Research and Development for Cyclotron Production of 225 Ac from 226 Ra—The Challenges in a Country Lacking Natural Resources for Medical Applications

: The high therapeutic effect of targeted radioisotope/radionuclide therapy (TRT) using α-emitters, especially 225 Ac, is attracting attention worldwide. However, the only 225 Ac production method that has been put into practical use is extraction from a 229 Th generator derived from the nuclear fuel 233 U, and it is unlikely that this method alone is able to meet future global medical demand. Development towards new 225 Ac production methods is in progress. These new 225 Ac production methods require the irradiation of 232 Th or 226 Ra using an accelerator or a nuclear reactor. Global competition has already begun in the race to secure a reliable supply of 232 Th and 226 Ra, as well as 229 Th for the conventional production method. Japan is a “resource-poor country” that depends on foreign countries for most of its needs. As such, it is difficult for Japan to secure raw materials such as 232 Th and 226 Ra for medical application. In this paper, we look back on our research at the National Institutes for Quantum Science and Technology (QST) in the fields of 225 Ac production and 225 Ac-labeled pharmaceutical development. We present the history and details of our research from 2011, as well as the development of a collaboration between QST and Nihon Medi-Physics that focuses on research into 225 Ac production via 226 Ra(p,2n) 225 Ac reaction using an accelerator. Furthermore, we review the valuable discussion at the 2018 Joint IAEA-JRC Workshop—“Supply of Actinium-225”, an international conference that we participated in. Overall, the statuses of external 225 Ac supply, domestic production, and distribution are discussed, as are the latest developments in 225 Ac production methods, 225 Ac pharmaceuticals, and future prospects for the domestic production of 225 Ac in Japan, a country lacking natural resources for medical applications.


Introduction
In line with the recent trend toward personalized or precision medicine, the concept of radiotheranostics has become popular in the field of nuclear medicine.In this concept, a diagnosis is made using nuclides suitable for PET/SPECT, and the subsequent targeted radioisotope/radionuclide therapy (TRT) or the targeted alpha therapy (TAT) is performed after replacement with therapeutic nuclides [1].In 2013, the world's first alphaparticle-emitting radionuclide, the 223 Ra pharmaceutical Xofigo™, was approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for introduction to the market [2].The approval of Xofigo™ substantially increased the number of diseases that could be treated (from rare diseases to common diseases such as prostate cancer), so the potential for TRT and TAT greatly increased.Since the Journal of Nuclear Medicine (JNM) reported two surprising cases of complete remission (CR) in the treatment of metastatic prostate cancer in 2016 [3], the potentials for 225 Ac-labeled pharmaceuticals and other alpha-particle-emitting radionuclide therapies have been receiving a great deal of attention [1].However, for the effective application of these alpha-emitting radiopharmaceuticals, it is important to not only develop the drugs but also to develop radionuclide production methods.Securing sufficient supplies of target raw materials for each manufacturing method is an important issue.The supply of target raw materials, such as 233 U, 229 Th, and other nuclear-fuel-derived nuclides, as well as other thorium isotopes ( 232 Th, 230 Th, 226 Th, etc.), has attracted attention.Furthermore, 226 Ra, which has previously been treated as medical waste in various countries around the world, has been found to have potential as a useful target material, and therefore, international competition has developed in securing a reliable supply.
Japan has a large-scale economy in terms of gross domestic product and is generally regarded as a rich country.On the other hand, it is a "resource-poor country" that depends on foreign countries for about 90% of its energy resources.Food self-sufficiency is also regarded as a security risk for Japan because it has been at around only 40% for many years [4].Overseas dependence is conspicuous in the pharmaceutical field, with 50% of the raw materials necessary for general generic drug production dependent on imports.It was estimated that the fraction of generic drugs that could be covered by domestically produced raw materials was only about 30%, so self-sufficiency is limited [5].This trend is even more pronounced in the supply of radionuclides and radio-labeled pharmaceuticals.Since the supply of 99m Tc, which is a diagnostic radionuclide, is 100% dependent on foreign imports, the suspension of clinical procedures with 99m Tc-labeled pharmaceuticals has occurred several times in the past due to unplanned shutdowns of overseas nuclear reactors and eruptions of volcanos in Iceland [6].After each incident, the Cabinet Office of Japan issued an action plan promoting the idea of domestic selfsufficiency [7].However, there is no sign of improvement to date.
In recent years, the use of the diagnostic nuclide 68 Ga and the therapeutic nuclide 177 Lu for radiopharmaceuticals has been expanding worldwide. 68Ga is used not only in Europe and North America, but also in 10 Asian, 1 African, and 3 South American countries [8].Multiple 68 Ga-and 177 Lu-labelled pharmaceuticals have already been approved and are becoming widely used as insurance-supported medical treatments [9].In contrast, Japan is far behind in terms of insurance support and clinical use.Lutathera ™ was finally approved in 2021, and a few doctor-initiated clinical trials using 68 Galabelled pharmaceuticals also began in 2021 [10,11].Of the 14 radiopharmaceuticals (including those for diagnosis and treatment) approved in Japan since 2000, there have been no products developed by domestic pharmaceutical companies [12].In addition, all five of the radiopharmaceuticals approved as TRT agents by the regulatory authority (the Pharmaceuticals and Medical Devices Agency, PMDA) depend on overseas imports.Moreover, their labeling nuclides ( 131 I, 90 Y, 223 Ra, 177 Lu) must also be imported, so there is no prospect of domestically researched and developed pharmaceuticals.Despite the recent advent of a super-aging society unlike any other in the world, it can be said that Japan continues to be reliant on foreign resources for the pharmaceutical field and, in particular, for radionuclides.From the perspectives of the current COVID-19 pandemic, the decline in international transportation capacity due to Russia's invasion of Ukraine, and other security risks, the Cabinet Office of Japan and other domestic authorities are beginning to move toward building a self-sufficiency system for medical resources.For the field of nuclear medicine, this means developing domestic sources for the diagnostic nuclide 99m Tc and the therapeutic alpha-emitter 225 Ac [12].
In this paper, we, the National Institutes for Quantum Science and Technology (QST), would like to present the status of research and development in the TRT and TAT fields in Japan, a country lacking natural resources for medical applications.In particular, we wish to discuss the efforts of the QST towards the domestic production and development of the new therapeutic alpha nuclide 225 Ac.

Towards Development of Alpha-Emitting Radiopharmaceuticals at QST
At the National Institute of Radiological Sciences (NIRS), the predecessor to QST, research and development for the domestic production of alpha-emitters started in 2011.This research was inspired by the results announced for Alpharadin ™ ( 223 radium chloride; the name used for Xofigo ™ at that time), for which clinical trials began around 2008-2010 [13].In 2012, public research funds were obtained so that full-scale research and development of alpha-emitter production, as the "Radiation Therapy Strategic Infrastructure Project for Internal Cancer," could begin for the first time in Japan.At that time, a therapeutic study was planned with 211 At as the first candidate for alpha-emitter because the target material, 209 Bi, was easily accessible, even in Japan.We devised a QSToriginal vertical target system for producing 211 At and proceeded to lay the foundation for domestic alpha-emitter research [14]. 211At is produced by irradiating bismuth with helium ions using an accelerator.Astatine, which is located under iodine in the periodic table, was in 1940 the first element to be artificially synthesized in research to expand the periodic table using an accelerator [15].Now, around 80 years later, it is very interesting to see that such an artificial element may be useful for the health and welfare of humankind.
In 2016, the NIRS, the Quantum Beam Science Research Directorate, and the Fusion Energy Directorate of the Japan Atomic Energy Agency were reorganized and integrated as the National Institutes for Quantum Science and Technology.In the 7-year medium-tolong-term research plan that was drafted at that time, a national TRT and TAT research project called "Next Generation Cancer Treatment Research" started as one of the three pillars of the national "Research and development for innovative medical use of radiation" strategy.With the expertise of the Quantum Beam Science Research Directorate, which excels in labeling technology for halogen group elements, 211 At-labeled meta-astato-benzylguanidine (MABG), which is a nuclide conversion agent of 131 I-labeled meta-iodo-benzylguanidine (MIBG) for the treatment of malignant pheochromocytoma, was developed as part of continued research from the NIRS era [16].The results of alphaemitter research have been steadily accumulating over the past 6 years, and a doctorinitiated clinical trial, which is the first human study of MABG, is about to start at Fukushima Medical University in 2022 [17,18].Another doctor-initiated clinical trial of [ 211 At]NaAt, which is a first-in-human study for the treatment of intractable thyroid cancer, was started in 2021 at Osaka University [19].The research and development of alpha-emitting radiopharmaceuticals focusing on 211 At is gradually progressing at multiple facilities across Japan.In general, the physical half-life of 211 At is relatively short at 7.2 h, which is inconvenient for commercial supply and logistics, so it is not currently regarded as the highest priority for the future development of TRT and TAT worldwide, and only a few countries, such as, the United States, Sweden, Denmark, and Canada, are under development [1].However, as a country lacking natural resources for medical applications, Japan is one of the few countries promoting the clinical research and development of 211 At-labeled therapeutic agents.

R and D for the Production of 225 Ac at QST
As noted above, led by Osaka University, the research and development of alphaemitting radiopharmaceuticals in Japan is focused on mainly 211 At.On the other hand, the QST has set itself apart from other domestic research institutes by conducting full-scale research on the production of 225 Ac, as well as 211 At.In 2016, the only method to produce 225 Ac relied on extraction from 229 Th derived from 233 U, but this 229 Th generator method is not feasible in Japan because we do not have access to fissiles of 233 U.However, as one of the leading accelerator and medical research facilities in Japan, the QST has focused on a 225 Ac production method via proton irradiation first reported by Apostolidis et al. in 2005 [20].This advanced technique irradiates an α-emitter, 226 Ra, with protons to obtain another α-emitter.Due to difficulties in handling 222 Rn, which is a gas that emanates as a daughter of 226 Ra, this reaction channel has received little attention.At the QST, we started research and development of 225 Ac production with charged particles using 226 Ra that had once been used as a sealed source for brachytherapy and was now being kept as radioactive waste.Thanks to the national waste management program, a certain amount of 226 Ra was available as a target for proton irradiation, even in our resource-poor country.
In 1901, just three years after the discovery and isolation of 226 Ra by Pierre and Marie Curie in 1898 [21], 226 Ra was utilized for medical purposes. 226Ra decays to 222 Rn and has been applied to radiotherapy using the beta rays and gamma rays emitted by the daughter nuclides. 226Ra in the form of a brachytherapy needle was inserted into an affected area to suppress tumor growth.However, from the middle of the 20th century, brachytherapy has focused on the use of other, more manageable nuclides, so the existing 226 Ra brachytherapy needles were collected and stored as medical waste.In Japan, several tens of grams of sealed 226 Ra sources that were no longer used as radium needles or tubes were recovered and were in storage by the 2010s.Since 226 Ra has a long half-life of 1600 years, emits high energy gamma rays, and emanates 222 Rn, it is difficult to obtain the approval of the local governments for landfill disposal.The handling and storage of 226 Ra is a troublesome issue in Japan and many other countries.Nobody in Japan seemed to recognize the potential usefulness of 226 Ra at that time.
However, the situation in the United States was quite different.A method that used 226 Ra as a target to produce 227 Ac via neutron irradiation (i.e., 226 Ra(n,γ) 227 Ra) was already known.Beta decay of 227 Ra with a half-life of 43 min produced the desired 227 Ac [22].The DOE was producing 227 Ac in this way.Since 227 Ac can be used as the parent nuclide of a 223 Ra generator in Xofigo TM production, the DOE had been working with Bayer between 2007 and 2017 to engage in the production of 227 Ac, and they made a big profit.Later, in 2018, the DOE and Bayer renewed their cooperation for the provision of nuclides [23].We pay homage to the DOE because they were the first to see the potential of collecting medical waste from around the world for the production of 223 Ra and other nuclides.We cannot help but be discouraged by Japan's lack of foresight in not seeing that it might be possible to make effective use of the limited amount of 226 Ra that it had as a resource for medical applications.
In 2015, most of the 226 Ra stored in Japan was transferred to the US Department of Energy (DOE) for recycling, while a small number of 226 Ra needles were provided to us for research purposes.However, besides radioactivity, there was no other information (e.g., manufacturer, chemical form, or presence of additives (carriers)) available for the 226 Ra needles.It was a challenging task to develop a suitable refining technology (including de-capping, the identification of the chemical formula, the presence of additives, separation, and isolation of 226 Ra from the needle).Our TRT and TAT research project had a big handicap from the beginning.
Research and development into 225 Ac production started at the QST via the 226 Ra(p,2n) 225 Ac reaction, and we eventually succeeded in the trial production of 225 Ac.In 2018, the QST, as a contracted research institute, participated in the "Cyclic Innovation for Clinical Empowerment (CiCLE)" project of the Japanese Agency for Medical Research and Development (AMED).The project was led by Nihon Medi-Physics (NMP) [24].As a result, a large amount of AMED research funding was invested in the QST so that a fullscale 225 Ac production research and development project could begin.

Joint IAEA-JRC Workshop 2018-"Supply of Actinium-225"
After the 2016 report on prostate cancer treatment by Kratochwil et al., global competition had begun towards the aim of establishing a stable mass production method for both 225 Ac by itself and 225 Ac-labeled compounds that were sufficient for clinical use.In 2018, the International Atomic Energy Agency (IAEA) and the Joint Research Center (JRC) of the European Commission jointly held an international workshop [25].As far as we know, this was the world's first international conference dedicated to 225 Ac.Meeting attendees included representatives from the IAEA, JRC, and the DOE.Chemistry, pharmacy, engineering, and medical professionals from 15 countries, (i.e., Argentina, Belgium, Canada, Cuba, Czech Republic, Finland, France, Germany, Japan, Republic of Korea, Poland, Russia, South Africa, Switzerland, and the United States) attended.From Japan, Professor Jun Hatazawa (then at Osaka University) and two of the authors (Higashi and Nagatsu, QST) participated.Technical issues and opinions related to 225 Ac production were widely discussed, and information on the current state of research and regulatory issues for clinical use in each country was exchanged.It was a valuable meeting.A report by the IAEA summarizing the workshop was published on the web for those readers who would like to know more details [25].
It should be noted that the following sentences that we include here are from the oral presentations that we personally witnessed as participants at the workshop and may differ from the details that are presently officially approved by each facility or institution.
(Comment: As of 2022, four years after the workshop, it is interesting to look back at these presentations because, while there are some projects that have made steady progress, there are also some development plans that have not been heard of since then.We think there may be a number of cases where the results have not been announced due to reasons such as economic strategy.Please refer to the latest data for the latest development status of each country.)

Outline of Workshop Discussion
At that time, the main production method for 225 Ac was the conventional generator extraction method from 229 Th (Th-GEx method).Other known methods that used an accelerator included: ① spallation via the 232 Th(p,x) 225 Ac reaction, ② transmutation by protons targeted at 226 Ra, and ③ photonuclear reaction induced by high-energy electrons bombarding 226 Ra.One production method that relied on the reaction of 226 Ra(3n,2β) 229 U→ 229 Pa→ 229 Th→ 225 Ra→ 225 Ac induced by high neutron flux using a nuclear reactor (abbreviated as the reactor method) was also known.
It was noted that the Th-GEx method was performed at a large scale at the JRC and Oak Ridge National Laboratory (ORNL) in the United States.Method ① was conducted on an experimental scale at Los Alamos National Laboratory (LANL) and Brookhaven National Laboratory (BNL) in the United States; the Conseil Européen pour la Recherche Nucléaire (CERN), TRIUMF, in Canada; and a few institutes in Russia.Method ② was originally developed by the JRC in Europe, but many other facilities around the world, including the QST in Japan, were investigating the method at a small scale.The JRC and Munich University were preparing to work at a medium scale.Method ③ was conducted at an experimental scale in the United States and Australia, and the reactor method was being investigated at a similar scale at ORNL in the United States.
(Note: Table 1 lists the alternative 225 Ac production methods that used an accelerator.It was created by adding the latest data [26][27][28] to the 2018 document [25]. In 2018, the 225 Ac yield via the Th-GEx method was 33 GBq (0.9Ci) per year from ORNL in the US [29], 11 GBq (0.3Ci) per year from the JRC in Europe, and 22 GBq (0.6Ci) per year from the Institute of Physics and Power Engineering (IPPE) in Obrinsk, Russia.The overall global annual production capacity was, thus, 66 GBq (1.8Ci) per year.
(Note: The supply from Russia, which corresponded to about one-third of the world's production capacity in 2018, was suspended due to the invasion of Ukraine in 2022, and the impact on future global TRT and TAT development is not negligible.)Considering future global clinical demand, it is necessary to increase the production capacity of 225 Ac.It was estimated that 1850 GBq (50Ci) would be required annually per pharmaceutical, which is roughly about sub-tens of TBq (hundreds of Ci) in total [30].It was, therefore, predicted that the Th-GEx method is not able to meet all of the future 225 Ac demand.As a consequence, it is a matter of urgency to establish new production methods (as well as quality evaluation, dose evaluation, cost benefit, logistics, etc.) for 225 Ac.
It was noted that there were 3 tons of 233 U in the United States, of which 1 ton was refined and the remaining 2 tons were contained in spent reactor fuel.In other words, from the perspective of a secure supply of raw materials, a strategy to expand commercial supply via the Th-GEx method in the US is highly promising [31].
There was also a strong opinion that it was meaningless to increase production without considering quality, cost, purity, and current good manufacturing practice (cGMP).Considering future regulatory approval, the concentration of impurities, acceptable thresholds for possible contaminants, and (radio)toxicity are key factors for the addition of potential alternative production methods to the FDA Drug Master File.
(Note: In 2021, the Th-GEx method was listed in the FDA Drug Master File [32].) In particular, the handling of 227 Ac (T1/2 = 21.8 years), which is considered to be radiotoxic, was an issue.Thus, the separation and purification of 227 Ac were also important.Since the waste exemption level of 227 Ac is extremely low, radioactive waste and sewerage management should be also considered.
There was also a strong opinion that Method ① had a potential issue with 227 Ac contamination.As the FDA is quite strict in regards to purity, it was thought to be unlikely that this method would be approved.
(Note: The issue of 227 Ac contamination was resolved, and in 2020, Method ① was added to the FDA Drug Master File [33].Since the Th-GEx method and Method ① are now listed in the FDA Drug Master File, these two production paths will be mainly used in the manufacture of 225 Ac-labelled radiopharmaceutical investigational drugs developed by the "mega pharmas".It is expected that these two 225 Ac production paths will be the main paths for commercial 225 Ac-labelled therapeutic agents in the global pharmaceutical market.It is necessary in the future to register the original 225 Ac production protocol developed in Japan with the FDA or a similar official authority.)

European Situation
The JRC found it difficult to completely eliminate 225 Ra from the 225 Ac that it supplied six times a year using the Th-GEx method.However, using various resins and columns (anion exchange resin, UTEVA column, TEHDGA column, etc.), a radionuclidic purity of >99.98% was achieved for 225 Ac.In addition, the JRC also demonstrated a prototype 225 Ac/ 213 Bi generator (3.7 GBq (100 mCi) of 225 Ac).The JRC's strategies were clear, and it had already established itself as an international research center for drug discovery using 225 Ac.
(Note: In 2020, Endocyte (owned by Novartis Pharmaceuticals) started to use JRCsupplied 225 Ac, and a phase I clinical trial of TRT and TAT for advanced prostate cancer with the 225 Ac-labeled PSMA-617 radiopharmaceutical (initially developed and characterized at JRC Karlsruhe in 2013) started in South Africa and Australia.It is our impression that the trial is proceeding smoothly now [34].) It was noted that SCK-CEN (Belgian Nuclear Research Center) was able to produce high-quality, GMP-grade 225 Ac and continuously supplied it with a backup system.SCK-CEN was also affiliated with Global Morpho Pharma (France) and IRE Elit in the production of GMP-grade 225 Ac.SCK-CEN, having a BR2 reactor and an acceleratordriven subcritical reactor called MYRRHA (Multi-purpose hYbrid Research Reactor for High-tech Application), already had several hundred grams of 226 Ra, and irradiation would start from 2019.Furthermore, SCK-CEN would be able to produce GMP-grade 225 Ac at 37 GBq (1000 mCi)/week using an IBA (Ion Beam Applications S.A., EURONEXT) Rhodotron by irradiating with 40 MeV electrons at 125 kW.In addition, another cyclotron belonging to IBA, KIUBE, was able to supply GMP-grade 177 Lu.
(Note: In 2021, SCK-CEN and IBA signed an R and D partnership agreement for the joint production of 225 Ac, and future trends should be watched [35].)

The Situation in the United States
Since the 1990s, ORNL has produced 50 GBq (1.4 Ci) of 225 Ac using the Th-GEx method.To separate and purify 225 Ac, various resins and columns (anion exchange, resin, MP1 column, AG50W microcolumn, etc.) were used.It was claimed that 740 MBq (20 mCi) of 225 Ac could be prepared every 2-3 months and a maximum of 5.2 GBq (140 mCi) annually.In addition, ORNL also performed the reactor method in a high-flux reactor, and a maximum of 5.2 GBq (140 mCi) of 225 Ac could be produced annually with that method.However, the production efficiency was poor, and 228 Th and 227 Ac were often mixed.
The United States has been working on development under the framework of the Tri-Lab project led by the DOE since 2009.Production via Method ① was also investigated in cooperation with the NIDC (National Isotope Development Center), ORNL, BNL, and LANL.At that time, ORNL had already produced a total of 67 GBq (1800 mCi) of 225 Ac and exported a total of 8.7 GBq (235 mCi) to Europe for research purposes.Their production procedure had already been submitted for consideration to the FDA Drug Master File.They said that 227 Ac (T1/2 = 21.8 years) contamination could be an issue, but related studies showed that 227 Ac in the 225 Ac had little or no impact on dosimetry and toxicity [36], and therefore, it was expected that GMP production and certification would be possible.
(Note: Method ① was listed in the FDA Drug Master File in 2020 [33].)TERRA POWER is a company that was established in the United States by Bill Gates in 2007.It is developing next-generation nuclear reactors, such as a traveling wave reactor or a molten salt reactor, to reduce CO2 emission from electric power plants.They aimed to expand 225 Ac production using the Th-GEx method, and they already had 45 g, or 370 GBq (10 Ci), of 229 Th, which was derived from stored 233 U.The parent 233 U for 229 Th contains 220 ppm of 232 U as an impurity that breeds 208 Tl (T1/2 = 3 min)-emitting 2.6 MeV gammas, so it was troublesome to handle.The process to isolate 229 Th from 233 U and extract 225 Ac from 229 Th was still in the development phase.They expected that they would be able to ship 225 Ac by 2020 or later.
(Note: The Th-GEx method was listed in the FDA Drug Master File in 2021, and as of 2022, TerraPower is aiming to build a supply network in partnership with the US DOE [37].)NIOWAVE promoted Method ③.An electron accelerator had already been licensed in accordance with local and national laws (Radioactive Material Act, Financial Act, National Environmental Policy Act (NEPA), and the US Department of Transportation (DoT) regulations).The company expected to receive future approval for cGMP registration from the FDA.Their 225 Ac-labeled compounds were expected to complete phase I by April 2019, phase II by September 2020, and then proceed to phase III and commercialization.NIOWAVE aimed to produce 370 GBq (10 Ci) of 225 Ac annually.They stated that they had already secured sub-ten GBq (several hundred mCi) of 226 Ra devolved from sources obtained at nearby hospitals.Two huge chambers that were developed as an accumulation system were installed at the top of the hot lab stores for 222 Rn (T1/2 = 3.8 d) management.The chambers effectively reduced the 222 Rn burden to the environment by allowing physical decay in the chambers.
(Note: NIOWAVE's production capacity is currently scaled up to produce 370 GBq (10 Ci) of 225 Ac every week using Method ③ .In addition, they also started 225 Ac production via Method ① and aim to produce 225 Ac at 18,500 GBq (500 Ci) annually [38]).

The Situation in Canada
The Canadian Nuclear Lab (CNL) held a maximum of 400 g of high-purity 233 U in the form of UO2 ( 232 U <10 ppm; however, 20% was insoluble → regeneration required) formerly used in a thorium fuel cycle.It was said that a 229 Th/ 225 Ac generator that combined UTEVA resin and DGA resin was prepared using a thorium solution separated from uranium (AGMP resin).An automated milking system using a commercially available device (OMNI Lab) was under development, and it was said that the Th-GEx method could produce 225 Ac at a yield of 0.4-0.8MBq (10-20 µCi)/day from a load of 37 MBq (1 mCi) of 229 Th.Having four of these automated milking devices, they succeeded in labeling a monoclonal antibody targeting epidermal growth factor receptor (EGFR) with 225 Ac.However, the specific activity of 229 Th was low, which caused a breakthrough of thorium from the generator.As part of a national strategy for 225 Ac supply, the CNL was affiliated with TRIUMF, AECL/EACL, and Saskatchewan University.
TRIUMF (Canada) promoted Method ③ .They planned to use an eLINAC (superconducting RF accelerator technology, 30 MeV, 10 mA at maximum) at the Advanced Rare Isotope Laboratory (ARIEL, a government-funded facility in collaboration with 21 Canadian universities).As such, it was theoretically possible to produce up to 74 TBq (2000 Ci) of 225 Ac every month.Potential issues were high-level radiation exposure during 226 Ra handling (8.1 mSv/h at 1 m) and 222 Rn management.They had not considered applying for FDA approval at that time.They were also considering Method ①.
TRIUMF (Canada) has the world's largest cyclotron, which can provide 500 MeV protons at 110 µA at maximum.With the settings they were using (480 MeV proton, 85 µA × 31 h on 10 g Th), 0.44 GBq (12 mCi) of 225 Ac was successfully produced in 2017, and plans were in place to increase to 3.7 GBq (100 mCi) in a batch-yield using 500 MeV x 110 µA on a 100 g-Th-232 target.It was said that GMP approval would be obtained, but the quality control of 225 Ac, especially the removal of 227 Ac, was still an issue.
(Note: TRIUMF and Osaka University have been strengthening their cooperation in recent years, and an Osaka-University-based venture company, Alpha Fusion Inc., initiated the import of 225 Ac for preclinical use from TRIUMF [39].)

The Situation in Russia
At IPPE (Obrinsk, Russia), 225 Ac was produced by the Th-GEx method at about 15.5 GBq (0.4 Ci) per year, and all of that was shipped overseas at that time.The purity of the parent nuclide, 233 U, was 90.55% (9.45% contaminants, including 232 U = 26 ppm and Th = 0.24%), and 187 mg of 229 Th (approximately 1.55 GBq (40 mCi)) could be extracted from 1 kg of uranium (approximately 370 GBq (10 Ci)).The isotopic purity of 229 Th was only 6.81% ( 232 Th = 93.11%, 230Th = 0.08%, and 228 Th = trace level), but the quality of the obtained 225 Ac was excellent ( 229 Th < 0.007, 228 Th < 0.007, 224 Ra < 0.02, 225 Ra < 0.02, and other nuclides < 0.02, as percentages of 225 Ac radioactivity).In addition, a plan for increasing 229 Th inventory via the 229 Ac → 229 Th path combined with the 228 Ra(n,γ) 229 Ra → 229 Ac reaction was proposed.The 228 Ra target could be obtained from 232 Th (T1/2 = 1.4 × 10 10 y; it is estimated that 0.4 mg of 228 Ra is contained in 1 ton of natural 232 Th).They were also considering the production of 229 Th by irradiating natural 230 Th (20 g of 230 Th in 1 ton of 238 U) with fast neutrons, and this production method was patented in Russia.There was also a presentation from the Institute of Nuclear Research (INR).
(Note: As mentioned above, the supply from Russia, which was equivalent to about one-third of the world production capacity at that time, was stopped due to the invasion of Ukraine in 2022.The influence of that change to the supply is not be small for future TRT and TAT development around the world.)

Possibilities of Method ②, Transmutation by Protons Targeted at 226 Ra
The JRC has been promoting low-or mid-energy proton irradiation of a 226 Ra target for 20 years and already obtained patents in Europe in 1996 and in the United States in 2001.This method has the advantages of high yield and high radionuclidic purity, as validated by the JRC and the Munich group, as well as the fact that the reaction can be performed with protons of energies of 20 MeV or less on a moderate accelerator platform.As a result, this method has already been validated at many facilities around the world.Possible disadvantages are the limited supply and handling of 226 Ra, targeting preparation (solid and liquid), optimizing the energy window, and management of 222 Rn (T1/2 = 3.8 d).Further technical improvements, cost, waste, cGMP, quality assurance, and so on still needed to be considered.
The mining, purification, and commercial distribution of 226 Ra had already stopped by the 1960s, but the amount in storage around the globe was estimated to be several kilograms.Considering the possibility of collecting 226 Ra as a co-extracted product in uranium mining, it was thought that 257 mg of 226 Ra could be recovered from 1 ton of uranium-containing ore, suggesting that the annual productivity for fresh 226 Ra could reach 12.85 kg.

Our Impression as a Participant from a Country Lacking Natural Resources for Medical Applications
The United States and the European Union are moving to build a supply system for 225 Ac as a national policy, and the raw materials (i.e., 229 Th and 226 Ra) are abundant.Their levels of political strategy, as well as the speed of decision making and the performance capability in R and D, are several orders of magnitude superior to our country.
Japanese nuclear medicine is already behind the world, and the number of clinical procedures with 68 Ga-or 177 Lu-labelled compounds and therapeutic agents is critically poor.This situation is the same for 225 Ac, and urgent action is needed to reinforce domestic production, establish secure import routes, promote drug development, and regulate for clinical application to catch up with other countries.In particular, we have to realize that securing 226 Ra as a "medical resource" is an urgent task.

Full-Scale Production and Development of 225 Ac at QST
Two of the authors, (Higashi and Nagatsu), visited the JRC in Germany prior to participating in the IAEA international workshop held in Vienna.The tour of the JRC facility was conducted under the guidance of Prof. Alfred Morgenstern, who directed the research and wrote the 2005 paper on the Method ② 226 Ra(p,2n) 225 Ac reaction [20].We had several problems that had to be overcome in our own development at that time, but this site visit gave us many valuable hints for solving the problems, which eventually led to the success of our subsequent research and development.We would like to thank Prof. Caciuffo and Prof. Morgenstern for allowing us to visit the JRC.
The "CiCLE" project funded by AMED in 2018 has progressed steadily [24].The QST is proceeding with full-scale research and development with a radiopharmaceutical company representing Japan, NMP.The production of 225 Ac using the 226 Ra(p,2n) 225 Ac channel was eventually put into practical use [40].In the four years since 2018, the QST has proceeded with many developments (described below) and has applied for international patents for a number of related elemental technologies, (i.e., a target station design that enables high-intensity irradiation, an isolation and recovery method for 226 Ra, and a separation and purification method for 225 Ac).We believe that the QST and NMP have established a clinically adaptable practical technique for 225 Ac production.In addition, NMP established the accelerator facility of "CRADLE", which is capable of a clinical trial level of production of 225 Ac, in September 2019 in Sodegaura City, Chiba, as an achievement of the AMED/CiCLE project.The construction of this facility meant that a domestic clinical-trial-scale supply of 225 Ac-labelled radiopharmaceuticals became available in Japan [41].With these achievements, NMP was able to establish a commercial platform for the production of alpha-emitters to support TRT-and TAT-related industry, including clinical applications in Japan and overseas.We are proud to say that the Japanese are now ready for a new era of 225 Ac-based cancer treatment.

Current Status of 225 Ac Distribution and Related R and D in Japan
Four years have passed since the above-mentioned international workshop was held.Many 225 Ac-related studies have been reported at international conferences, suggesting that 225 Ac-labeled radiopharmaceuticals are steadily progressing toward clinical application worldwide.Table 1 shows the latest information we have about each institute working on the production of 225 Ac using an accelerator.Interestingly, two new production paths have been developed since 2018.As mentioned above, Method ① was listed in the FDA Drug Master File in 2020, as was the Th-GEx method in 2021 [32,33].As of 2022, TerraPower is aiming to build a supply network in partnership with the US Department of Energy (DOE) [37].
Table 2 summarizes the movements in each country in March 2022 regarding clinical trials with α-emitter-labeled radiopharmaceuticals.In 2020, phase I clinical trials for targeting advanced prostate cancer with 225 Ac-labeled PSMA-617 were initiated in South Africa and Australia [34].These trials seemed to be a stimulant for subsequent clinical trials with 225 Ac (e.g., 225 Ac-labeled antibody human kallikrein-2 (hK2) [42] and an 225 Aclabeled insulin-like growth factor-1 receptor (IGF-1R)-targeting humanized monoclonal antibody radiopharmaceutical called FPI-1175) [43].It can be said that the development of 225 Ac-labeled radiopharmaceuticals in each country is booming.It was mentioned earlier that a doctor-initiated, first-in-human, clinical study with 211 At-NaAt was started in Japan in 2021 for the treatment of intractable thyroid cancer at Osaka University [19].However, what is the status of 225 Ac-labeled drug research in Japan?
The QST, which has been a major driving force in domestic 225 Ac production research, is also a leading institute for 225 Ac-related biological studies.For example, using an antipodoplanin (PDPN) antibody developed by Prof. Yukinari Kato at Tohoku University, the QST started a TRT and TAT study for treating malignant mesothelioma with 90 Y-and 225 Ac-PDPN-antibodies aided by 111 In for diagnostics [44].Malignant mesothelioma, which is frequently found in developed countries, is an intractable malignant tumor that develops mainly in the pleura, and 10,000 new cases are reported annually.The relationship between exposure to asbestos and this disease has been known for many years.In Japan in 2005, there was an incident known as the "Kubota shock", which revealed the risk of asbestos in the neighborhood surrounding manufacturers of major industrial machinery and construction materials.In response to this, the Japanese government enacted the "Act on Relief of Health Damage Caused by Asbestos" in 2006 and is still taking measures against health damage [45].PDPN, a platelet aggregationinducing protein, is expressed in some normal tissues, but it is also expressed in many cancers, including malignant mesothelioma.Kato's group succeeded in developing an NZ series of antibodies that selectively recognized PDPN expressed in tumors.Further work eventually obtained NZ-16, which had the highest affinity and stability in vivo.We modified the NZ-16 antibody by labeling it with therapeutic nuclides to validate the efficacy and successfully obtained proof-of-concept (POC) results in a xenograft model [46].Based on this achievement, our project was funded by the AMED grants of "Translational Research Program-pre-B" and "Non-clinical study for practical application of innovative cancer therapeutic agents (pharmaceuticals)" [47].Since the protocol for these nonclinical trials has been finalized, including consultation on the regulatory science through an interview with PMDA, we are steadily preparing for clinical trials.
Another 225 Ac-labeled therapeutic agent, 225 Ac-labeled OTSA101, was developed.OTSA101 is a humanized antibody recognizing human FZD10, which is a transmembrane protein belonging to the frizzled family [48].It is overexpressed in most synovial sarcomas, indicating a promising therapeutic target for such sarcoma.A phase I trial of beta-emitting 90 Y-OTSA101 was conducted in France [49], and another phase I trial is recruiting in Japan (NCT04176016).Some of the enrolled patients showed a stable-disease response to therapy for recurrent sarcomas.To provide an additional option to such patients, we evaluated the efficacy of 225 Ac-OTSA101 in synovial sarcoma mouse models [50].The alpha-emitting radiopharmaceutical achieved a complete response in 60% of mice, and no recurrence was observed.Radioimmunotherapy with 225 Ac-OTSA101 is a promising therapeutic option for synovial sarcoma.
Based on the above-mentioned AMED/CiCLE research, NMP reported the efficacy of an 225 Ac-labeled humanized antibody for pancreatic cancer model mice with a targeting strategy of cancer-cell-related mucin MUC5AC and verified the tumor growth inhibitory effect [51].
In collaboration with Heidelberg University in Germany, Osaka University developed a fibroblast activation protein (FAP) derivative, 225 Ac-labelled FAPI-04, that is attracting worldwide attention.They are proceeding to verify the inhibitory effect in pancreatic cancer model mice [52].
What is the status of 225 Ac production research in Japan?Unfortunately, the biggest concern for Japan is still the prospect of securing raw 226 Ra. Figure 1 shows Japan's status with respect to 225 Ac supply from 2018 to 2021.At present, 225 Ac supply depends on imports from overseas, i.e., the National Isotope Development Center (NIDC) in the United States, Global Morpho Pharma (GMP) in France, and IPPE in Russia.The amount of imported 225 Ac has increased year by year, suggesting that basic TAT research is surely progressing in our country.Furthermore, as it has a tight relationship with TRIUMF, Osaka University established a venture company, Alpha Fusion Inc., that launched a research project named Quantum beam Applications for Safe and Smart society (QASS).QASS has a couple of social missions, one of which is to develop novel TAT agents with cyclotron technology.QASS collaborated with the Japan Radioisotope Association (JRIA) to import 225 Ac from TRIUMF as one of their initial activities [39].Regarding domestic research into 225 Ac production by the QST and NMP, it can be said that Japan has taken several large steps [40,41].In addition, NMP succeeded in producing the world's first GBq amount of 225 Ac using the transmutation method in April 2022 [53].Unfortunately, the QST had a fire accident at its accelerator vault in November 2021.Two cyclotrons were critically damaged.It is expected that recovery will take a considerable time [54].Consequently, in-house production of 225 Ac at our laboratory has been impossible since then, and related biological studies have also suffered significantly after this accident.The recovery or replacement of our main research equipment is highly desired.
In October 2019, Hitachi Co. Ltd., Tohoku University, and Kyoto University jointly issued a press release about their successful test production of 225 Ac with Method ③ [55].Another group from the University of Tokyo, the QST, and Tohoku University also employed this reaction channel.Due to the small amount of target material and the low intensity of the electrons, the actual yield of 225 Ac from this method is currently insufficient.In summary, the diversification of domestic 225 Ac production capacity is good news for Japan, but the fact that all 225 Ac production platforms need 226 Ra as the target indicates that securing a good supply of 226 Ra is a very important issue for Japan.

Atomic Energy Commission "Special Subcommittee for Securing Medical Radioisotope Production and Utilization"
In November 2021, the Atomic Energy Commission under the jurisdiction of the Cabinet Office established a special subcommittee, "Medical Radioisotope Production and Utilization," with the aim of achieving full-scale domestic self-sufficiency and establishing economic security for medically important radioisotopes [56].This action was based on the statement that "the government will work towards radioisotope production by means of research reactors or other technology", which is contained in the Growth Strategy Follow-up (decided by the Cabinet on 18 June 2021) issued by the Prime Minister and the Minister of Education, Culture, Sports, Science, and Technology (MEXT) [57].Thus, the subcommittee is deliberating on an action plan for the secure production and utilization of medical radioisotopes, including related policy decisions, with observers from related ministries, such as the Cabinet Office, MEXT, the Ministry of Health, Labor, and Welfare (MHLW), the Ministry of Economy, Trade, and Industry (METI), the Nuclear Regulation Authority (NRA), and the Reconstruction Agency.An action plan is expected to be issued in 2022, and it is hoped that it will have a positive impact on our nuclear medicine and atomic energy society.
As a member of this committee, the QST has pointed out that Japan's slow progress in the field of nuclear medicine, as evidenced by the inability to use PET nuclide 68 Ga and therapeutic nuclide 177 Lu, could be caused by the "vertically divided administration" model of the government.We have requested the establishment of a supervisory ministry similar to the US DOE that can provide strategic management for the development and effective utilization of energy and medical resources.It has already been 4 years since we learned about the national policies and strategies of many countries with respect to the R and D for 225 Ac and TAT at the international workshop.We have finally established a cross-ministerial subcommittee for the R and D of radioisotopes in Japan.Considering the foresight involved in the US DOE's swift and appropriate response, as well as similar actions found in other countries, our action seems quite late.However, it is expected that a socially effective action plan will be issued from the subcommittee to enable us to catch up with world progress.The QST made the following two recommendations to the subcommittee as our contribution: Recommendation 1: Realizing that Japan is a "country lacking natural resources for medical applications", the government should promote the establishment of an 225 Ac supply system as a national policy and also secure important raw materials, such as 226 Ra and thorium.
Recommendation 2: Remove the "vertically divided administration" model and build a system centered on the Cabinet Office that can strategically develop and utilize energy resources effectively, including medical resources, and formulate policies related to radioisotopes.
In response to requests from many societies, including cancer patient groups and radiation-related organizations, one of the major goals of the subcommittee is to promote the domestic production of radioisotopes using research reactors, such as the "Joyo" facility in Ibaraki [58].If the mass production of radioisotopes in a research test reactor becomes possible in the future, it will be a big step forward for the development of 225 Ac in Japan.The core research on reactor-based 225 Ac production is advocated by Tokyo City University [59].This research has already been adopted in the "National Issue-Based R&D Promotion Project (Nuclear System R&D Project)" in 2020 in collaboration with the Japan Atomic Energy Agency (JAEA), NucMed Inc., Mitsubishi Heavy Industries, Ltd., and Kanazawa University [60].The primal step in this R and D project is to restart the currently suspended test reactor "Joyo" and, after that, begin irradiating 226 Ra or 230 Th to produce 225 Ac at test and larger scales [59].From the perspective of securing the important raw material of 226 Ra, the JAEA may be able to contribute by utilizing the former uranium mine at Ningyo-toge Pass.
The solutions listed above are receiving a lot of attention from cancer patient groups, the Society of Nuclear Medicine, and related political and business circles in Japan.We sincerely hope that these actions will stimulate the development of TRT and TAT so that it will be available to cancer patients.

Closing Remarks
Japan is the only country that has been exposed to public radiation multiple times (Hiroshima, Nagasaki, and Fukushima), and many citizens have a vague fear and dislike of radiation.When the 223 Ra radiopharmaceutical Xofigo ® was introduced to Japan in 2016, a lawmaker who was concerned about its safety repeatedly asked the Diet to suspend the introduction.After the 2011 Fukushima Daiichi nuclear accident, the operation of all nuclear reactors in Japan was suspended.In the unlikely event of a nuclear-reactor-related accident or the risk of ultimate attack in connection with the invasion of Ukraine, it may be difficult to restart the fast test reactor "Joyo".While novel, alpha-emitting, 225 Aclabelled radiopharmaceuticals are expected to have a strong therapeutic effects, the risk of fatal side effects is not zero, and the treatment of medical radioactive waste has not been resolved.We researchers and medical professionals also need to be aware of the clinical introduction of 225 Ac and TRT and TAT so that we can help gain the understanding of citizens who are anxious about radiation.The 225 Ac production technology we have developed can be thought of as a method that converts and regenerates the "social poison" of 226 Ra waste into a highly valuable "drug", and from that point of view, we believe that public acceptance is more than possible.
At the QST, the large cyclotron AVF-930 and the smaller medical cyclotron HM-18 were damaged in a fire accident so that the routine production of 225 Ac and a scaling-up study were interrupted.On the other hand, preclinical research using a 225 Ac-labeled anti-PDPN antibody was approved by the AMED Innovative Cancer Research Project in 2022, and preparations are being made for clinical trials.Even if we cannot perform in-house production of 225 Ac on our own, we must proceed with research on 225 Ac-labeled radiopharmaceuticals.We have no time to mourn the misfortune of the accident.We must continue to work positively to deliver TRT and TAT with 225 Ac-labeled radiopharmaceuticals to cancer patients.We would like to thank all the members.We express our gratitude to Jeff Kershaw for proofreading and editing the manuscript.

Figure 1 .
Figure 1. 225Ac production, R and D, import, and distribution status in Japan.

Author
Contributions: Conceptualization, T.H., K.N.; validation, T.H., K.N.A.B.T. and M.-R.Z.; investigation, K.N., A.B.T.; data curation, K.N., A.B.T.; writing-original draft preparation, T.H.; writing-review and editing, T.H., K.N.; supervision, T.H., M.-R.Z.; project administration, T.H., M.-R.Z.; funding acquisition, T.H., M.-R.Z.All authors have read and agreed to the published version of the manuscript.Funding: This research was funded by "Cyclic Innovation for Clinical Empowerment (CiCLE)" project of the Japanese Agency for Medical Research and Development (AMED) with the task number JP17pc0101014.This research was also funded by AMED task numbers 21ym0126002h0001 and 22ck0106730h0001.Institutional Review Board Statement: Not applicable.Informed Consent Statement: Not applicable.Data Availability Statement: Not applicable.Acknowledgments: Most of the achievements in R and D for 225 Ac production in this paper were the results of collaborative work between Nihon Medi-Physics and the QST through an AMED CiCLE research fund.The research contents of this paper from the QST are the results of the Fusion Promotion Research (TRT) group in Chiba and Takasaki.The content of MABG research in this paper was the result of a collaborative study with the MABG research and development group of Fukushima Prefectural Medical University and the QST.The antipodoplanin antibody research was the result of joint research with Professor Yukinari Kato at Tohoku University and CRIETO of the Clinical Research Promotion Center at Tohoku University Hospital.

Table 1 .
Summary of projects investigating alternative 225 Ac production using accelerators.