitivity, specificity, accuracy, and cost-effectiveness for the diagnosis of patients with neuroendocrine tumors (Oberg K., Gallium-68 somatostatin receptor PET / CT: Is it time to replace 111Indium DTPA octrotide for patients with neuroendocrine tumors? Endocrine 2012; 42:3~4; Schreiter NF, Brenner W., Nogami M., Buchert R., Huppertz A., Pape UF, Prasad V., Hamm B., Maurer MH, Cost comparison of 111In-DTPA-octrotide scintigraphy and 68Ga-DOTATOC PET / CT for staging enteropancreatic neuroendocrine tumors. Eur. J. Nucl.). Med. Mol. Imaging 2012; 39: 72~82; Hofman MS, Kong G., Neels OC, Eu P., Hong E., Hicks RJ, High management impact of Ga-68 DOTATATE (GaTate) PET / CT for imaging neuro-endocrine and other somatostatin expressing tumors. J. Med. Imaging Radiat. Oncol. 2012; 56-40~47).

[0005] Another reason for the current preference for gallium-68 is that it can be produced on-site by widely available 68Ge / 68Ga generators. Such 68Ge / 68Ga generators are widely accessible in nuclear medicine facilities that do not have on-site cyclotrons. The simplicity and lower capital cost of 68Ge / 68Ga generators have made them more widespread in nuclear medicine facilities with relatively few requirements regarding 68Ga-labeled doses (Rosch F. Past, present and future of 68Ge / 68Ga generators. Appl. Radiat. Isot. 2013; 76: pp. 24-30).

[0006] Radioactive metal-labeled large agglutination human serum albumin (MAA) The use of macroaggregated human serum albumin (MAA) as a perfusion agent has been evaluated since 1965 (Furth ED, Okinawa AJ, Focht EF, Becker DV, The distribution, metabolic fate and radiation dosimetry of 131I-labeled macroaggregated albumin. J. Nucl. Med. 1965; 6:506~518). In 1974, a simple kit for the preparation of 99mTc-labeled MAA was evaluated using single-photon emission computed tomography (SPECT) for this purpose (Charidra R., Shamoun J., Braunstein P., DuHov OL, Clinical evaluation of an instant kit for preparation of 99mTc MAA for lung scanning. J. Nucl. Med. 1974; 14-9:702~705). This drug has become the standard for pulmonary perfusion studies and still dominates the market (Suga K., Kawakami Y., Zaki M., Yamashita T., Matsumoto T., Matsunaga N., Pulmonary perfusion assessment with respiratory gated Tc-99m macroaggregated albumin SPECT: preliminary results. Nucl. Med. Commun. 2004; 25: pp. 183-193). Today, numerous FDA-approved MAA labeling kits for 99mTc are commercially available (e.g., Pulmocis® (from CisBio), LyoMAA® (from Covidien), HAS-B20® (from Rotop), MAASOL® (from GE), etc.). All of these kits are supplied in the form of sterile, disposable vials containing approximately 2.0 mg of MAA particles, approximately 0.05 mg of SnCl2 (as a 99mTc reducing agent), and approximately 5.0 mg of free albumin.

[0007] Given the global shortage of 99Mo, which is attenuated to form 99mTc and used in approximately 600,000 medical imaging procedures worldwide every week, it is necessary to consider alternatives that can be independent of any shortage of 99mTc. 68Ge / 68Ga generators represent such an attractive alternative. Furthermore, PET / CT provides images with significantly higher resolution than SPECT. Therefore, 68Ga-labeled MAA for PET / CT perfusion imaging represents an attractive alternative to 99mTc-labeled MAA.

[0008] MAA was first successfully labeled with 68Ga in 1986 (Maziere B., Loc'h C., Steinling M., Comar D., Stable labelling of serum albumin microspheres with gallium-68. Int. J. Radiat. Appl. Instrum. Part A 1986; 37:360~361) and 1989 (Even GA, Green MA, Gallium-68-labeled macroaggregated human serum albumin, 68Ga-MAA. Int. J. Radiat. Appl. Instr. 1989; 16:319~321), but it was almost certainly not used at the time due to the unreliability of existing 68Ge / 68Ga generators and the low availability of PET imaging cameras. Later, Mathias et al. (Mathias CJ, Green MA, A convenient route to [68Ga]Ga-MAA for use as a particulate PET perfusion tracer. Appl. Radiat. Isot. 2008; 66: pp. 1910-1912) also succeeded in labeling MAA with 68Ga.Similar results have been reported using commercially available 99mTc-MAA kit systems (Jain A., Subramanian S., Pandey U., Sarma HD, Ram R., Dash A., In-house preparation of macroaggregated albumin (MAA) for 68Ga labelling and its comparison with commercially available MAA. J. Radioanal. Nucl. Chem. 2016; 308:817~824; Amor-Coarasa A., Milera A., Carvajal D., Gurec S., McGoron AJ, Lyophilized kit for the preparation of the PET perfusion agent [68Ga]-MAA. Int. J. Mol. Imaging 2014:1~7; Ament SJ, Maus S., Reber H., Buchholz HG, Bausbacher N., Brochhausen C., Graf F., Miederer). M., Schreckenberger M., PET lung ventilation / perfusion imaging using 68Ga aerosol (Galligas) and 68Ga-labeled macroaggregated albumin. Recent Results Cancer Res. 2013; 194:395~423). To remove undesirable components, such as stannous chloride, which is usually used as a reducing agent, the lyophilized MAA kit system was resuspended and washed with 0.9% physiological saline using centrifugation.Preconjugation of MAA with a DOTA chelating agent for efficient 68Ga labeling (Kotzerke J., Andreeff M., Wunderlich G., Wiggermann P., Zphel K., Ventilation / Perfusion scans using Ga-68 labeled tracers. Abstracts of invited lectures. World J. Nucl. Med. 2011; 10: pp. 26-59) is not necessary in this procedure. After labeling, 68Ga-MAA was purified using centrifugation, but this is time-consuming, significantly reduces the final yield, and is difficult to automate. The authors were also able to demonstrate that there are no differences in morphological structure between unlabeled and labeled MAA particles. Maus et al. (Maus S., Buccholz HG, Ament S., Brochhausen C., Bausbacher N., Schreckenberger M., Labeling of commercially available human serum albumin kits with 68Ga as surrogates for 99mTc-MAA microspheres. Appl. Radiat. Isot. 2011; 69: pp. 171-175) found similar results and used this method to investigate labeling efficiency by using HEPES buffer. A maximum labeling efficiency of 70% was observed, and the radiochemical purity after the final solid-phase extraction (SPE) purification step (using a C18 SEP-Pack cartridge) was higher than 95%. This final SPE purification was still shown to dramatically reduce the yield of the final 68Ga-MAA (more than 30% of the labeled MAA remained packed in the SPE cartridge). All these reports on the radiolabeling of MAA directly disclose the use of a crude fraction of the 68Ge / 68Ga generator eluate. The use of a crude fraction of the eluate prevents the separation of the generator's 68Ge breakthrough from the final product during the labeling procedure. Furthermore, this method utilizes only a portion of the elutable 68Ga radioactivity.To overcome this drawback, Mueller et al. (Mueller D., Kulkarni H., Baum RP, Odparlik A., Rapid synthesis of 68Ga-labeled macroaggregated human serum albumin (MAA) for routine application in perfusion imaging using PET / CT. 2017; 122:72~77) recently provided a convenient preparation of 68Ga-MAA using cation pre-purification of the generator eluate. This method allows for the use of most of the 68Ga radioactivity eluted from the generator and does not require any purification steps of the reaction medium, as 68Ge leakage is removed during cation pre-purification. Nevertheless, in the absence of a final purification step, production may be lost in the case of low-yield labeling. The authors also show that a MAA pre-washing step using centrifugation to remove tin chloride is not necessary to achieve efficient labeling yields.

[0009] Commercial gallium-68 (68Ge / 68Ga) generators are widely available. The parent isotope 68Ge has a half-life of 270.95 days and can be easily delivered to hospitals as a generator, where it can be used as a source of Ga-68 for at least one year. The short half-life of 68Ga allows for easy elution from the generator at any time at the application site. Chromatographic 68Ga generators are glass columns using a modified TiO2-based adsorbent. The parent radionuclide 68Ge is immobilized on this adsorbent. The column is placed in a lead-shielded container and is equipped with an eluent and elution line. The 68Ga generated as a result of 68Ge decay is eluted from the column using, for example, a 0.1 M HCl solution. The parent isotope radioactivity is, for example, between 10 mCi (370 MBq) and 100 mCi (3700 MBq). 68Ge leakage is typically less than 0.005%. [Prior art documents] [Non-patent literature]

[0010] [Non-licensed Document 1] Velikyan I., Prospective of 68Ga-radiopharmaceutical development. Theranostics 2014; 4:47~80 pages [Non-licensed Document 2] Banerjee SR, Pomper MG Clinical applications of Gallium-68. Appl. Radiat. Isot. 2013; 76:2~13 pages [Non-licensed Document 3] Zimmerman BE Current status and future needs for standards of radionuclides used in positron emission tomography. Appl. Radiat. Isot. 2013; pp. 76:31~37 [Non-licensed Document 4] Smith DL, Breeman WAP, Sims-Mourtada J., The untapped potential of Gallium-68 PET: The next wave of 68Ga-agents. Appl. Radiat. Isot. 2013; 76:14~23 pages [Non-licensed Document 5] Oberg K., Gallium-68 somatostatin receptor PET / CT: Is it time to replace 111Indium DTPA octrotide for patients with neuroendocrine tumors? Endocrine 2012; pp. 42:3~4 [Non-licensed Document 6] Schreiter NF, Brenner W., Nogami M., Buchert R., Huppertz A., Pape UF, Prasad V., Hamm B., Maurer MH, Cost comparison of 111In-DTPA-octrotide scintigraphy and 68Ga-DOTATOC PET / CT for staging enteropancreatic neuroendocrine tumours. Eur. J. Nucl. Med. Mol. Imaging 2012; 39: pages 72~82 [Non-licensed Document 7] Hofman MS, Kong G., Neels OC, Eu P., Hong E., Hicks RJ, High management impact of Ga-68 DOTATATE (GaTate) PET / CT for imaging neuro-endocrine and other somatostatin expressing tumors. J. Med. Imaging Radiat. Oncol. 2012; pp. 56-40~47 [Non-licensed Document 8] Rosch F. Past, present and future of 68Ge / 68Ga generators. Appl. Radiat. Isot. 2013; pp. 76:24~30 [Non-licensed Document 9] Furth ED, Okinaka AJ, Focht EF, Becker DV, The distribution, metabolic fate and radiation dosimetry of 131I labeled macroaggregated albumin. J. Nucl. Med. 1965; 6:506~518 pages [Non-licensed Document 10] Charidra R., Shamoun J., Braunstein P., DuHov O.L., Clinical evaluation of an instant kit for preparation of 99mTc MAA for lung scanning. J. Nucl. Med. 1974; 14-9:702~705 pages

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Summary of the Invention

Problems to be Solved by the Invention

[0011] Problems to be Solved 99mTc-labeled MAA is a widely used established lung perfusion agent using SPECT. Due to the superiority of PET over SPECT and the future shortage of 99Mo, 68Ga-labeled MAA for PET / CT perfusion imaging represents an attractive alternative to 99mTc-labeled MAA.

[0012] The labeling conditions of 68Ga with MAA are clearly defined, but there is a lack of an effective, automated, simple disposable cassette-based system and a final purification method with high time / yield efficiency for labeled 68Ga-MAA particles from the bulk reaction medium that removes 68Ge leakage, consistently ensures high radiochemical purity, enables safe patient injection, and does not affect the final synthesis yield.

[0013] Today, such final purification is carried out either by using centrifugation, which requires extra equipment, is time-consuming, negatively impacts the overall synthesis yield (approximately 20% radioactivity loss), and is undesirable from a radiation protection standpoint, or by using SPE purification, which negatively impacts the yield (over 30% radioactivity loss due to labeled particles stuck in the cartridge). A recent example uses time-consuming cation pre-purification of generator eluate without any final purification that does not meet regulatory requirements. Therefore, an alternative synthesis method with a highly effective final purification step is highly desirable. The selected purification method must be sufficiently effective and reliable to ensure a high level of radiochemical purity.

[0014] Objective of the present invention The present invention aims to carry out the synthesis of 68Ga-labeled MAA particles, which can be easily automated in a ready-to-use consumable, including the efficient final purification of the labeled particles. [Means for solving the problem]

[0015] Summary of the present invention The present invention relates to a method for the synthesis and purification of radiolabeled coagulated human serum albumin (MAA) for forming a bulk solution injectable to a patient, and further details: - A process of preparing radioactive metals in the form of a generator eluent inside the generator. - Depending on the case, the generator eluate may be pre-purified on a cation cartridge, and the pre-purified generator eluate may be eluted. - A step of synthesizing radiolabeled MAA in a reactor using MAA particles from a commercially available labeling kit for 99mTc and the generator eluate, pre-purified or unpurified; - A step of passing synthesized radiolabeled MAA particles through a syringe filter membrane whose membrane composition, diameter, and pore size are selected to capture radiolabeled MAA particles, while not retaining impurities consisting of free radioactive metal isotopes, radiophilic metal leakage, and stannous chloride present in the MAA labeling kit for 99mTc derived from bulk solution. - A step to decapture the captured radiolabeled MAA particles from the syringe filter using saline or buffer solution passing through the syringe filter in the opposite direction to the capture operation, and to prepare the final bulk solution in a vial that can be injected into the patient. Regarding methods including

[0016] According to a preferred embodiment, the method has the following features: - The purified radiolabeled MAA particles are MAA particles labeled with detectable metal ions selected from the group consisting of 99mTc, 94mTc, 48V, 52Fe, 55Co, 64Cu, 68Ga, 67Ga, 111In, 113In, 86Y, 89Zr, 203Pb, 212Bi, 82Rb, 186Re, and 81mKr; - The purified radiolabeled MAA particles are MAA particles labeled with a detectable metal ion selected from the group consisting of 99mTc, 68Ga, 86Y, 89Zr, and 64Cu; - The radioactively labeled MAA particles to be purified are MAA particles labeled with 99mTc or 68Ga; - The pore size of the syringe filter membrane is within the range of 0.1 to 10.0 μm; - The pore size of the syringe filter membrane is within the range of 0.1 to 5.0 μm; - The pore size of the syringe filter membrane is within the range of 0.1 to 0.45 μm; - The diameter of the syringe filter membrane is within the range of 10 to 33 mm; - The diameter of the syringe filter membrane is within the range of 20-33 mm; - The syringe filter membrane is a low-protein-binding hydrophilic membrane selected from the group consisting of PVDF, PES, CA, hydrophilic PTFE, nylon, glass fiber, RC, CE, CN, and PP; - Syringe filters are disposable filter cartridges that likely have Luer lock fittings; - Syringe filters are attached to disposable cassettes in an automated manner; - Prior to the step of capturing the generator eluate on a syringe filter, the generator eluate is kept at room temperature for 2 to 30 minutes or heated at 40-80°C for 2 to 20 minutes; - The reactor used to synthesize radioactive metal-labeled MAA is an automated synthesis apparatus. or further including one of the preferred combinations thereof. Brief explanation of the drawing [Brief explanation of the drawing]

[0017] [Figure 1] This diagram schematically illustrates the processes of capturing radioactive metal-labeled MAA (left side, particles are captured on the filter, while impurities pass through the filter and become waste) and decapsulation (right side, the solution stream decapsulates the particles). [Modes for carrying out the invention]

[0018] Disclosure of the present invention The present invention enables the purification of 68Ga-labeled MAA particles prepared using the entire generator eluate directly, or by pre-purifying the generator eluate cations. The method is further compatible with any commercially available MAA labeling kit for 99mTc.

[0019] This efficient purification is achieved by using syringe filters. Syringe filters are disposable filter cartridges. Syringe filters may have Luer lock fittings, though not universally. In manual purification, the syringe filter is attached to the tip of the syringe being used. In automated methods, the syringe filter may be fixed to a disposable cassette. The use of a needle is optional and, if desired, can be fixed to the tip of the syringe filter. Syringe filters generally consist of a plastic housing with a membrane that serves as a filter. The fluid to be purified can be cleaned by passing it through the filter and pumping it up. Syringe filter membranes are characterized by their composition (material and pore size) and diameter. Commonly available pore sizes are 0.1, 0.2, 0.22, 0.45, 5, and 10 μm, but intermediate pore sizes are readily available. Membrane diameters of 10, 13, 25, and 33 mm are also common. The syringe filter body can be made from materials such as polypropylene and nylon. The filter membrane may be made from polytetrafluoroethylene (PTFE), nylon, cellulose acetate (CA), polyvinylidene fluoride (PVDF), cellulose ester (CE), polyethersulfone (PES), polypropylene (PP), glass fiber (GF), regenerated cellulose (RC), cellulose nitrate (CN), etc.

[0020] As the reaction medium passes through the syringe filter membrane, labeled and unlabeled MAA particles are retained on the filter by size exclusion, while 68Ge leakage and the remaining free 68Ga3+ pass through the syringe filter membrane and become waste (Figure 1, left).

[0021] To decapture particles from the syringe filter, the solution passes through the syringe filter membrane in the opposite (or reverse) direction of the capture operation to the final product vial (Figure 1, right). Decapture is achieved by the flow of the decapture solution. The aforementioned decapture solution is injectable (e.g., a suitable phosphate buffer solution or physiological saline, i.e., 0.154 mol / L or 9 g / L NaCl), and the resulting tracer solution is readily injectable into the patient.

[0022] This brings several advantages: reduced preparation time leading to increased overall yield; simplification of automated equipment required for the synthesis of radiopharmaceuticals; a purification process compatible with any radiolabeled MAA particles, and therefore not limited to 68Ga or Tc99m; and a guarantee of high levels of radiochemical purity, even in the case of low-yield labeling.

[0023] According to the present invention, the purification process is carried out by passing the synthesis bulk of radiolabeled MAA particles through a syringe filter which can be placed in a disposable cassette for automation. This syringe filter has the characteristic of retaining labeled (and unlabeled) MAA products but not retaining free unlabeled radioisotopes (i.e., 68Ga3+ in the case of 68Ga-MAA labeling, and likewise 68Ge leakage), ensuring a high level of radiochemical purity, but also not retaining tin chloride derived from either of the original MAA labeling kits.

[0024] In some embodiments of the present invention, the purified radiolabeled MAA particles are MAA particles labeled with detectable metal ions such as 99mTc, 94mTc, 48V, 52Fe, 55Co, 64Cu, 68Ga, 67Ga, 111In, 113In, 86Y, 89Zr, 203Pb, 212Bi, 82Rb, 186Re, and 81mKr.

[0025] In some preferred embodiments of the present invention, the radiolabeled MAA particles to be purified are MAA particles labeled with 99mTc, 68Ga, 86Y, 89Zr, or 64Cu.

[0026] In some preferred embodiments of the present invention, the radiolabeled MAA particles to be purified are MAA particles labeled with 99mTc or 68Ga.

[0027] In some embodiments, the pore size of the syringe filter membrane is in the range of 0.1 to 10.0 μm.

[0028] In some preferred embodiments, the pore size of the syringe filter membrane is in the range of 0.1 to 5.0 μm.

[0029] In some preferred embodiments, the pore size of the syringe filter membrane is in the range of 0.1 to 0.45 μm.

[0030] In some embodiments, the diameter of the syringe filter membrane is in the range of 10 to 33 mm.

[0031] In some embodiments, the diameter of the syringe filter membrane is in the range of 20 to 33 mm.

[0032] In some embodiments, the syringe filter membrane is selected from the group of low protein-binding hydrophilic membranes (PVDF, PES, CA, hydrophilic PTFE, nylon, glass fiber, RC, CE, CN, PP). [Examples]

[0033] (Example 1) This example demonstrates the efficiency of using a syringe filter to purify bulk 68Ga-MAA. 68Ga-MAA was synthesized in an automated synthesizer using cation pre-purification of the generator eluate, with the Eckert & Ziegler 68Ge / 68Ga generator eluted with 5 mL of 0.1 M HCl. The generator eluate was captured on a PS-H+ cation cartridge that retained the eluted 68Ga3+. The radioactive material was then eluted into the reactor using an acidified concentrated NaCl solution. MAA from the Pulmocis® labeling kit was dissolved in acetate buffer and added to the reactor. After heating at 60°C for 6 minutes, the reaction medium was transferred to a final product vial and formulated with phosphate buffer to obtain a final pH of 7.0 (final volume is 10 mL). The unattenuated (ndc) radiochemical yield was 75% (111.4 MBq), and the radiochemical purity was 80%. This final product solution (111.4 MBq) was manually passed through a 25 mm, 5 μm pore PVDF syringe filter membrane (Millipore standard SLSV025LS). The entire labeled 68Ga-MAA particle was retained on the filter (radioactivity on filter: 88.6 MBq), while free 68Ga3+ passed through the filter (radioactivity in filtrate: 22.8 MBq). After capture, 10 mL of physiological saline was passed through the syringe filter in the opposite direction of the capture process to decapsulate the labeled particles. An efficient decapsulation of 98.2% was achieved (2 MBq remaining on the filter). Thin-layer chromatography (TLC) analysis showed a radiochemical purity of 98.9% of the decapsulated 68Ga-MAA particles.

[0034] (Example 2) This example demonstrates the efficiency of using a syringe filter to capture and decapsulate bulk 99mTc-MAA. 99mTc-MAA is synthesized using a commercial Pulmocis® labeling kit and following a routine procedure: Tc-generators are directly eluted into the Pulmocis® labeling kit. After 15 minutes at room temperature with gentle mixing, the bulk solution of 99mTc-labeled MAA is manually passed through a syringe filter (25mm diameter, 5μm pore size, PVDF membrane, Millipore standard SLSV025LS). Labeled particles are retained on the filter (radioactivity on filter: 44163 cps / 10s). After capture, 10 mL of saline is passed through the filter in the opposite direction of the capture operation. The decapsulation efficiency is 91% (radioactivity remaining on filter: 4523 cps / 10s).

[0035] (Examples 3-11) The following examples demonstrate the efficiency of using syringe filters to purify bulk 68Ga-MAA. 68Ga-MAA is synthesized in an automated synthesizer using final purification on syringe filters placed in disposable cassettes, without pre-purification of the generator eluate (i.e., using the entire generator eluate). The Eckert & Ziegler 68Ge / 68Ga generator is eluted directly into a reactor containing MAA particles from a Pulmocis® labeling kit dissolved in 2 mL of 0.35 M acetate solution with 5 mL of 0.1 M HCl. After heating at 60°C for 6 minutes, the reaction medium is passed through a syringe filter holding the labeled particles, while eluted 68Ga3+ and 68Ge leakage pass through the filter as waste. The labeled particles are then decapsulated using 10 mL of saline solution and placed in a final product vial. The synthesis time is 12 minutes after generator elution. The experiment was repeated with different types of filter syringes (Examples 3-11). Table 1 shows the uncalibrated (ndc) radiochemical yield (RCY), radiochemical purity (RCP), and 68Ge content (when measured) in the final product vial for Examples 3 to 11.

[0036] [Table 1]

[0037] Table 1 demonstrates the high efficiency of using a syringe filter for the purification of radiolabeled MAA. High-level radiochemical yields are almost always achieved, even in cases of low labeling yield and low capture / decapsulation yield. The procedure is also time-efficient, as the synthesis time, including final purification and dispensing into the final product vial, is 12 minutes after generator elution.

Claims

1. A method for synthesizing and purifying radiolabeled coagulated human serum albumin (MAA) for forming a bulk solution injectable to a patient, wherein the method comprises the following steps: - A process of preparing radioactive metals in the form of a generator eluent inside the generator. - Depending on the circumstances, the generator eluate is pre-purified on a cation cartridge, and the pre-purified generator eluate is eluted. - A step of synthesizing the radiolabeled MAA in a reactor using MAA particles from a commercially available labeling kit for 99mTc and the generator eluate, pre-purified or unpurified; - A step of passing the synthesized radiolabeled MAA particles through a syringe filter membrane whose membrane composition, diameter, and pore size are selected to capture the radiolabeled MAA particles while not retaining impurities from the bulk solution, wherein the impurities essentially consist of free radioactive metal isotopes, radiophilic metal leaks, and stannous chloride present in the MAA labeling kit for 99mTc. - The process of passing all bulk solution through a syringe filter membrane. - A step of decapsulating the captured radiolabeled MAA particles from the syringe filter by using saline solution or buffer solution passing through the syringe filter in the opposite direction to the capture operation, and preparing a final bulk solution in a vial that can be injected into the patient. Includes, A method wherein the pore size of the syringe filter membrane is in the range of 0.1 to 5.0 μm.

2. The method according to claim 1, wherein the purified radiolabeled MAA particles are MAA particles labeled with a detectable metal ion selected from the group consisting of 99mTc, 94mTc, 48V, 52Fe, 55Co, 64Cu, 68Ga, 67Ga, 111In, 113In, 86Y, 89Zr, 203Pb, 212Bi, 82Rb, 186Re, and 81mKr.

3. The method according to claim 1, wherein the purified radiolabeled MAA particles are MAA particles labeled with a detectable metal ion selected from the group consisting of 99mTc, 68Ga, 86Y, 89Zr, and 64Cu.

4. The method according to claim 1, wherein the purified radiolabeled MAA particles are MAA particles labeled with 99mTc or 68Ga.

5. The method according to claim 1, wherein the pore size of the syringe filter membrane is in the range of 0.1 to 0.45 μm.

6. The method according to claim 1, wherein the diameter of the syringe filter membrane is in the range of 10 to 33 mm.

7. The method according to claim 1, wherein the diameter of the syringe filter membrane is in the range of 20 to 33 mm.

8. The method according to any one of claims 1 to 7, wherein the syringe filter membrane is a low protein-binding hydrophilic membrane selected from the group consisting of PVDF, PES, CA, hydrophilic PTFE, nylon, glass fiber, RC, CE, CN, and PP.

9. The method according to claim 1, wherein the syringe filter is a disposable filter cartridge which may have a Luer lock fitting.

10. The method according to claim 1, wherein the syringe filter is attached to a disposable cassette in an automated manner.

11. The method according to claim 1, wherein, prior to the step of capturing the generator eluate on the syringe filter, the generator eluate is maintained at room temperature for 2 to 30 minutes or heated at 40 to 80°C for 2 to 20 minutes.

12. The method according to claim 1, wherein the reactor for synthesizing the radiolabeled MAA is an automated synthesis apparatus.

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