Production of 211At and Automated Radiosynthesis of [211At]MABG via Electrophilic Astatodesilylation

Production of 211At and Automated Radiosynthesis of [211At]MABG via Electrophilic Astatodesilylation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Production of 211 At and Automated Radiosynthesis of [ 211 At]MABG via Electrophilic Astatodesilylation Yuto Kondo, Taiki Joho, Shigenori Sasaki, Kazumasa Mochizuki, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6886403/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 05 Aug, 2025 Read the published version in EJNMMI Radiopharmacy and Chemistry → Version 1 posted 5 You are reading this latest preprint version Abstract Background: [ 211 At] m -Astatobenzylguanidine ([ 211 At]MABG) has demonstrated potent antitumor efficacy in preclinical models of malignant neuroendocrine tumours. The high linear energy transfer and short tissue penetration range of alpha particles enable highly localized cytotoxic effects, potentially overcoming therapeutic limitations associated with conventional beta-emitting radiopharmaceuticals. However, under clinical-scale (i.e., high radioactivity) conditions, the efficient and stable production of [ 211 At]MABG has been hindered by radiolytic degradation during the manufacturing process limiting the availability of reliable methods offering high radiochemical yield and purity. In this study, we aimed to develop a scalable production methodology for [ 211 At]MABG suitable for clinical translation. Results: 211 At was produced via the 209 Bi(α,2n) 211 At nuclear reaction using a cyclotron, with 210 At formation minimised by precise control of the alpha particle energy. The resulting product was purified using an automated dry distillation system. [ 211 At]MABG was synthesised using the COSMiC-Mini automated synthesiser in 28.2 ± 2.8 min from initial 211 At activities of up to 586.1 MBq. The radiochemical yield and purity were 80.3 ± 4.4% (decay-corrected RCY: 84.0 ± 4.5%) and 99.0 ± 0.7%, respectively (n = 6). The addition of sodium ascorbate as a radical scavenger contributed to maintaining a high radiochemical yield and purity during large-scale production. The final product was obtained as a sterile solution. Conclusions: In this study, we established a reliable and scalable production methodology for [ 211 At]MABG, consistently achieving high radiochemical yield and purity across a wide range of radioactivity levels through optimization of the automated radiosynthesis process and the use of radiolytic stabilizers. This approach provides a solid technical foundation for the clinical application of [ 211 At]MABG in targeted alpha therapy for neuroendocrine tumours. Astatine-211 MABG dry distillation automated synthesizer astatodesilylation radiochemistry TAT Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Background The norepinephrine transporter is highly overexpressed in neuroendocrine tumours (NETs), including neuroblastoma, pheochromocytoma/paraganglioma, and carcinoid tumours, making it an attractive target for the selective delivery of therapeutic radiopharmaceuticals. [ 123 I]MIBG and [ 131 I]MIBG are among the most widely used radiopharmaceuticals for NETs, offering dual functionality for both disease imaging and targeted radionuclide therapy. 1 , 2 Despite their clinical benefits, limitations in their therapeutic efficacy—particularly in refractory or advanced disease—have prompted the search for alternative radionuclides to improve outcomes. Among the alternatives, [ 211 At]MABG has emerged as a promising candidate, demonstrating potent antitumor activity in preclinical models of malignant pheochromocytoma and neuroblastoma. 3 – 5 As an alpha-particle emitter, 211 At provides a high linear energy transfer and a short range in tissues, resulting in intense, localized cytotoxicity. Such properties are promising for overcoming several limitations associated with [ 131 I]MIBG, including suboptimal therapeutic efficacy in certain clinical contexts and challenges in managing radiation safety during implementation. 6 Encouraging preclinical studies have highlighted the potential of [ 211 At]MABG in significantly enhancing therapeutic efficacy, warranting further investigation into its clinical translation. Radiosynthetic methods for [²¹¹At]MABG have been extensively studied by Zalutsky et al. 7 – 9 Approaches employing C 18 solid-phase extraction (SPE) columns in the purification process were prone to radiolytic degradation during the concentration steps. Notably, the use of ion exchange columns eliminated the need for these concentration steps, enabling the production of [ 211 At]MABG at large scales ( 211 At : 14–658 MBq) with an RCY of 63 ± 9% and RCP exceeding 90%. 9 However, residual radio-byproducts (~ 10%) and variability in RCY remained unresolved, indicating that radiolytic degradation during the manufacturing process was not completely suppressed, possibly hindering further scale-up. Furthermore, the use of organotin precursors introduces the risk of residual tin in the final [ 211 At]MABG solution, requiring additional post-synthetic quality control analyses via inductively coupled plasma mass spectrometry (ICP-MS). These findings highlight the persistent challenges in establishing reliable and scalable radiosynthesis protocols suitable for clinical application. More recently, alternative astatination strategies that avoid the use of tin precursors—such as those employing iodonium salts 10 – 14 or aryl boronic acids 15 , 16 —have gained increasing attention, offering diverse radiolabeling routes. However, scalable methods for large-scale production of [ 211 At]MABG remain limited. Therefore, to address these challenges, we aimed to develop a robust and scalable production methodology for [ 211 At]MABG, optimised for clinical translation. Methods Reagents and instrumentation Reagents used for synthesis and analysis were purchased from Fujifilm Wako Chemical Corp. (Osaka, Japan) and Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). Unless otherwise indicated, these reagents were used without additional purification. 1-(3-(Trimethylsilyl)benzyl)guanidine (TMSBG) was purchased from ABX (Radeberg, Germany). Bismuth (6N) was purchased from Goodfellow Cambridge Ltd. (Huntingdon, England). γ-Ray spectrometry was performed using a high-purity germanium (HP-Ge) detector (ORTEC GEM30-70) coupled to a multichannel analyser (Seiko EG&G MCA-7). Spectra were acquired with the sample placed at a distance of 50 cm from the detector. For measurements performed after the purification of 211 At, an 8-mm thick lead shield was inserted between the sample and the detector to reduce dead time and radiation damage. Radioactivity measurements were performed using a CRC-25R dose calibrator (Capintec Inc., Mirion Technologies, Inc. NJ, USA). High performance liquid chromatography (HPLC) analyses were performed using an LC-20AB system (Shimadzu, Kyoto, Japan) equipped with a CBM-20A communication bus module, DGU-20A3R degassing unit, CTO-20AC column oven, SPD-M20A ultraviolet (UV) detector (all Shimadzu), and GABI Star radioactivity detector (Elysia-raytest GmbH, Straubenhardt, Germany). Reverse-phase HPLC was carried out on a YMC-Triart C 18 column (4.6 mm I.D. × 300 mm; YMC CO., LTD.). Data acquisition and processing were performed using LabSolutions software (Shimadzu). HPLC analysis was performed using a YMC-Triart C 18 column (4.6 mm i.d. × 300 mm) with gradient elution. The mobile phases were: solvent A, acetonitrile containing 0.1% (v/v) TFA; and solvent B, water containing 0.1% (v/v) TFA. The gradient program was as follows: 0–20 min, 30–70% A; 20–21 min, 70–100% A; 21–30 min, 100% A; 30–35 min, 100–30% A; 35–50 min, 30% A. The flow rate was set at 1.0 mL/min, the column temperature was maintained at 25 °C, and the injection volume was 100 µL. Gas chromatography (GC) analyses were performed using a Shimadzu GC-2010 PlusAF system equipped with flame ionization detector (FID). Separations were carried out on an Inertcap 624 column (30 m × 0.53 mm i.d., 3.0 µm film thickness; GL Sciences Inc.). Helium (99.999%) was used as the carrier gas at a constant flow rate of 0.5 mL/min. Samples (0.5 µL) were injected in split mode at an injector temperature of 240 °C. The oven temperature was initially set at 40 °C (held for 7 min), ramped to 120 °C at a rate of 20 °C/min (held for 1 min), decreased to 40 °C at a rate of −30 °C/min (held for 3 min). The FID temperature was maintained at 240 °C. Data acquisition and processing were performed using LabSolutions software (Shimadzu). Production of 211 At 211 At was produced on MP-30 (Sumitomo Heavy Industries, Tokyo, Japan) via the 209 Bi(a,2n) 211 At reaction in the Advanced Clinical Research Center of Fukushima Medical University. The 209 Bi target plate was produced via physical vapor deposition using the RD-1230 (SANVAC Co. Ltd., Tokyo, Japan). High-purity 209 Bi (purity: 99.9999%, 2 mg) was vaporized under vacuum pressure to form the 209 Bi layer (0.09 mm) on an aluminium base (Φ = 23 mm, l = 4 mm). For irradiation, the 209 Bi plate was mounted in a target holder, and alpha particles with an initial energy of 31.6 MeV were directed perpendicularly to the target surface (Figure 1). During irradiation, the target was cooled using helium gas and water. An aluminium degrader foil (thickness: 35 µm) was positioned upstream of the target to reduce the particle energy at the target surface to 28.6 MeV. The beam current was typically maintained at 20 µA, with irradiation durations ranging from 1 to 3 h depending on the desired yield. The thick target yields (TTYs, expressed as MBq/μA·h) were determined from the measured activity of 211 At at the end of bombardment (EOB), beam current, and irradiation time. Following irradiation, the production of 211 At was confirmed via γ-ray spectrometry using an HP-Ge detector (ORTEC GEM30-70) coupled to a multichannel analyser (Seiko EG&G MCA-7). The activated target was subsequently transferred to a dry distillation system for 211 At separation and purification. Separation and purification of 211 At 211 At was separated and isolated from the irradiated 209 Bi target via dry distillation using the automated dry distillation system At-HDS100 (Sumitomo Heavy Industries, Ltd, Tokyo, Japan) installed in a hot cell (Figure 2). Prior to distillation, one of the electric furnace heaters was preheated to 800 °C. The irradiated 209 Bi target was then promptly placed inside the quartz column and heated to 850 °C under a continuous flow of 30% O 2 /N 2 gas (40 mL/min). The gas stream was introduced into a Teflon tube (2 mm ID x 3 mm OD, 50 cm), and its activity was monitored using a γ-ray spectrometer GR1-A (Kromek, County Durham, UK). Once the radioactivity of the irradiated target reached a plateau, the gas supply and heating were discontinued. The trapped 211 At was eluted from the Teflon tube using either chloroform (CHCl 3 ; 500 µL ×2) or methanol (MeOH; 500 µL ×2) and collected into a glass vial. The radioactivity and radionuclidic purity were measured and evaluated using a dose calibrator and an HP-Ge detector connected to a multichannel analyser, respectively. Automatic synthesis of [ 211 At]MABG [ 211 At]MABG was synthesised via an astatodesilylation reaction using an aryl silyl precursor (Scheme 1) and a general-purpose automated radiosynthesiser, COSMiC-Mini (NMP Business Support Co., Ltd., Hyogo, Japan), 17-19 described in Figure 3. Prior to initiating the automatic sequence, the reagents were prepared; a trifluoracetic acid (TFA) solution of the reaction reagents, sterile water, and 20% EtOH/H 2 O were loaded into disposable syringes and attached to ports SLV101−106. An SPE column (Sep-Pak tC 18 Plus Short; Waters Corp., MA, USA) was washed with ethanol and 20%EtOH/H 2 O, conditioned with sterile water, and attached to SLV108 and SLV109. Subsequently, 10 μL of 25% w/v sodium ascorbate/H 2 O was added into the product recovery vial as a stabilizer, and was attached to SLV110 and DP2. Four lines were inserted into the reaction vial and connected to NP2, DP1, and SLV107. For syntheses using 211 At in methanol, potassium carbonate (K 2 CO 3 ; 72 μmol) was added to the reaction vial. Following system setup, the automation synthesis program was initiated. A CHCl 3 or MeOH solution of 211 At (44.6−586.1 MBq, 100−500 μL) was introduced to the reaction vial through the sideline (Polyetheretherketone, PEEK) using a disposable syringe. Furthermore, CHCl 3 or MeOH (200 μL) was added to flush the line. The solvent was then evaporated under a nitrogen gas flow at 40 °C for 3 min (CHCl 3 ) or 5 min (MeOH). After cooling to room temperature, the TFA solution of TMSBG (1.0 μmol/250 μL) was automatically added from a disposable syringe attached to SLV102, followed by the TFA solution of N -chlorosuccinimide (NCS; 2.0 μmol/250 μL) from SLV103. The reaction mixture was heated to 70 °C for 10 min using an integrated air heater, then allowed to cool below 40 °C. The line was rinsed with sterile water (5 mL) from SLV101, followed by the addition of sterile water (10 mL) from SLV104 into the reaction vial. The aqueous solution was transferred to the SPE column, followed by an additional 5 mL rinse from SLV105. Finally, 20% EtOH/H 2 O (3.5 mL) was passed through the SPE column from SLV106 into the product vial containing 25% w/v sodium ascorbate in H 2 O (10 μL). The line was purged with nitrogen gas and the collected solution was concentrated at 40 °C for 3 min using a smart evaporator. The obtained solution was analysed via radio-HPLC and the RCP (%) was determined by the peak area ratio of the radio-chromatogram. The radiochemical yield (RCY) was calculated as follows: RCY (%) = [(activity of eluted [ 211 At]MABG from SPE column)/(activity of 211 At used for reaction)] × 100 The [ 211 At]MABG peak was identified based on the retention time of m -iodobenzylguanidine (MIBG) as a reference compound. Upon completion, the automated synthesis system was disassembled, and the residual radioactivity was quantified in the liquid delivery lines, waste bottles (Waste-1, -2, and -3), filter, reaction vial, and SPE column, to assess the distribution of unreacted 211 At. Radiopharmaceutical preparation A Millex-FG filter unit (0.20 μm, PTFE, 25 mm; Merck Millipore Ltd.) and Millex-GV filter unit (0.22 μm, PVDF, 33 mm; Merck Millipore Ltd.) were connected to a 50-mL sterile vial with injection needles. Saline (6 mL) was added to the obtained product solution using a sterile disposable syringe, and the diluted product solution was drawn into the syringe and transferred into the sterile vial through the GV filter. This procedure was repeated with an additional 10 mL of saline. Subsequently, 20 mL of sterile saline was introduced into the vial through the GV filter. Portions of the final sterile solution (2 and 1 mL) were sampled into a sterile disposable syringe and GC glass vial, respectively, for analysis via GC and HPLC to assess residual solvents and determine RCP. The pH of the final sterile solution was measured using a benchtop pH meter F-74 (HORIBA, Ltd, Kyoto, Japan), calibrated using standard pH buffer solutions. Endotoxin testing was conducted using the turbidimetric method with a Toxinometer® ET-6000 (FUJIFILM Wako Pure Chemical, Tokyo, Japan) in accordance with the Japanese Pharmacopoeia guidelines. Based on a maximum dose of 40 mL, the acceptance criterion was set at 3.75 EU/mL, and the [ 211 At]MABG solution was diluted 10-fold. Sterility testing was performed by direct inoculation into two different culture media; 0.5 mL of the [ 211 At]MABG solution was added to 10 mL of fluid thioglycollate medium and soybean casein digest medium, respectively. The samples were incubated at 32.5 and 22.5 °C using a double chamber incubator IQ822 (Yamato Scientific Co., Ltd, Tokyo, Japan), and the microbial growth was assessed on day 14. Method suitability testing confirmed microbial growth in the presence of the [ 211 At]MABG solution and positive control for all six strains listed in the Japa­nese Pharmacopoeia ( Bacillus subtilis , Candida albicans , and Aspergillus brasiliensis in soybean casein digest medium; Pseudomonas aeruginosa , Staphylococcus aureus , and Clostridium sporogenes in fluid thioglycollate medium) within 3 or 5 d. A filter integrity test was conducted to evaluate the performance of the sterilised filter. The bubble point pressure of the aqueous solution, as specified by the manufacturer (> 345 kPa), was used as the acceptance criterion and was measured using a UG-FT02 filter integrity tester (Universal Giken, Kanagawa, Japan). Results Production of 211 At Astatine-211 ( 211 At) was produced via the 209 Bi(α,2n) 211 At reaction using the MP 30 accelerator (Figure 4A). The 209 Bi target plate was prepared by physical vapor deposition onto an aluminium plate and irradiated with 28.6 MeV alpha particles at a beam current of 20 µA. No visible melting or deformation of the 209 Bi target was observed following irradiation (Figure 4B). The theoretical TTY of the 209 Bi(α,2n) 211 At reaction under the aforementioned irradiation conditions was 28.7 MBq/μA·h. The experimentally determined TTY was 27.4 ± 0.8 MBq/μA·h, corresponding to 95.5% of the theoretical value. The recovery yield of 211 At following dry purification was 65.1 ± 5.0% (n = 14) at EOB, and the working time required from placing the irradiated target in the dry distillation system to obtaining the 211 At solution was 25–30 min. γ-Ray spectrometry of the isolated 211 At solution revealed characteristic peaks corresponding to 211 At (687.00 keV), 211 Po (897.80 and 569.65 keV), and 207 Bi (569.70 keV) (Figure S1). Notably, no peaks derived from 210 At (1181.40 keV) and 210 Po (803.06 keV) were detected. Automation synthesis of [ 211 At]MABG Table 1 summarizes the synthesis outcomes obtained in this study. Entries 1–6 correspond to experiments conducted using CHCl 3 as the elution solvent, yielding RCYs of 80.3 ± 4.4% (decay-corrected RCY: 84.0 ± 4.5%, n = 6). In entries 7–10, MeOH was employed as the elution solvent and potassium carbonate was added; however, its effect was minimal, and no substantial decrease in RCYs was observed (RCY: 72.6 ± 13.6%, decay-corrected RCY: 76.1 ± 14.3%, n = 4). Across all tested conditions (Entries 1–10), RCP exceeded 98% and the automated synthesis of [ 211 At]MABG was completed within 33 min. Due to the absence of stable astatine isotopes, identification of [ 211 At]MABG was based on the retention time of MIBG as a reference compound. As shown in Figure 5, the retention time of [ 211 At]MABG was 8.3 min, while that of MIBG (authentic sample) was 8.0 min. The significant decrease in RCY is typically caused by the radioactivity, being effectively suppressed by the addition of sodium ascorbate. Following synthesis, the system was disassembled and the radioactivity of the delivery lines, waste bottles, filter, reaction vial, and column was measured. The majority of residual 211 At was observed in the SPE column (8.4 ± 4.1%; n = 10) and the side line (2.8 ± 2.6%; n = 10). The radioactivity detected in Waste-1, which collected the waste solution, was 1.2 ± 1.0% (n = 10). The low levels of radioactivity observed in Waste-2 (1.6 ± 1.7%; n = 10) and Waste-3 (1.0 ± 0.9%; n = 10), both connected to the exhaust line, indicated negligeable volatilization losses of 211 At during synthesis. Radiopharmaceutical preparation The [ 211 At]MABG solution was diluted with saline and passed through a sterile Millex-GV filter; minimal adsorption of [ 211 At]MABG to the filter was observed. The RCP value of [ 211 At]MABG in the final sterile solution was > 99% (Figure 6), and no degradation of [ 211 At]MABG associated with the diluted and filtrate process was detected. Furthermore, GC and HPLC analyses confirmed that the residual CHCl 3 level was below the detection limit, the residual TFA level (0.2 mg) was < 6.0 mg (PDE), and the ethanol content (1.3%) was < 2.0%. The pH of the final [ 211 At]MABG sterile solution was 4.4. The endotoxin concentration was below the lower limit (0.01 EU/mL) of the calibration curve, and sterility tests showed no microbial growth. The bubble-point value for the filter integrity test was 432 kPa (≥ 345 kPa). γ-Ray spectrometry of the [ 211 At]MABG solution confirmed characteristic peaks for 211 At (687.00 keV), 211 Po (897.80 and 569.65 keV), and 207 Bi (569.70 keV) (Figure S2). Discussion During the production of 211 At via the 209 Bi(α,2n) 211 At reaction, it is essential to maintain the energy of the α-beam below the threshold (28.6 MeV) for the production of 210 At in the (α,3n) reaction. 21 210 At undergoes β + decay with a half-life of 8.1 h, yielding 210 Po, a highly toxic isotope with a longer half-life of 138.4 d compared with 211 Po (0.516 s). It is therefore crucial to suppress the production of 210 At and ensure the radionuclidic purity of 211 At. In this study, no peaks corresponding to 210 At were detected in the γ-ray spectrum of the purified 211 At solution. 211 At was purified using a dry distillation system and was recovered from the Teflon tubing using a volatile solvent, thereby minimizing the impact of the recovery solution on subsequent astatination reactions. CHCl 3 and MeOH have been previously employed as elution solvents at the Advanced Clinical Research Center, based on reports regarding the loss of volatile astatine during the concentration process. CHCl 3 has been shown to reduce astatine loss during solvent concentration. 22 Furthermore, our previous study demonstrated that when MeOH is used, coexisting alkaline metal salts such as potassium carbonate, can similarly mitigate astatine loss during solvent concentration. 23 In this study, both approaches were integrated into the automated synthesis system for [ 211 At]MABG, and their RCYs were compared. As a result, optimization of the synthetic process enabled high-yield production in both cases [decay-corrected RCY: 84.0 ± 4.5% (CH 3 Cl) vs 76.1 ± 14.3% (MeOH)]. However, the ~ 20% points decrease in RCY observed in a preliminary experiment (Entry 7, Table 1) was attributed to insufficient interaction between K 2 CO 3 and the MeOH solution of 211 At prior to the concentration step. Considering reproducibility and simplicity, CHCl 3 was selected as the preferred eluent in this study. Nonetheless, the feasibility of employing MeOH as the eluent with K 2 CO 3 during the concentration process warrants attention from both academic relevance and practical applicability. The liquid transfer in COSMiC-mini is regulated by adjusting the pressure within vials or bottles using a diaphragm pump and nitrogen gas flow. During the addition of the reaction reagents and the dilution process, rapid liquid transfer did not affect the reaction yield. However, transferring the diluted solution to the SPE column required a precisely controlled flow rate. Preliminary experiments indicated that high flow rates of the diluted reaction solution to the SPE column significantly decreased the retention of [ 211 At]MABG on the column. Therefore, to enhance the retention of [ 211 At]MABG on the SPE column, the pressure in the reaction vial was gradually increased using nitrogen gas, while the pressure in the Waste-1 bottle was gradually reduced using a vacuum pump during solution transfer. The decomposition of radiopharmaceuticals via radiolysis leads to decreased RCPs. Reactive species such as hydroxyl radicals are generated through the radiolysis of water, induced by the ionizing effects of radiation. These species contribute to the degradation of radiopharmaceuticals. Specifically, as the radioactive concentration of [ 211 At]MABG increases, the production of reactive species is enhanced, resulting in decomposition of the compound. Therefore, the addition of a reducing radical scavenger (e.g. sodium ascorbate) is essential for maintaining the stability of [ 211 At]MABG during synthesis. Figure S3 (Supplementary Information) presents preliminary data from our facility evaluating the inhibitory effect of sodium ascorbate on the degradation of [ 211 At]MABG. The stability of [ 211 At]MABG (113.1 MBq/2 mL) was assessed under two conditions: without additives and with sodium ascorbate. The results clearly demonstrate that sodium ascorbate effectively suppresses the degradation of [ 211 At]MABG. In entries 1–10 (Table 1), a sodium ascorbate solution was preloaded into the product vials. Even at a high activity level of 586.1 MBq, no degradation of [ 211 At]MABG was observed after 24 h. Vaidyanathan et al. reported a high-level synthesis of [ 211 At]MABG using a tin precursor immobilized on a solid support. The precursor undergoes astatination upon treatment with a methanolic solution of 211 At in the presence of acetic acid and hydroxy peroxide. 9 [ 211 At]MABG is subsequently isolated using C 18 SPE or a cation exchange resin cartridge. The C 18 -based approach achieved RCYs of 63 ± 13%, but suffered from ~ 50% activity loss during methanol evaporation—possibly due to radiolysis, which, based on our findings, could potentially be mitigated by sodium ascorbate. The alternative isolation strategy using a cation exchange resin cartridge maintained comparable RCYs (63 ± 9%; from initial 211 At activity 14.4–658.6 MBq), with > 90% RCPs. The total synthesis time was ~ 120 min for the C 18 method and ~ 70 min for the cation exchange method. In this study, [ 211 At]MABG was synthesized with high yields (RCY 80.3 ± 4.4%; decay-corrected RCY 84.0 ± 4.5%; from an initial 211 At activity of 44.6–586.1 MBq; Entries 1–6) and RCP (99.0 ± 0.7%; Entries 1–6), surpassing previously reported methods. Furthermore, the synthesis time was significantly reduced to 28.2 ± 2.8% min (Entries 1–6). Notably, even at high radioactivity levels (563.5–586.1 MBq), a high RCY was maintained (RCY 77.6–82.1%; decay-corrected RCY 81.2–85.9%; Entries 5 and 6), enabling the production of 437–473 MBq of [ 211 At]MABG in a single synthesis. Even though the [ 211 At]MABG produced by the established methodology is comparable in quality to the conventionally synthesized material, further in vivo studies are required to evaluate biodistribution, therapeutic efficacy, and toxicity. Comparative in vivo studies using mouse models are currently underway. Considering the reaction yield, synthesis time, and availability of precursors, the automated astatodesilylation method using COSMiC-Mini presents an efficient approach for [ 211 At]MABG production. Furthermore, the programmable nature of COSMiC-Mini allows on-site customisation, facilitating the adaptation of this protocol for the synthesis of other 211 At-labeled radiopharmaceuticals. Therefore, the manufacturing techniques and expertise described in this study offer a valuable tool for the future production of 211 At-labeled radiopharmaceuticals. Conclusions In this study, a robust methodology was established for the clinical-scale production of [ 211 At]MABG. The process encompasses the production of 211 At via the 209 Bi (α,2n) 211 At reaction using an MP-30 cyclotron, followed by purification via dry distillation with the At-HDS100 system, and automated radiosynthesis of [ 211 At]MABG using the COSMiC-mini. The automated synthesis consistently yielded [ 211 At]MABG with high radiochemical yields (RCYs: 80.3 ± 4.4%; decay-corrected RCY: 84.0 ± 4.5%) and radiochemical purity (RCP: 99.0 ± 0.7%) within a short synthesis time of 28.2 ± 2.8 min. Notably, the addition of sodium ascorbate significantly enhanced the radiolytic stability of [ 211 At]MABG, contributing to the reproducibility and reliability of the method. The final product was obtained as a sterile, injectable solution that meets standard physicochemical and radiochemical quality requirements. This integrated approach represents a significant advancement toward the clinical translation of [ 211 At]MABG as a next-generation targeted alpha therapy for neuroendocrine tumours. Abbreviations NET Neuroendocrine tumour MIBG m -Iodobenzylguanidine MABG m -Astatobenzylguanidine FKM Fluoroelastomer RCY Radiochemical yield RCP Radiochemical purity ICP-MS Inductively coupled plasma mass spectrometry EOB End of bombardment TTY Thick target yield TMSBG 1-(3-(Trimethylsilyl)benzyl)guanidine HPLC High performance liquid chromatography UV Ultraviolet TFA Trifluoracetic acid GC Gas chromatography FID Flame ionization detector K 2 CO 3 Potassium carbonate CHCl 3 Chloroform MeOH Methanol PEEK Polyetheretherketone NCS N -chlorosuccinimide SPE Solid-phase extraction PTFE Polytetrafluoroethylene PVDF Polyvinylidene fluoride Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and materials All data generated or analysed during this study are included in this published article and its supplementary information files. Competing interests Shigenori Sasaki and Kazumasa Mochizuki are employees of SHI Accelerator Service Ltd., a subsidiary of Sumitomo Heavy Industries, Ltd., which manufactures the cyclotron system used in this study. The company was not involved in the study design, data analysis, or manuscript preparation. Funding This work was supported by JSPS KAKENHI (JP23K27543, JP24K23270, and 25K19142). This study was supported by a joint research project between the QST and the Tokyo Institute of Technology, titled "Research aimed at the development and examination of an improved manufacturing method for [ 211 At]MABG using GMP-compliant automated synthesis equipment." As part of this project, Hiroshi Tanaka conducted research using funding provided by QST. Author’s Contributions All experiments were designed and conceived by YK, TJ, and KT. Production and purification of 211 At was performed by SS and KM. Radiosynthesis of [ 211 At]MABG and radiopharmaceutical preparation was conducted by YK, JT, and NH. The manuscript was designed and written by YK. All authors discussed the results and contributed to the final manuscript. Author information Authors and Affiliations a. Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, 1 Hikarigaoka, Fukushima 960-1295, Japan. Yuto Kondo, Taiki Joho, Shigenori Sasaki, Kazumasa Motizuki, Naoko Hasegawa, Naoyuki Ukon, Ken-ichi Nishijima, Kohshin Washiyama, and Kazuhiro Takahashi b. SHI Accelerator Service Ltd., 7-1-1 Nishigotanda, Shinagawa, Tokyo, 141-0031, Japan. Shigenori Sasaki and Kazumasa Mochizuki c. Department of Chemical Science and Engineering, Tokyo Institute of Technology, 12-12-1-H101 Ookayama, Meguro, Tokyo 152-8552, Japan. Laboratory of Pharmaceutical Chemistry, Juntendo University, 6-8-1 Hinode, Urayasu, Chiba 279-0013, Japan. Hiroshi Tanaka d. Department of Molecular Imaging and Theranostics, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, 4-9-1, Anagawa, Inage, Chiba-City, Chiba, 263-8555, Japan. Higashi Tatsuya. e. Department of Quantum-Applied Biosciences, Takasaki Institute for Advanced Quantum Science, National Institutes for Quantum Science and Technology, 1233 Watanuki, Takasaki, Gunma 370-1292, Japan. Noriko S. Ishioka Corresponding author Correspondence to Kazuhiro Takahashi ( [email protected] ) Acknowledgements We would like to thank Editage (www.editage.jp) for English language editing. References Streby KA, Shah N, Ranalli MA, Kunkler A, Cripe TP. Nothing but NET: a review of norepinephrine transporter expression and efficacy of 131 I-mIBG therapy. Pediatr Blood Cancer. 2015;62:5–11. https://doi.org/10.1002/pbc.25200 . Pandit-Taskar N, Modak S. Norepinephrine Transporter as a Target for Imaging and Therapy. J Nucl Med. 2017;58:S39–53. https://doi.org/10.2967/jnumed.116.186833 . Cunningham SH, Mairs RJ, Wheldon TE, Welsh PC, VaidyanathanG, Zalutsky MR. Toxicity to neuroblastoma cells and spheroids of benzylguanidine conjugated to radionuclides with short-range emissions. Br J Cancer. 1998;77:2061–8. https://doi.org/10.1038/bjc.1998.348 . Ohshima Y, Sudo H, Watanabe S, Nagatsu K, Tsuji AB, Sakashita T, Ito YM, Yoshinaga K, Higashi T, Ishioka NS. Antitumor effects of radionuclide treatment using alpha-emitting meta-(211)Atastato-benzylguanidine in a PC12 pheochromocytoma model. Eur J Nucl Med Mol Imaging. 2018;45:999–1010. https://doi.org/10.1007/s00259-017-3919-6 . Ohshima Y, Kono N, Yokota Y, Watanabe S, Sasaki I, Ishioka NS, Sakashita T, Arakawa K. Anti-tumor effects and potential therapeutic response biomarkers in alpha-emitting meta-(211)At-astato-benzylguanidine therapy for malignant pheochromocytoma explored by RNA-sequencing. Theranostics. 2019;9:1538–49. https://doi.org/10.7150/thno.30353 . Kobayakawa M, Shiga T, Takahashi K, Sugawara S, Nomura K, Hanada K, Ishizuka N, Ito H. Evaluation of pharmacokinetics, safety, and efficacy of [ 211 At] meta-astatobenzylguanidine ([ 211 At] MABG) in patients with pheochromocytoma or paraganglioma (PPGL): A study protocol. PLoS ONE. 2024;19:e030362. https://doi.org/10.1371/journal.pone.0303623 . Vaidyanathan G, Zalutsky MR. 1-(m-[ 211 At]astatobenzyl)guanidine: synthesis via astato demetalation and preliminary in vitro and in vivo evaluation. Bioconjug Chem. 1992;3:499–503. https://doi.org/10.1021/bc00018a006 . Vaidyanathan G, Affleck DJ, Alston KL, Zalutsky MR. A tin precursor for the synthesis of no-carrier-added [*I]MIBG and [ 211 At]MABG. J Label Compd Radiopharm. 2007;50:177–82. https://doi.org/10.1002/jlcr.1243 . Ganesan Vaidyanathan DJ, Affleck KL, Alston X-G, Zhao M, Hens DH, Hunter J, Babich MR. Zalutsky. A kit method for the high level synthesis of [ 211 At]MABG. Bioorg Med Chem. 2007;15:3430–6. Guerard F, Lee Y-S, Baidoo K, Gestin J-F, Brechbiel MW. Unexpected behavior of the heaviest halogen astatine in the nucleophilic substitution of aryliodonium salts. Chem Eur J. 2016;22:12332–9. https://doi.org/10.1002/chem.201600922 . Guerard F, Navarro L, Lee Y-S, Roumesy A, Alliot C, Cherel M, Brechbiel MW, Gestin J-F. Bifunctional aryliodonium salts for highly efficient radioiodination and astatination of antibodies. Bioorg Med Chem. 2017;25:5975–80. https://doi.org/10.1016/j.bmc.2017.09.022 . Navarro L, Berdal M, Cherel M, Pecorari F, Gestin J-F, Guerard F. Prosthetic groups for radioiodination and astatination of peptides and proteins: a comparative study of five potential bioorthogonal labeling strategies. Bioorg Med Chem. 2019;27:167–74. https://doi.org/10.1016/j.bmc.2018.11.034 . Matsuoka K, Obata H, Nagatsu K, Kojima M, Yoshino T, Ogawa M, Matsunaga S. Transition-metal-free nucleophilic 211 At-astatination of spirocyclic aryliodonium ylides. Org Biomol Chem. 2021;19:5525–8. https://doi.org/10.1039/d1ob00789k . Maingueneau C, Berdal M, Eychenne R, Gaschet J, Cherel M, Gestin J-F, Guerard F. 211 At and 125 I-labeling of (hetero)aryliodonium ylides: astatine wins again. Chem - Eur J. 2022;28:e202104169. https://doi.org/10.1002/chem.202104169 . Reilly SW, Makvandi M, Xu K, Mach RH. Rapid Cu-catalyzed [ 211 At] astatination and [ 125 I] iodination of boronic esters at room temperature. Org Lett. 2018;20:1752–5. https://doi.org/10.1021/acs.orglett.8b00232 . Watanabe S, Kondo Y, Sasaki I, Ohshima Y, Kimura H, Ishioka NS. Copper-mediated astatination of 211 At-labelled prostate-specific membrane antigen probes in the presence of basic salts. Tetrahedron. 2024;156:133920–133920. https://doi.org/10.1016/j.tet.2024.133920 . Song R, Tago T, Tatsuta M, Shiraishi N, Iwai K, Hirano K, Toyohara J. Tanaka. H. N -Alkyl 3-aminobut-2-enenitrile as a non-radioactive side product in nucleophilic 18 F-fluorination. ChemistrySelect. 2021;6:2826. https://doi.org/10.1002/slct.202100723 . Liu Z, Fukagawa Y, Yamano M, Tago T, Iwai K, Hirano K, Kumazoe M, Tachibana H, Toyohara J, Tanaka H. A gold-complex initiated functionalization of biologically active polyphenols applied to a 18 F-labeled chemical probe. Org Biomol Chem. 2023;21:5990. https://doi.org/10.1039/d3ob00856h . Iida S, Tago T, Tada M, Toyohara J, Tanaka H. 18 F-Fluorination of 2-methyl-6-nitrobenzenesulfonate ester and its application for the synthesis of an 18 F-labeled amino acid. Asian J Org Chem. 2023;12:e202300412. https://doi.org/10.1002/ajoc.202300412 . International Atomic Energy Agency (IAEA). Medical Radioisotopes Production, Online database, Accessed date 11-6-2025. https://www-nds.iaea.org/medical/bi9a1at0.html Morzenti S, Bonardi ML, Groppi F, et al. Cyclotron production of 211 At/ 211g Po by 209 Bi(α,2n) reaction. J Radioanal Nucl Chem. 2018;276:843–7. https://doi.org/10.1007/s10967-008-0642-6 . Aneheim E, Palm S, Jensen H, Ekberg C, Albertsson P, Lindegren S. Towards elucidating the radiochemistry of astatine - Behavior in chloroform. Sci Rep. 2019;9:15900. https://doi.org/10.1038/s41598-019-52365-5 . Tanaka H, Takahashi K, Suzuki M. Simple Astatine Concentration Method. WO 2021/225147 A1. 2021 Nov 11. Schemes Scheme 1 is available in the Supplementary Files section Supplementary Files Scheme1.docx Supportinginformationver.6.1EJNMMI.pdf Cite Share Download PDF Status: Published Journal Publication published 05 Aug, 2025 Read the published version in EJNMMI Radiopharmacy and Chemistry → Version 1 posted Editorial decision: Minor revision 29 Jun, 2025 Reviewers agreed at journal 16 Jun, 2025 Reviewers invited by journal 16 Jun, 2025 Editor assigned by journal 16 Jun, 2025 First submitted to journal 15 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6886403","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":472065784,"identity":"984e2856-81df-4442-8f6b-d33262eaeea8","order_by":0,"name":"Yuto Kondo","email":"","orcid":"","institution":"Fukushima Medical University: Fukushima Kenritsu Ika Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Yuto","middleName":"","lastName":"Kondo","suffix":""},{"id":472065785,"identity":"4289f06a-03f0-4e96-a817-a5cbac83d9c0","order_by":1,"name":"Taiki Joho","email":"","orcid":"","institution":"Fukushima Medical University: Fukushima Kenritsu Ika Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Taiki","middleName":"","lastName":"Joho","suffix":""},{"id":472065786,"identity":"bcea9e0e-d3b6-40cc-8d95-79fa617527f9","order_by":2,"name":"Shigenori Sasaki","email":"","orcid":"","institution":"SHI Accelerator Service Ltd.","correspondingAuthor":false,"prefix":"","firstName":"Shigenori","middleName":"","lastName":"Sasaki","suffix":""},{"id":472065787,"identity":"25dc8227-f3ea-41f2-af6b-ad5a03bbae0c","order_by":3,"name":"Kazumasa Mochizuki","email":"","orcid":"","institution":"SHI Accelerator Service Ltd.","correspondingAuthor":false,"prefix":"","firstName":"Kazumasa","middleName":"","lastName":"Mochizuki","suffix":""},{"id":472065788,"identity":"5db393cf-40dd-4b90-b33a-47d7cc75e30c","order_by":4,"name":"Naoko Hasegawa","email":"","orcid":"","institution":"Fukushima Medical University: Fukushima Kenritsu Ika Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Naoko","middleName":"","lastName":"Hasegawa","suffix":""},{"id":472065789,"identity":"1337bdcf-148b-46dd-a00c-284579cbcde8","order_by":5,"name":"Naoyuki Ukon","email":"","orcid":"","institution":"Fukushima Medical University: Fukushima Kenritsu Ika Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Naoyuki","middleName":"","lastName":"Ukon","suffix":""},{"id":472065790,"identity":"3e482c77-2320-4d3d-99bf-da39d5d0d578","order_by":6,"name":"Ken-ichi Nishijima","email":"","orcid":"","institution":"Fukushima Medical University: Fukushima Kenritsu Ika Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Ken-ichi","middleName":"","lastName":"Nishijima","suffix":""},{"id":472065791,"identity":"ab240b01-5625-492d-ae16-1946ad4169cc","order_by":7,"name":"Kohshin Washiyama","email":"","orcid":"","institution":"Fukushima Medical University: Fukushima Kenritsu Ika Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Kohshin","middleName":"","lastName":"Washiyama","suffix":""},{"id":472065792,"identity":"e3289bc0-d0bf-4778-8c8d-0304c9e118a2","order_by":8,"name":"Hiroshi Tanaka","email":"","orcid":"","institution":"Juntendo University: Juntendo Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Tanaka","suffix":""},{"id":472065793,"identity":"706cda1b-c64b-4454-9104-5566ca3f9f20","order_by":9,"name":"Higashi Tatsuya","email":"","orcid":"","institution":"National Institutes for Quantum and Technology: Kokuritsu Kenkyu Kaihatsu Hojin Ryoshi Kagaku Gijutsu Kenkyu Kaihatsu Kiko","correspondingAuthor":false,"prefix":"","firstName":"Higashi","middleName":"","lastName":"Tatsuya","suffix":""},{"id":472065794,"identity":"d07e802e-8fb6-4d20-88ae-39a567d77582","order_by":10,"name":"Noriko S. Ishioka","email":"","orcid":"","institution":"National Institutes for Quantum and Technology: Kokuritsu Kenkyu Kaihatsu Hojin Ryoshi Kagaku Gijutsu Kenkyu Kaihatsu Kiko","correspondingAuthor":false,"prefix":"","firstName":"Noriko","middleName":"S.","lastName":"Ishioka","suffix":""},{"id":472065795,"identity":"a41927a9-c245-47ef-89d9-125625441feb","order_by":11,"name":"Kazuhiro Takahashi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA20lEQVRIiWNgGAWjYBACCQYGZgbGBgYGfuYDEBEQB78WNqgWybYEUrUYHEsg0mGS85sfG/zcYWdvfIw7TYKhxo6BeTYBa6TZ2IwTe88kJ247xrtNguFYMgPjnAP4tcixMRgf4G1jTjC73wvUwnaAgXEGARfKsbF/Pvi3rd7euA1kyz8itEiz8Rgn87YdZtzABtTC2EaEFsm2nGJj2bbjiTOO8W62SOxL5iHoF4nDxzdLvm2rtudv491448M3OzlDQiGGCoBO4jGcQYoOMJCXIFnLKBgFo2AUDHMAAN16PnR4SFHYAAAAAElFTkSuQmCC","orcid":"","institution":"Fukushima Medical University: Fukushima Kenritsu Ika Daigaku","correspondingAuthor":true,"prefix":"","firstName":"Kazuhiro","middleName":"","lastName":"Takahashi","suffix":""}],"badges":[],"createdAt":"2025-06-13 08:39:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6886403/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6886403/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s41181-025-00376-1","type":"published","date":"2025-08-05T15:57:42+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":84908571,"identity":"5d1f354f-9905-4367-9006-2e0c08318e29","added_by":"auto","created_at":"2025-06-18 16:29:44","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":105146,"visible":true,"origin":"","legend":"\u003cp\u003e(a) Schematic cross section of the irradiation port; (b) 3D schematic of the target capsule.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6886403/v1/afca9cf13b72ecf896b6186e.png"},{"id":84908570,"identity":"12679e16-c3a4-444b-a2e9-e2f7019275b9","added_by":"auto","created_at":"2025-06-18 16:29:44","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":135981,"visible":true,"origin":"","legend":"\u003cp\u003e(a) Photograph of the At-HDS100 dry distillation system; (b) Schematic of the dry distillation system for the purification of \u003csup\u003e211\u003c/sup\u003eAt.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6886403/v1/c493cba46611bb60e58768b3.png"},{"id":84908585,"identity":"ee86069b-43a6-44d2-af59-5ba5d1520589","added_by":"auto","created_at":"2025-06-18 16:29:45","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":102520,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic of the automated production system for [\u003csup\u003e211\u003c/sup\u003eAt]MABG.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6886403/v1/b9c7f7c9a3c3825930a17684.png"},{"id":84908576,"identity":"a769ae7e-d3e5-4274-935f-954d7b015c63","added_by":"auto","created_at":"2025-06-18 16:29:44","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":465409,"visible":true,"origin":"","legend":"\u003cp\u003e(A) MP-30 accelerator and (B) target of \u003csup\u003e209\u003c/sup\u003eBi plate (a) before irradiation and (b) after irradiation.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6886403/v1/c68f33dc2f13fb726f4e74b8.png"},{"id":84908581,"identity":"3d6086ab-64f6-47d7-85ee-4c5d3d292645","added_by":"auto","created_at":"2025-06-18 16:29:44","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":37294,"visible":true,"origin":"","legend":"\u003cp\u003eHPLC chromatogram of MIBG (authentic sample) and [\u003csup\u003e211\u003c/sup\u003eAt]MABG.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-6886403/v1/f8ed4941c63140de5c82d728.png"},{"id":84908578,"identity":"a5c4af5a-0c2e-433c-bddd-4ec78d816f15","added_by":"auto","created_at":"2025-06-18 16:29:44","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":41599,"visible":true,"origin":"","legend":"\u003cp\u003eUV and radio-HPLC chromatograms of the [\u003csup\u003e211\u003c/sup\u003eAt]MABG solution after sterile filtration.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-6886403/v1/204f2dc9d80b326901349ad6.png"},{"id":88814173,"identity":"1b0264bc-bc1f-436d-9d6a-36410fd44016","added_by":"auto","created_at":"2025-08-11 16:07:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1776846,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6886403/v1/232c97e0-6816-45be-809c-d492799f6886.pdf"},{"id":84908572,"identity":"8b6f208d-270c-48c9-aa87-6908c749b496","added_by":"auto","created_at":"2025-06-18 16:29:44","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":67703,"visible":true,"origin":"","legend":"","description":"","filename":"Scheme1.docx","url":"https://assets-eu.researchsquare.com/files/rs-6886403/v1/741127e52d6426c2686863a3.docx"},{"id":84908573,"identity":"a31156fb-659f-4dc6-8319-b408273f5376","added_by":"auto","created_at":"2025-06-18 16:29:44","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":302302,"visible":true,"origin":"","legend":"","description":"","filename":"Supportinginformationver.6.1EJNMMI.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6886403/v1/0ae721fa81b2a616197bec74.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eProduction of \u003csup\u003e211\u003c/sup\u003eAt and Automated Radiosynthesis of [\u003csup\u003e211\u003c/sup\u003eAt]MABG via Electrophilic Astatodesilylation\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eThe norepinephrine transporter is highly overexpressed in neuroendocrine tumours (NETs), including neuroblastoma, pheochromocytoma/paraganglioma, and carcinoid tumours, making it an attractive target for the selective delivery of therapeutic radiopharmaceuticals. [\u003csup\u003e123\u003c/sup\u003eI]MIBG and [\u003csup\u003e131\u003c/sup\u003eI]MIBG are among the most widely used radiopharmaceuticals for NETs, offering dual functionality for both disease imaging and targeted radionuclide therapy.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Despite their clinical benefits, limitations in their therapeutic efficacy\u0026mdash;particularly in refractory or advanced disease\u0026mdash;have prompted the search for alternative radionuclides to improve outcomes.\u003c/p\u003e \u003cp\u003eAmong the alternatives, [\u003csup\u003e211\u003c/sup\u003eAt]MABG has emerged as a promising candidate, demonstrating potent antitumor activity in preclinical models of malignant pheochromocytoma and neuroblastoma.\u003csup\u003e\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e As an alpha-particle emitter, \u003csup\u003e211\u003c/sup\u003eAt provides a high linear energy transfer and a short range in tissues, resulting in intense, localized cytotoxicity. Such properties are promising for overcoming several limitations associated with [\u003csup\u003e131\u003c/sup\u003eI]MIBG, including suboptimal therapeutic efficacy in certain clinical contexts and challenges in managing radiation safety during implementation.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Encouraging preclinical studies have highlighted the potential of [\u003csup\u003e211\u003c/sup\u003eAt]MABG in significantly enhancing therapeutic efficacy, warranting further investigation into its clinical translation.\u003c/p\u003e \u003cp\u003eRadiosynthetic methods for [\u0026sup2;\u0026sup1;\u0026sup1;At]MABG have been extensively studied by Zalutsky et al.\u003csup\u003e\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Approaches employing C\u003csub\u003e18\u003c/sub\u003e solid-phase extraction (SPE) columns in the purification process were prone to radiolytic degradation during the concentration steps. Notably, the use of ion exchange columns eliminated the need for these concentration steps, enabling the production of [\u003csup\u003e211\u003c/sup\u003eAt]MABG at large scales (\u003csup\u003e211\u003c/sup\u003eAt : 14\u0026ndash;658 MBq) with an RCY of 63\u0026thinsp;\u0026plusmn;\u0026thinsp;9% and RCP exceeding 90%.\u003csup\u003e9\u003c/sup\u003e However, residual radio-byproducts (~\u0026thinsp;10%) and variability in RCY remained unresolved, indicating that radiolytic degradation during the manufacturing process was not completely suppressed, possibly hindering further scale-up. Furthermore, the use of organotin precursors introduces the risk of residual tin in the final [\u003csup\u003e211\u003c/sup\u003eAt]MABG solution, requiring additional post-synthetic quality control analyses via inductively coupled plasma mass spectrometry (ICP-MS). These findings highlight the persistent challenges in establishing reliable and scalable radiosynthesis protocols suitable for clinical application. More recently, alternative astatination strategies that avoid the use of tin precursors\u0026mdash;such as those employing iodonium salts\u003csup\u003e\u003cspan additionalcitationids=\"CR11 CR12 CR13\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e or aryl boronic acids\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e\u0026mdash;have gained increasing attention, offering diverse radiolabeling routes. However, scalable methods for large-scale production of [\u003csup\u003e211\u003c/sup\u003eAt]MABG remain limited. Therefore, to address these challenges, we aimed to develop a robust and scalable production methodology for [\u003csup\u003e211\u003c/sup\u003eAt]MABG, optimised for clinical translation.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eReagents and instrumentation\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eReagents used for synthesis and analysis were purchased from Fujifilm Wako Chemical Corp. (Osaka, Japan) and Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). Unless otherwise indicated, these reagents were used without additional purification. 1-(3-(Trimethylsilyl)benzyl)guanidine (TMSBG) was purchased from ABX (Radeberg, Germany). Bismuth (6N) was purchased from Goodfellow Cambridge Ltd. (Huntingdon,\u0026nbsp;England).\u003c/p\u003e\n\u003cp\u003e\u0026gamma;-Ray spectrometry was performed using a high-purity germanium (HP-Ge) detector (ORTEC GEM30-70) coupled to a multichannel analyser (Seiko EG\u0026amp;G MCA-7). Spectra were acquired with the sample placed at a distance of 50 cm from the detector. For measurements performed after the purification of \u003csup\u003e211\u003c/sup\u003eAt, an 8-mm thick lead shield was inserted between the sample and the detector to reduce dead time and radiation damage.\u003c/p\u003e\n\u003cp\u003eRadioactivity measurements were performed using a CRC-25R dose calibrator (Capintec Inc., Mirion Technologies, Inc.\u0026nbsp;NJ, USA).\u003c/p\u003e\n\u003cp\u003eHigh performance liquid chromatography (HPLC) analyses were performed using an LC-20AB system (Shimadzu, Kyoto, Japan) equipped with a CBM-20A communication bus module, DGU-20A3R degassing unit, CTO-20AC column oven, SPD-M20A ultraviolet (UV) detector (all Shimadzu), and GABI Star radioactivity detector (Elysia-raytest GmbH, Straubenhardt, Germany). Reverse-phase HPLC was carried out on a YMC-Triart C\u003csub\u003e18\u003c/sub\u003e column (4.6 mm I.D. \u0026times; 300 mm; YMC CO., LTD.). Data acquisition and processing were performed using LabSolutions software (Shimadzu). HPLC analysis was performed using a YMC-Triart C\u003csub\u003e18\u003c/sub\u003e column (4.6 mm i.d. \u0026times; 300 mm) with gradient elution. The mobile phases were: solvent A, acetonitrile containing 0.1% (v/v) TFA; and solvent B, water containing 0.1% (v/v) TFA. The gradient program was as follows: 0\u0026ndash;20 min, 30\u0026ndash;70% A; 20\u0026ndash;21 min, 70\u0026ndash;100% A; 21\u0026ndash;30 min, 100% A; 30\u0026ndash;35 min, 100\u0026ndash;30% A; 35\u0026ndash;50 min, 30% A. The flow rate was set at 1.0 mL/min, the column temperature was maintained at 25 \u0026deg;C, and the injection volume was 100 \u0026micro;L.\u003c/p\u003e\n\u003cp\u003eGas chromatography (GC) analyses were performed using a Shimadzu GC-2010 PlusAF system equipped with flame ionization detector (FID). Separations were carried out on an Inertcap 624 column (30 m \u0026times; 0.53 mm i.d., 3.0 \u0026micro;m film thickness; GL Sciences Inc.). Helium (99.999%) was used as the carrier gas at a constant flow rate of 0.5 mL/min. Samples (0.5 \u0026micro;L) were injected in split mode at an injector temperature of 240 \u0026deg;C. The oven temperature was initially set at 40 \u0026deg;C (held for 7 min), ramped to 120 \u0026deg;C at a rate of 20 \u0026deg;C/min (held for 1 min), decreased to 40 \u0026deg;C at a rate of \u0026minus;30 \u0026deg;C/min (held for 3 min). The FID temperature was maintained at 240 \u0026deg;C. Data acquisition and processing were performed using LabSolutions software (Shimadzu).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eProduction of \u003csup\u003e211\u003c/sup\u003eAt\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e211\u003c/sup\u003eAt was produced on MP-30 (Sumitomo Heavy Industries, Tokyo, Japan) via the \u003csup\u003e209\u003c/sup\u003eBi(a,2n)\u003csup\u003e211\u003c/sup\u003eAt reaction in the Advanced Clinical Research Center of Fukushima Medical University. The \u003csup\u003e209\u003c/sup\u003eBi target plate was produced via physical vapor deposition using the RD-1230 (SANVAC Co. Ltd., Tokyo, Japan). High-purity \u003csup\u003e209\u003c/sup\u003eBi (purity: 99.9999%, 2 mg) was vaporized under vacuum pressure to form the \u003csup\u003e209\u003c/sup\u003eBi layer (0.09 mm) on an\u0026nbsp;aluminium base (\u0026Phi; = 23 mm, l = 4 mm).\u003c/p\u003e\n\u003cp\u003eFor irradiation, the \u003csup\u003e209\u003c/sup\u003eBi plate was mounted in a target holder, and alpha particles with an initial energy of 31.6 MeV were directed perpendicularly to the target surface (Figure 1). During irradiation, the target was cooled using helium gas and water. An aluminium degrader foil (thickness: 35 \u0026micro;m) was positioned upstream of the target to reduce the particle energy at the target surface to 28.6 MeV. The beam current was typically maintained at 20 \u0026micro;A, with irradiation durations ranging from 1 to 3 h depending on the desired yield.\u0026nbsp;The thick target yields (TTYs, expressed as MBq/\u0026mu;A\u0026middot;h) were determined from the measured activity of \u003csup\u003e211\u003c/sup\u003eAt at the\u0026nbsp;end of bombardment (EOB), beam current, and irradiation time.\u003c/p\u003e\n\u003cp\u003eFollowing irradiation, the production of \u003csup\u003e211\u003c/sup\u003eAt was confirmed via \u0026gamma;-ray spectrometry using an HP-Ge detector (ORTEC GEM30-70) coupled to a multichannel analyser (Seiko EG\u0026amp;G MCA-7). The activated target was subsequently transferred to a dry distillation system for \u003csup\u003e211\u003c/sup\u003eAt separation and purification.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSeparation and purification of \u003csup\u003e211\u003c/sup\u003eAt\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e211\u003c/sup\u003eAt was separated and isolated from the irradiated \u003csup\u003e209\u003c/sup\u003eBi target via dry distillation using the automated dry distillation system At-HDS100 (Sumitomo Heavy Industries, Ltd, Tokyo, Japan) installed in a hot cell (Figure 2). Prior to distillation, one of the electric furnace heaters was preheated to 800 \u0026deg;C. The irradiated \u003csup\u003e209\u003c/sup\u003eBi target was then promptly placed inside the quartz column and heated to 850 \u0026deg;C under a continuous flow of 30% O\u003csub\u003e2\u003c/sub\u003e/N\u003csub\u003e2\u003c/sub\u003e gas (40 mL/min). The gas stream was introduced into a Teflon tube (2 mm ID x 3 mm OD, 50 cm), and its activity was monitored using a \u0026gamma;-ray spectrometer GR1-A (Kromek, County Durham, UK). Once the radioactivity of the irradiated target reached a plateau, the gas supply and heating were discontinued. The trapped \u003csup\u003e211\u003c/sup\u003eAt was eluted from the Teflon tube using either chloroform (CHCl\u003csub\u003e3\u003c/sub\u003e; 500 \u0026micro;L \u0026times;2) or methanol (MeOH; 500 \u0026micro;L \u0026times;2) and collected into a glass vial. The radioactivity and radionuclidic purity were measured and evaluated using a dose calibrator and an HP-Ge detector connected to a multichannel analyser, respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAutomatic synthesis of [\u003csup\u003e211\u003c/sup\u003eAt]MABG\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;[\u003csup\u003e211\u003c/sup\u003eAt]MABG was synthesised via an astatodesilylation reaction using an aryl silyl precursor (Scheme 1) and a general-purpose automated radiosynthesiser, COSMiC-Mini (NMP Business Support Co., Ltd., Hyogo, Japan),\u003csup\u003e17-19\u003c/sup\u003e described in Figure 3. Prior to initiating the automatic sequence, the reagents were prepared; a trifluoracetic acid (TFA) solution of the reaction reagents, sterile water, and 20% EtOH/H\u003csub\u003e2\u003c/sub\u003eO were loaded into disposable syringes and attached to ports SLV101\u0026minus;106. An SPE column (Sep-Pak tC\u003csub\u003e18\u003c/sub\u003e Plus Short; Waters Corp., MA, USA) was washed with ethanol and 20%EtOH/H\u003csub\u003e2\u003c/sub\u003eO, conditioned with sterile water, and attached to SLV108 and SLV109. Subsequently, 10 \u0026mu;L of 25% w/v sodium ascorbate/H\u003csub\u003e2\u003c/sub\u003eO was added into the product recovery vial as a stabilizer, and was attached to SLV110 and DP2. Four lines were inserted into the reaction vial and connected to NP2, DP1, and SLV107. For syntheses using \u003csup\u003e211\u003c/sup\u003eAt in methanol, potassium carbonate (K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e; 72 \u0026mu;mol) was added to the reaction vial. Following system setup, the automation synthesis program was initiated. A CHCl\u003csub\u003e3\u003c/sub\u003e or MeOH solution of \u003csup\u003e211\u003c/sup\u003eAt (44.6\u0026minus;586.1 MBq, 100\u0026minus;500 \u0026mu;L) was introduced to the reaction vial through the sideline (Polyetheretherketone, PEEK) using a disposable syringe. Furthermore, CHCl\u003csub\u003e3\u003c/sub\u003e or MeOH (200 \u0026mu;L) was added to flush the line. The solvent was then evaporated under a nitrogen gas flow at 40 \u0026deg;C for 3 min (CHCl\u003csub\u003e3\u003c/sub\u003e) or 5 min (MeOH). After cooling to room temperature, the TFA solution of TMSBG (1.0 \u0026mu;mol/250 \u0026mu;L) was automatically added from a disposable syringe attached to SLV102, followed by the TFA solution of \u003cem\u003eN\u003c/em\u003e-chlorosuccinimide (NCS; 2.0 \u0026mu;mol/250 \u0026mu;L) from SLV103. The reaction mixture was heated to 70\u0026nbsp;\u0026deg;C for 10 min using an integrated air heater, then allowed to cool below 40\u0026nbsp;\u0026deg;C. The line was rinsed with sterile water (5 mL) from SLV101, followed by the addition of sterile water (10 mL) from SLV104 into the\u0026nbsp;reaction vial. The aqueous solution was transferred to the SPE column, followed by an additional 5 mL rinse from SLV105. Finally, 20% EtOH/H\u003csub\u003e2\u003c/sub\u003eO (3.5 mL) was passed through the SPE column from SLV106 into the\u0026nbsp;product vial containing 25% w/v sodium ascorbate in H\u003csub\u003e2\u003c/sub\u003eO (10 \u0026mu;L). The line was purged with nitrogen gas and the collected solution was concentrated at 40\u0026nbsp;\u0026deg;C for 3 min using a smart evaporator. The obtained solution was analysed via radio-HPLC and the RCP (%) was determined by the peak area ratio of the radio-chromatogram. The radiochemical yield (RCY) was calculated as follows:\u003c/p\u003e\n\u003cp\u003eRCY (%) = [(activity of eluted [\u003csup\u003e211\u003c/sup\u003eAt]MABG from SPE column)/(activity of \u003csup\u003e211\u003c/sup\u003eAt used for reaction)] \u0026times; 100\u003c/p\u003e\n\u003cp\u003eThe [\u003csup\u003e211\u003c/sup\u003eAt]MABG peak was identified based on the retention time of \u003cem\u003em\u003c/em\u003e-iodobenzylguanidine (MIBG) as a reference compound. Upon completion, the automated synthesis system was disassembled, and the residual radioactivity was quantified in the liquid delivery lines, waste bottles (Waste-1, -2, and -3), filter, reaction vial, and SPE column, to assess the distribution of unreacted \u003csup\u003e211\u003c/sup\u003eAt.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eRadiopharmaceutical preparation\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA Millex-FG filter unit (0.20 \u0026mu;m, PTFE, 25 mm; Merck Millipore Ltd.) and Millex-GV filter unit (0.22 \u0026mu;m, PVDF, 33 mm; Merck Millipore Ltd.) were connected to a 50-mL sterile vial with injection needles. Saline (6 mL) was added to the obtained product solution using a sterile disposable syringe, and the diluted product solution was drawn into the syringe and transferred into the sterile vial through the GV filter. This procedure was repeated with an additional 10 mL of saline. Subsequently, 20 mL of sterile saline was introduced into the vial through the GV filter. Portions of the final sterile solution (2 and 1 mL) were sampled into a sterile disposable syringe and GC glass vial, respectively, for analysis via GC and HPLC to assess residual solvents and determine RCP.\u003c/p\u003e\n\u003cp\u003eThe pH of the final sterile solution was measured using a benchtop pH meter F-74 (HORIBA, Ltd, Kyoto, Japan), calibrated using standard pH buffer solutions.\u003c/p\u003e\n\u003cp\u003eEndotoxin testing was conducted using the turbidimetric method with a Toxinometer\u0026reg; ET-6000 (FUJIFILM Wako Pure Chemical, Tokyo, Japan) in accordance with the Japanese Pharmacopoeia guidelines. Based on a maximum dose of 40 mL, the acceptance criterion was set at 3.75 EU/mL, and the [\u003csup\u003e211\u003c/sup\u003eAt]MABG solution was diluted 10-fold.\u003c/p\u003e\n\u003cp\u003eSterility testing was performed by direct inoculation into two different culture media; 0.5 mL of the [\u003csup\u003e211\u003c/sup\u003eAt]MABG solution was added to 10 mL of fluid thioglycollate medium and soybean casein digest medium, respectively. The samples were incubated at 32.5 and 22.5 \u0026deg;C using a double chamber incubator IQ822 (Yamato Scientific Co., Ltd, Tokyo, Japan), and the microbial growth was assessed on day 14. Method suitability testing confirmed microbial growth in the presence of the [\u003csup\u003e211\u003c/sup\u003eAt]MABG solution and positive control for all six strains listed in the Japa\u0026shy;nese Pharmacopoeia (\u003cem\u003eBacillus subtilis\u003c/em\u003e, \u003cem\u003eCandida albicans\u003c/em\u003e, and \u003cem\u003eAspergillus brasiliensis\u0026nbsp;\u003c/em\u003ein soybean casein digest medium; \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e, \u003cem\u003eStaphylococcus aureus\u003c/em\u003e, and \u003cem\u003eClostridium sporogenes\u0026nbsp;\u003c/em\u003ein fluid thioglycollate medium) within 3 or 5 d.\u003c/p\u003e\n\u003cp\u003eA filter integrity test was conducted to evaluate the performance of the sterilised filter. The bubble point pressure of the aqueous solution, as specified by the manufacturer (\u0026gt; 345 kPa), was used as the acceptance criterion and was measured using a UG-FT02 filter integrity tester (Universal Giken, Kanagawa, Japan).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eProduction of \u003csup\u003e211\u003c/sup\u003eAt\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAstatine-211 (\u003csup\u003e211\u003c/sup\u003eAt) was produced via the \u003csup\u003e209\u003c/sup\u003eBi(α,2n)\u003csup\u003e211\u003c/sup\u003eAt reaction using the MP 30 accelerator (Figure 4A). The \u003csup\u003e209\u003c/sup\u003eBi target plate was prepared by physical vapor deposition onto an aluminium plate and irradiated with 28.6 MeV alpha particles at a beam current of 20 µA. No visible melting or deformation of the \u003csup\u003e209\u003c/sup\u003eBi target was observed following irradiation (Figure 4B).\u003c/p\u003e\n\u003cp\u003eThe theoretical TTY of the \u003csup\u003e209\u003c/sup\u003eBi(α,2n)\u003csup\u003e211\u003c/sup\u003eAt reaction under the aforementioned irradiation conditions was 28.7 MBq/μA·h. The experimentally determined TTY was 27.4 ± 0.8 MBq/μA·h, corresponding to 95.5% of the theoretical value. The recovery yield of \u003csup\u003e211\u003c/sup\u003eAt following dry purification was 65.1 ± 5.0% (n = 14) at EOB, and the working time required from placing the irradiated target in the dry distillation system to obtaining the \u003csup\u003e211\u003c/sup\u003eAt solution was 25–30 min. γ-Ray spectrometry of the isolated \u003csup\u003e211\u003c/sup\u003eAt solution revealed characteristic peaks corresponding to \u003csup\u003e211\u003c/sup\u003eAt (687.00 keV), \u003csup\u003e211\u003c/sup\u003ePo (897.80 and 569.65 keV), and \u003csup\u003e207\u003c/sup\u003eBi (569.70 keV) (Figure S1). Notably, no peaks derived from \u003csup\u003e210\u003c/sup\u003eAt (1181.40 keV) and \u003csup\u003e210\u003c/sup\u003ePo (803.06 keV) were detected.\u003c/p\u003e\n\u003cp\u003e\u003cimg 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\"\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAutomation synthesis of [\u003csup\u003e211\u003c/sup\u003eAt]MABG\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 1 summarizes the synthesis outcomes obtained in this study. Entries 1–6 correspond to experiments conducted using CHCl\u003csub\u003e3\u003c/sub\u003e as the elution solvent, yielding RCYs of 80.3 ± 4.4% (decay-corrected RCY: 84.0 ± 4.5%, n = 6). In entries 7–10, MeOH was employed as the elution solvent and potassium carbonate was added; however, its effect was minimal, and no substantial decrease in RCYs was observed (RCY: 72.6 ± 13.6%, decay-corrected RCY: 76.1 ± 14.3%, n = 4). Across all tested conditions (Entries 1–10), RCP exceeded 98% and the automated synthesis of [\u003csup\u003e211\u003c/sup\u003eAt]MABG was completed within 33 min. Due to the absence of stable astatine isotopes, identification of [\u003csup\u003e211\u003c/sup\u003eAt]MABG was based on the retention time of MIBG as a reference compound. As shown in Figure 5, the retention time of [\u003csup\u003e211\u003c/sup\u003eAt]MABG was 8.3 min, while that of MIBG (authentic sample) was 8.0 min. The significant decrease in RCY is typically caused by the radioactivity, being effectively suppressed by the addition of sodium ascorbate.\u003c/p\u003e\n\u003cp\u003eFollowing synthesis, the system was disassembled and the radioactivity of the delivery lines, waste bottles, filter, reaction vial, and column was measured. The majority of residual\u0026nbsp;\u003csup\u003e211\u003c/sup\u003eAt was observed in the SPE column (8.4 ± 4.1%; n = 10) and the side line (2.8 ± 2.6%; n = 10). The radioactivity detected\u0026nbsp;\u003cbr\u003ein Waste-1, which collected the waste solution, was 1.2 ± 1.0% (n = 10). The low levels of radioactivity observed in Waste-2 (1.6 ± 1.7%; n = 10) and Waste-3 (1.0 ± 0.9%; n = 10), both connected to the exhaust line, indicated negligeable volatilization losses of \u003csup\u003e211\u003c/sup\u003eAt during synthesis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eRadiopharmaceutical preparation\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe [\u003csup\u003e211\u003c/sup\u003eAt]MABG solution was diluted with saline and passed through a sterile Millex-GV filter; minimal adsorption of [\u003csup\u003e211\u003c/sup\u003eAt]MABG to the filter was observed. The RCP value of [\u003csup\u003e211\u003c/sup\u003eAt]MABG in the final sterile solution was \u0026gt; 99% (Figure 6), and no degradation of [\u003csup\u003e211\u003c/sup\u003eAt]MABG associated with the diluted and filtrate process was detected. Furthermore, GC and HPLC analyses confirmed that the residual CHCl\u003csub\u003e3\u003c/sub\u003e level was below the detection limit, the residual TFA level (0.2 mg) was \u0026lt; 6.0 mg (PDE), and the ethanol content (1.3%) was \u0026lt; 2.0%. The pH of the final [\u003csup\u003e211\u003c/sup\u003eAt]MABG sterile solution was 4.4. The endotoxin concentration was below the lower limit (0.01 EU/mL) of the calibration curve, and sterility tests showed no microbial growth. The bubble-point value for the filter integrity test was 432 kPa (≥ 345 kPa). γ-Ray spectrometry of the [\u003csup\u003e211\u003c/sup\u003eAt]MABG solution confirmed characteristic peaks for \u003csup\u003e211\u003c/sup\u003eAt (687.00 keV), \u003csup\u003e211\u003c/sup\u003ePo (897.80 and 569.65 keV), and \u003csup\u003e207\u003c/sup\u003eBi (569.70 keV) (Figure S2).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eDuring the production of \u003csup\u003e211\u003c/sup\u003eAt via the \u003csup\u003e209\u003c/sup\u003eBi(α,2n)\u003csup\u003e211\u003c/sup\u003eAt reaction, it is essential to maintain the energy of the α-beam below the threshold (28.6 MeV) for the production of \u003csup\u003e210\u003c/sup\u003eAt in the (α,3n) reaction.\u003csup\u003e21 210\u003c/sup\u003eAt undergoes β\u003csup\u003e+\u003c/sup\u003e decay with a half-life of 8.1 h, yielding \u003csup\u003e210\u003c/sup\u003ePo, a highly toxic isotope with a longer half-life of 138.4 d compared with \u003csup\u003e211\u003c/sup\u003ePo (0.516 s). It is therefore crucial to suppress the production of \u003csup\u003e210\u003c/sup\u003eAt and ensure the radionuclidic purity of \u003csup\u003e211\u003c/sup\u003eAt. In this study, no peaks corresponding to \u003csup\u003e210\u003c/sup\u003eAt were detected in the γ-ray spectrum of the purified \u003csup\u003e211\u003c/sup\u003eAt solution.\u003c/p\u003e \u003cp\u003e \u003csup\u003e211\u003c/sup\u003eAt was purified using a dry distillation system and was recovered from the Teflon tubing using a volatile solvent, thereby minimizing the impact of the recovery solution on subsequent astatination reactions. CHCl\u003csub\u003e3\u003c/sub\u003e and MeOH have been previously employed as elution solvents at the Advanced Clinical Research Center, based on reports regarding the loss of volatile astatine during the concentration process. CHCl\u003csub\u003e3\u003c/sub\u003e has been shown to reduce astatine loss during solvent concentration.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e Furthermore, our previous study demonstrated that when MeOH is used, coexisting alkaline metal salts such as potassium carbonate, can similarly mitigate astatine loss during solvent concentration.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e In this study, both approaches were integrated into the automated synthesis system for [\u003csup\u003e211\u003c/sup\u003eAt]MABG, and their RCYs were compared. As a result, optimization of the synthetic process enabled high-yield production in both cases [decay-corrected RCY: 84.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5% (CH\u003csub\u003e3\u003c/sub\u003eCl) vs 76.1\u0026thinsp;\u0026plusmn;\u0026thinsp;14.3% (MeOH)]. However, the ~\u0026thinsp;20% points decrease in RCY observed in a preliminary experiment (Entry 7, Table\u0026nbsp;1) was attributed to insufficient interaction between K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e and the MeOH solution of \u003csup\u003e211\u003c/sup\u003eAt prior to the concentration step. Considering reproducibility and simplicity, CHCl\u003csub\u003e3\u003c/sub\u003e was selected as the preferred eluent in this study. Nonetheless, the feasibility of employing MeOH as the eluent with K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e during the concentration process warrants attention from both academic relevance and practical applicability.\u003c/p\u003e \u003cp\u003eThe liquid transfer in COSMiC-mini is regulated by adjusting the pressure within vials or bottles using a diaphragm pump and nitrogen gas flow. During the addition of the reaction reagents and the dilution process, rapid liquid transfer did not affect the reaction yield. However, transferring the diluted solution to the SPE column required a precisely controlled flow rate. Preliminary experiments indicated that high flow rates of the diluted reaction solution to the SPE column significantly decreased the retention of [\u003csup\u003e211\u003c/sup\u003eAt]MABG on the column. Therefore, to enhance the retention of [\u003csup\u003e211\u003c/sup\u003eAt]MABG on the SPE column, the pressure in the reaction vial was gradually increased using nitrogen gas, while the pressure in the Waste-1 bottle was gradually reduced using a vacuum pump during solution transfer.\u003c/p\u003e \u003cp\u003eThe decomposition of radiopharmaceuticals via radiolysis leads to decreased RCPs. Reactive species such as hydroxyl radicals are generated through the radiolysis of water, induced by the ionizing effects of radiation. These species contribute to the degradation of radiopharmaceuticals. Specifically, as the radioactive concentration of [\u003csup\u003e211\u003c/sup\u003eAt]MABG increases, the production of reactive species is enhanced, resulting in decomposition of the compound. Therefore, the addition of a reducing radical scavenger (e.g. sodium ascorbate) is essential for maintaining the stability of [\u003csup\u003e211\u003c/sup\u003eAt]MABG during synthesis. Figure S3 (Supplementary Information) presents preliminary data from our facility evaluating the inhibitory effect of sodium ascorbate on the degradation of [\u003csup\u003e211\u003c/sup\u003eAt]MABG. The stability of [\u003csup\u003e211\u003c/sup\u003eAt]MABG (113.1 MBq/2 mL) was assessed under two conditions: without additives and with sodium ascorbate. The results clearly demonstrate that sodium ascorbate effectively suppresses the degradation of [\u003csup\u003e211\u003c/sup\u003eAt]MABG. In entries 1\u0026ndash;10 (Table\u0026nbsp;1), a sodium ascorbate solution was preloaded into the product vials. Even at a high activity level of 586.1 MBq, no degradation of [\u003csup\u003e211\u003c/sup\u003eAt]MABG was observed after 24 h.\u003c/p\u003e \u003cp\u003eVaidyanathan \u003cem\u003eet al.\u003c/em\u003e reported a high-level synthesis of [\u003csup\u003e211\u003c/sup\u003eAt]MABG using a tin precursor immobilized on a solid support. The precursor undergoes astatination upon treatment with a methanolic solution of \u003csup\u003e211\u003c/sup\u003eAt in the presence of acetic acid and hydroxy peroxide.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e [\u003csup\u003e211\u003c/sup\u003eAt]MABG is subsequently isolated using C\u003csub\u003e18\u003c/sub\u003e SPE or a cation exchange resin cartridge. The C\u003csub\u003e18\u003c/sub\u003e-based approach achieved RCYs of 63\u0026thinsp;\u0026plusmn;\u0026thinsp;13%, but suffered from ~\u0026thinsp;50% activity loss during methanol evaporation\u0026mdash;possibly due to radiolysis, which, based on our findings, could potentially be mitigated by sodium ascorbate. The alternative isolation strategy using a cation exchange resin cartridge maintained comparable RCYs (63\u0026thinsp;\u0026plusmn;\u0026thinsp;9%; from initial \u003csup\u003e211\u003c/sup\u003eAt activity 14.4\u0026ndash;658.6 MBq), with \u0026gt;\u0026thinsp;90% RCPs. The total synthesis time was ~\u0026thinsp;120 min for the C\u003csub\u003e18\u003c/sub\u003e method and ~\u0026thinsp;70 min for the cation exchange method.\u003c/p\u003e \u003cp\u003eIn this study, [\u003csup\u003e211\u003c/sup\u003eAt]MABG was synthesized with high yields (RCY 80.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4%; decay-corrected RCY 84.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5%; from an initial \u003csup\u003e211\u003c/sup\u003eAt activity of 44.6\u0026ndash;586.1 MBq; Entries 1\u0026ndash;6) and RCP (99.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7%; Entries 1\u0026ndash;6), surpassing previously reported methods. Furthermore, the synthesis time was significantly reduced to 28.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8% min (Entries 1\u0026ndash;6). Notably, even at high radioactivity levels (563.5\u0026ndash;586.1 MBq), a high RCY was maintained (RCY 77.6\u0026ndash;82.1%; decay-corrected RCY 81.2\u0026ndash;85.9%; Entries 5 and 6), enabling the production of 437\u0026ndash;473 MBq of [\u003csup\u003e211\u003c/sup\u003eAt]MABG in a single synthesis. Even though the [\u003csup\u003e211\u003c/sup\u003eAt]MABG produced by the established methodology is comparable in quality to the conventionally synthesized material, further in vivo studies are required to evaluate biodistribution, therapeutic efficacy, and toxicity. Comparative in vivo studies using mouse models are currently underway.\u003c/p\u003e \u003cp\u003eConsidering the reaction yield, synthesis time, and availability of precursors, the automated astatodesilylation method using COSMiC-Mini presents an efficient approach for [\u003csup\u003e211\u003c/sup\u003eAt]MABG production. Furthermore, the programmable nature of COSMiC-Mini allows on-site customisation, facilitating the adaptation of this protocol for the synthesis of other \u003csup\u003e211\u003c/sup\u003eAt-labeled radiopharmaceuticals. Therefore, the manufacturing techniques and expertise described in this study offer a valuable tool for the future production of \u003csup\u003e211\u003c/sup\u003eAt-labeled radiopharmaceuticals.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn this study, a robust methodology was established for the clinical-scale production of [\u003csup\u003e211\u003c/sup\u003eAt]MABG. The process encompasses the production of \u003csup\u003e211\u003c/sup\u003eAt via the \u003csup\u003e209\u003c/sup\u003eBi (α,2n) \u003csup\u003e211\u003c/sup\u003eAt reaction using an MP-30 cyclotron, followed by purification via dry distillation with the At-HDS100 system, and automated radiosynthesis of [\u003csup\u003e211\u003c/sup\u003eAt]MABG using the COSMiC-mini. The automated synthesis consistently yielded [\u003csup\u003e211\u003c/sup\u003eAt]MABG with high radiochemical yields (RCYs: 80.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4%; decay-corrected RCY: 84.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5%) and radiochemical purity (RCP: 99.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7%) within a short synthesis time of 28.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8 min. Notably, the addition of sodium ascorbate significantly enhanced the radiolytic stability of [\u003csup\u003e211\u003c/sup\u003eAt]MABG, contributing to the reproducibility and reliability of the method. The final product was obtained as a sterile, injectable solution that meets standard physicochemical and radiochemical quality requirements. This integrated approach represents a significant advancement toward the clinical translation of [\u003csup\u003e211\u003c/sup\u003eAt]MABG as a next-generation targeted alpha therapy for neuroendocrine tumours.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNET\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNeuroendocrine tumour\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMIBG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e \u003cem\u003em\u003c/em\u003e-Iodobenzylguanidine\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMABG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e \u003cem\u003em\u003c/em\u003e-Astatobenzylguanidine\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFKM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFluoroelastomer\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRCY\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRadiochemical yield\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRCP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRadiochemical purity\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICP-MS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInductively coupled plasma mass spectrometry\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEOB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEnd of bombardment\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTTY\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eThick target yield\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTMSBG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e1-(3-(Trimethylsilyl)benzyl)guanidine\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHPLC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHigh performance liquid chromatography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eUV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eUltraviolet\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTFA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTrifluoracetic acid\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGas chromatography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFID\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFlame ionization detector\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eK\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePotassium carbonate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCHCl\u003csub\u003e3\u003c/sub\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eChloroform\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMeOH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMethanol\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePEEK\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePolyetheretherketone\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNCS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e \u003cem\u003eN\u003c/em\u003e-chlorosuccinimide\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSPE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSolid-phase extraction\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePTFE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePolytetrafluoroethylene\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePVDF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePolyvinylidene fluoride\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in this published article and its supplementary information files.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eShigenori Sasaki and Kazumasa Mochizuki are employees of SHI Accelerator Service Ltd., a subsidiary of Sumitomo Heavy Industries, Ltd., which manufactures the cyclotron system used in this study. The company was not involved in the study design, data analysis, or manuscript preparation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by JSPS KAKENHI (JP23K27543, JP24K23270, and 25K19142).\u0026nbsp;This study was supported by a joint research project between the QST and the Tokyo Institute of Technology, titled \u0026quot;Research aimed at the development and examination of an improved manufacturing method for [\u003csup\u003e211\u003c/sup\u003eAt]MABG using GMP-compliant automated synthesis equipment.\u0026quot; As part of this project, Hiroshi Tanaka conducted research using funding provided by QST.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll experiments were designed and conceived by YK, TJ, and KT. Production and purification of \u003csup\u003e211\u003c/sup\u003eAt was performed by SS and KM. Radiosynthesis of [\u003csup\u003e211\u003c/sup\u003eAt]MABG and radiopharmaceutical preparation was conducted by YK, JT, and NH. The manuscript was designed and written by YK. All authors discussed the results and contributed to the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthors and Affiliations\u003c/p\u003e\n\u003cp\u003ea. Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, 1 Hikarigaoka, Fukushima 960-1295, Japan.\u003c/p\u003e\n\u003cp\u003eYuto Kondo, Taiki Joho, Shigenori Sasaki, Kazumasa Motizuki, Naoko Hasegawa, Naoyuki Ukon, Ken-ichi Nishijima, Kohshin Washiyama, and Kazuhiro Takahashi\u003c/p\u003e\n\u003cp\u003eb. SHI Accelerator Service Ltd., 7-1-1 Nishigotanda, Shinagawa, Tokyo, 141-0031, Japan.\u003c/p\u003e\n\u003cp\u003eShigenori Sasaki and Kazumasa Mochizuki\u003c/p\u003e\n\u003cp\u003ec. Department of Chemical Science and Engineering, Tokyo Institute of Technology, 12-12-1-H101 Ookayama, Meguro, Tokyo 152-8552, Japan. Laboratory of Pharmaceutical Chemistry, Juntendo University, 6-8-1 Hinode, Urayasu, Chiba 279-0013, Japan.\u003c/p\u003e\n\u003cp\u003eHiroshi Tanaka\u003c/p\u003e\n\u003cp\u003ed. Department of Molecular Imaging and Theranostics, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, 4-9-1, Anagawa, Inage, Chiba-City, Chiba, 263-8555, Japan.\u003c/p\u003e\n\u003cp\u003eHigashi Tatsuya.\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ee. Department of Quantum-Applied Biosciences, Takasaki Institute for Advanced Quantum Science, National Institutes for Quantum Science and Technology, 1233 Watanuki, Takasaki, Gunma 370-1292, Japan.\u003c/p\u003e\n\u003cp\u003eNoriko S. Ishioka\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorresponding author\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorrespondence to\u0026nbsp;Kazuhiro Takahashi ([email protected])\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Editage (www.editage.jp) for English language editing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eStreby KA, Shah N, Ranalli MA, Kunkler A, Cripe TP. Nothing but NET: a review of norepinephrine transporter expression and efficacy of \u003csup\u003e131\u003c/sup\u003eI-mIBG therapy. 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J Radioanal Nucl Chem. 2018;276:843\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s10967-008-0642-6\u003c/span\u003e\u003cspan address=\"10.1007/s10967-008-0642-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAneheim E, Palm S, Jensen H, Ekberg C, Albertsson P, Lindegren S. Towards elucidating the radiochemistry of astatine - Behavior in chloroform. Sci Rep. 2019;9:15900. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/s41598-019-52365-5\u003c/span\u003e\u003cspan address=\"10.1038/s41598-019-52365-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTanaka H, Takahashi K, Suzuki M. Simple Astatine Concentration Method. WO 2021/225147 A1. 2021 Nov 11.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Schemes","content":"\u003cp\u003eScheme 1 is available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"ejnmmi-radiopharmacy-and-chemistry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"erpc","sideBox":"Learn more about [EJNMMI Radiopharmacy and Chemistry](http://ejnmmipharmchem.springeropen.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/erpc/default.aspx","title":"EJNMMI Radiopharmacy and Chemistry","twitterHandle":"@officialEANM","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Astatine-211, MABG, dry distillation, automated synthesizer, astatodesilylation, radiochemistry, TAT","lastPublishedDoi":"10.21203/rs.3.rs-6886403/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6886403/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e[\u003csup\u003e211\u003c/sup\u003eAt]\u003cem\u003em\u003c/em\u003e-Astatobenzylguanidine ([\u003csup\u003e211\u003c/sup\u003eAt]MABG) has demonstrated potent antitumor efficacy in preclinical models of malignant neuroendocrine tumours. The high linear energy transfer and short tissue penetration range of alpha particles enable highly localized cytotoxic effects, potentially overcoming therapeutic limitations associated with conventional beta-emitting radiopharmaceuticals. However, under clinical-scale (i.e., high radioactivity) conditions, the efficient and stable production of [\u003csup\u003e211\u003c/sup\u003eAt]MABG has been hindered by radiolytic degradation during the manufacturing process limiting the availability of reliable methods offering high radiochemical yield and purity. In this study, we aimed to develop a scalable production methodology for [\u003csup\u003e211\u003c/sup\u003eAt]MABG suitable for clinical translation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e211\u003c/sup\u003eAt was produced via the \u003csup\u003e209\u003c/sup\u003eBi(α,2n)\u003csup\u003e 211\u003c/sup\u003eAt nuclear reaction using a cyclotron, with \u003csup\u003e210\u003c/sup\u003eAt formation minimised by precise control of the alpha particle energy. The resulting product was purified using an automated dry distillation system. [\u003csup\u003e211\u003c/sup\u003eAt]MABG was synthesised using the COSMiC-Mini automated synthesiser in 28.2 ± 2.8 min from initial \u003csup\u003e211\u003c/sup\u003eAt activities of up to 586.1 MBq. The radiochemical yield and purity were 80.3 ± 4.4% (decay-corrected RCY: 84.0 ± 4.5%) and 99.0 ± 0.7%, respectively (n = 6). The addition of sodium ascorbate as a radical scavenger contributed to maintaining a high radiochemical yield and purity during large-scale production. The final product was obtained as a sterile solution.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this study, we established a reliable and scalable production methodology for [\u003csup\u003e211\u003c/sup\u003eAt]MABG, consistently achieving high radiochemical yield and purity across a wide range of radioactivity levels through optimization of the automated radiosynthesis process and the use of radiolytic stabilizers. This approach provides a solid technical foundation for the clinical application of [\u003csup\u003e211\u003c/sup\u003eAt]MABG in targeted alpha therapy for neuroendocrine tumours.\u003c/p\u003e","manuscriptTitle":"Production of 211At and Automated Radiosynthesis of [211At]MABG via Electrophilic Astatodesilylation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-18 16:29:39","doi":"10.21203/rs.3.rs-6886403/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2025-06-30T02:39:29+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-06-16T15:23:27+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-16T15:00:45+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-16T14:56:09+00:00","index":"","fulltext":""},{"type":"submitted","content":"EJNMMI Radiopharmacy and Chemistry","date":"2025-06-15T20:29:18+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"ejnmmi-radiopharmacy-and-chemistry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"erpc","sideBox":"Learn more about [EJNMMI Radiopharmacy and Chemistry](http://ejnmmipharmchem.springeropen.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/erpc/default.aspx","title":"EJNMMI Radiopharmacy and Chemistry","twitterHandle":"@officialEANM","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"84185525-21c5-4e18-8113-7fcda0d2a05a","owner":[],"postedDate":"June 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-08-11T16:02:38+00:00","versionOfRecord":{"articleIdentity":"rs-6886403","link":"https://doi.org/10.1186/s41181-025-00376-1","journal":{"identity":"ejnmmi-radiopharmacy-and-chemistry","isVorOnly":false,"title":"EJNMMI Radiopharmacy and Chemistry"},"publishedOn":"2025-08-05 15:57:42","publishedOnDateReadable":"August 5th, 2025"},"versionCreatedAt":"2025-06-18 16:29:39","video":"","vorDoi":"10.1186/s41181-025-00376-1","vorDoiUrl":"https://doi.org/10.1186/s41181-025-00376-1","workflowStages":[]},"version":"v1","identity":"rs-6886403","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6886403","identity":"rs-6886403","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}