Cyclotron Production of 225Ac from an electroplated 226Ra Target

doi:10.21203/rs.3.rs-276600/v1

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Research Article

Cyclotron Production of 225Ac from an electroplated 226Ra Target

https://doi.org/10.21203/rs.3.rs-276600/v1

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Journal Publication

published 01 Jul, 2021

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Purpose

We demonstrate a cyclotron production of high-quality ²²⁵Ac using an electroplated ²²⁶Ra target.

Methods

All ²²⁶Ra used in this work was extracted from legacy Ra sources using a chelating resin. The subsequent ion-exchange purification gave pure ²²⁶Ra with a certain amount of carrier Ba. The radium target was prepared by electroplating. We successfully deposited about 1 mg (mCi) of ²²⁶Ra on a target box. Activation was performed by 16.5 MeV protons (on the target) at 20 µA for 5 h as the maximum. Purification of ²²⁵Ac as well as ²²⁶Ra recovery was performed using two functional resins with various concentrations of nitric acid. Cooling of the intermediate ²²⁵Ac for 2–3 weeks decayed the major byproduct of ²²⁶Ac and increased the radionuclidic purity of ²²⁵Ac. Then the same separation protocol was repeated to provide high-quality ²²⁵Ac.

Results

We obtained ²²⁵Ac at a yield of about 2.4 MBq (65 µCi) at EOB, and the subsequent primal purification gave 1.7 MBq (48 µCi) of ²²⁵Ac with ²²⁶Ac/²²⁵Ac ratio of < 4% at 4 d from EOB. Additional cooling time coupled with the repeated separation procedure (secondary purification) effectively increased the ²²⁵Ac (4n + 1 series) radionuclidic purity up to 99+%, which showed a similar identification to a commercially available ²²⁵Ac originating from a ²²⁹Th/²²⁵Ac generator.

Conclusion

The ²²⁶Ra(p,2n)²²⁵Ac reaction and the appropriate purification procedure has the potential to be a major alternative pathway for ²²⁵Ac production and can be performed in any facility with a compact cyclotron to address the increasing demand for ²²⁵Ac.

Nuclear Medicine & Medical Imaging

Nuclear Chemistry

Actinium-225

Radium-226

Alpha emitter

Targeted alpha therapy

Targeted alpha therapy (TAT), a therapeutic regimen by radiopharmaceuticals labeled with alpha emitters, has received great interest due to the clinical impact such as ²²³RaCl₂ and ²²⁵Ac-PSMA-617 [1, 2]. Compared to conventional targeted radionuclide therapy by beta emitters, a high linear energy transfer (LET) in a short range (40–100 µm / 5–9 MeV, [3]) is a favorable property of alpha particles, which may provide a remarkable cytotoxic effect in a limited area of the target. Hence, unwanted radiation doses to other healthy tissues and organs may be limited.

The accessibility of various radioisotopes for diagnostic nuclear medicine is well established. Short-lived ones are produced by an in-house accelerator, while those with longer half-lives are commercially distributed at nearly on demand. On the other hand, a shortage of ²²⁵Ac is expected [4], because accessibility of ²²⁵Ac is limited and large-scale commercial production is in the development phase, but interest has drastically risen. Many reports on the ²²⁵Ac production describe that the most realistic current practice in the supply of ²²⁵Ac is relying on the natural decay product by ²²⁹Th/²²⁵Ac generator system [5, 6] stocked in few institutes, i.e., Joint Research Centre (JRC, Karlsruhe, Germany), Oak Ridge National Laboratory (ORNL, TN, USA), and Institute of Physics and Power Engineering (IPPE, Kaluga Oblast, Russia); and their annual capacity of total ²²⁵Ac supply is estimated to be approximately 63 GBq (1.7 Ci) [7]. Consequently, artificial production pathways of ²²⁵Ac are highly desired.

Many studies on the artificial ²²⁵Ac production have demonstrated or planned with high potential to address the increasing demand. Practical options include (1) high-energy protons on ²³²Th (spallation channel, [8]), (2) moderate energy protons on ²²⁶Ra (nuclear transmutation channel, [9]), and (3) high-intensity gammas on ²²⁶Ra (photonuclear/ Bremsstrahlung channel, [10–12]). Among them, option (1) holds promise because ²³²Th is not a fissile material with regard to nuclear regulations, but the reaction requires a projectile with extraordinarily high energy and intensity (e.g., 100 MeV or higher proton) to perform this spallation channel efficiently. Consequently, very few facilities can practically produce ²²⁵Ac via this route. On the other hand, options (2) and (3) use ²²⁶Ra as their target material. While nasty issues (i.e., radon (²²²Rn) emanation and high-energy gamma emission from the descendants) make handling this material difficult, option (2) can be advantageous when planning ²²⁵Ac production in general facilities. For instance, as reported in [9], the reaction of ²²⁶Ra(p,2n)²²⁵Ac can be performed efficiently with relatively low amount of ²²⁶Ra in a low-energy window, which can be provided by medical compact cyclotrons, Ep ≤ 20 MeV. In this study, we evaluate the production feasibility of ²²⁵Ac from a ²²⁶Ra target that includes (1) ²²⁶Ra recovery from legacy needles, (2) radium target preparation, (3) activation, (4) separation chemistry, and (5) recycling of ²²⁶Ra. This report should be beneficial when considering the production capability as well as quality control for further large-scale ²²⁵Ac production.

Materials

Hydrochloric acid (ultra-pure, 10 M) was purchased from Kanto Chemical Corporation (Tokyo, Japan). Ammonium acetate solution (10 M) was obtained from Nacalai Tesque (Kyoto, Japan). Ammonium solution (25%), nitric acid (70%), pure water, Dowex Monosphere 550A anion exchange resin (OH form, 590 ± 50 µm), and Dowex AG1-X8 anion exchange resin (Cl form, 100–200 mesh) were obtained from FUJIFILM Wako Chemicals (Tokyo, Japan). These reagents were used as received or diluted with the appropriate volume of pure water, as needed. Chelex-100 (Na form, 100–200 mesh) was purchased from Bio-Rad Laboratories (Tokyo, Japan). It was preconditioned as the ammonium form before use. Actinium-225 nitrate (37 MBq, 99.99% radionuclidic purity) was purchased from Oak Ridge National Laboratory and used as an authentic ²²⁵Ac source.

Methods

General

All the following procedures were performed in a ventilated glove box. Inside pressure of the glove box was set at negative 50 Pa, and no specific system for ²²²Rn handling was installed. A bag-in/out protocol with polyethylene bag (thickness 100 µm) was employed when transferring samples across the glove box to avoid releasing ²²²Rn and other possible radioactive materials into laboratory [Online Resource 1–3]. The maximum daily permission for handling ²²⁶Ra in our laboratory is 148 MBq (4 mCi).

Ra recovery from legacy needles

Radium needles (∅1.6 × 25 mm; 1–2 mCi-²²⁶Ra/needle) were sectioned into 5–6 pieces by an ordinal tube cutter (nipper type, for 1/16” stainless tubes). The pieces, which were collected in a 50-mL glass bottle with a polypropylene screw cap (Duran Wheaton Kimble, Germany), were mixed with 3 mL of a Chelex-100 resin slurry and 7 mL of pure water. The tightly capped bottle was sonicated daily for a period of one week to one month. Additional processes were not conducted.

Afterward, the Chelex-100 resin was filtered from those mixed materials by an empty cartridge (Bond Elut, 5 mL, Agilent Technologies, CA, USA), where the extracted ²²⁶Ra had been adsorbed on the resin. Then 1 M HCl (5 mL) and subsequent pure water (10 mL) for rinsing were loaded into the cartridge to elute ²²⁶Ra from Chelex-100. The eluant was loaded into an anion exchange resin (16 mL, Monosphere) to remove chlorides. Then the resin was washed with 10 mL pure water. The recovered solution was evaporated at 130°C under a vacuum, yielding dried ²²⁶Ra in the hydroxide form.

If the activity of the mixture of needle pieces and Chelex-100 residue was above a certain threshold, the mixture was returned to the bottle. To ensure the Chelex-100 function for adsorbing ²²⁶Ra effectively, a portion of conc. ammonium solution was added to adjust the pH of the slurry ≥ 10, and the same procedure was carried out repeatedly.

Target box design and target preparation

The ²²⁶Ra target is prepared by electrodeposition. Figure 1 shows the target box assembly. A Ti cylindrical cavity (#3 in Fig. 1) with a volume of about 3.5 mL was used for the reservoir for electroplating and the dissolving vessel for the Ra target after activation. A Pt rod (∅3 mm, anode for electroplating) was held by a polyimide-made screw with O-rings (#7). The bottom of the Ag cavity (#5) was assembled with both #3 and a polyimide electric insulator (#4). It should be noted that the Ra-depositing surface with a conical shape (#5) was fabricated with Au by hot isostatic pressing on the Ag body to ensure chemical resistance.

Purified dried ²²⁶Ra, which ranged from 400 to 1050 µCi (or µg on the weight scale), was dissolved in 1 mL of 0.1 M HCl and 2 mL of 0.5 M ammonium acetate to prepare the electrolyte. The electrolyte was placed in the target box, and a constant current of 100 mA DC was applied in the pulse mode (5 Hz, on in 0.1 s and off in 0.1 s) for 3 h with a 15-mm gap between the cathode and the anode. After the electrodeposition process, the electrolyte was removed from the cavity by pipette work, and introduced in and removed from 2 mL of pure water twice to wash out the residual electrolyte. These solutions, which may contain undeposited free ²²⁶Ra, were collected. Then the deposition efficiency was evaluated by measuring the ²²⁶Ra activity. The cavity stood undisturbed overnight (> 15 h) to dry the Ra surface naturally in a ventilated glove box. Eventually, the Pt anode was withdrawn from the cavity and sealed with a thin Nb foil (50 µm). The cavity at the beam entrance was sealed with a 50-µm-thick Nb foil (#2 in Fig. 1) with #1.

Activation

Activations were carried out by 34 MeV H₂⁺ (ionized molecular hydrogen) provided by NIRS-AVF-930 cyclotron at a nominal intensity of 10 µA for 3–5 h. This condition increased the intensity of lower energy particles accelerated by a relatively larger cyclotron to give 17 MeV protons at nearly 20 µA by splitting of the kinetic H₂⁺ ion at the vacuum isolation window. The estimated proton energy on the target material was 15.6 MeV by passing through the vacuum foil (Al, 100 µm), the He cooling layer (30 mm), and the target foil (Nb, 50 µm).

To enrich the expected ²²⁵Ac yield as much as possible, the proton energy was set slightly higher than the energy for the estimated highest cross-section of the ²²⁶Ra(p,2n)²²⁵Ac [9]. In the case where Ra increases, this activation condition is applicable directly, and a minimal difference is expected in the yield and radionuclidic purity of ²²⁵Ac.

Separation of ²²⁵Ac from the target matrix

Figure 2 shows our newly developed separation procedure, which was implemented 3–4 days after the end of bombardment (EOB). The eluent concentration was determined to be a thinner condition that does not affect the separation performance, considering ease of handling, reduction of corrosion risk to the equipment (automation to be performed in our future study), and to carry out the purification process repeated twice by the same procedure. The activated target was dissolved in 3 mL of 0.7 M HNO₃, and the solution was loaded slowly into a DGA cartridge (N,N,N’,N’-tetra-n-octyldiglycolamide, 1 mL, Eichrom Technologies, IL, USA). To increase the recovery of leftover of Ac/Ra, another 3 mL of 0.7 M HNO₃ was introduced into the target cavity twice and the respective rinsing fractions were also loaded into the same DGA cartridge.

The DGA cartridge was washed with 20 mL of 0.7 M HNO₃ to remove residual ²²⁶Ra. Then 5 mM HNO₃ (10 mL) was loaded into the DGA to elute ²²⁵Ac, which is the fraction collected in an intermediate reservoir. Subsequently, the crude ²²⁵Ac fraction was loaded into a LN cartridge (di(2-ethylhexyl)orthophosphoric acid, 2 mL, Eichrom Technologies), the cartridge was washed with 10 mL of 50 mM HNO₃ to eliminate trace amounts of ²²⁶Ra, and then well purged. All the above waste fractions were collected as the Ra recovery fraction, which was recycled for the next use. Eventually, ²²⁵Ac was stripped by loading 0.7 M HNO₃ (10 mL) and collected into another intermediate reservoir.

The actinium-225 solution in this separation step contained by-produced ²²⁶Ac (β 83%, EC 17%, α 6×10^− 3%; T_1/2 = 29.4 h), which was unavoidably generated via the ²²⁶Ra(p,n)-channel in our activation condition. To increase the radionuclidic purity of ²²⁵Ac, the intermediate product was allowed to cool for 2–3 weeks, which is equivalent to 10 half-lives or more for ²²⁶Ac. After the cooling, the above separation protocol was repeated as the secondary purification.

Although the twice purified ²²⁵Ac was free from or had negligible ²²⁶Ac contamination in 0.7 M HNO₃ (10 mL), it was too acidic for further use. Thus, an anion exchange resin (AG1-X8, 100–200 mesh, Cl form) was employed to exchange the counter anion of ²²⁵Ac with chloride and remove HCl from the product by evaporation of the above sample (130°C under vacuum). The final product, which was in a chemical form of ²²⁵AcCl₃, was reconstituted in a buffer and volume for further use.

Recycle mode for Ra

All fractions possibly containing ²²⁶Ra were collected into a single vessel. The solution was adjusted to a pH ≥ 10 by adding conc. ammonium solution and then loaded into a column filled with the Chelex-100 resin (0.5 mL, NH₄ form) to concentrate ²²⁶Ra. After washing the column with 10 mL of pure water, ²²⁶Ra was stripped by passing 1 M HCl (5 mL), and the eluant was led to an anion exchange resin column directly (16 mL, Monosphere, OH form). The Ra fraction was desalted by the anion exchanger, and an additional 10 mL of pure water was loaded to wash out the residual ²²⁶Ra. The collected ²²⁶Ra with a volume of about 15 mL was subsequently evaporated at 130°C under a vacuum to yield purified ²²⁶Ra in the hydroxide form, which was ready for the next use as the electrolyte.

Ra liberation from legacy needles

In most cases, the ²²⁶Ra prepared in the radium needle had a form of RaSO₄. Despite being an ionic compound, which is typically very soluble, Group II sulfates, including RaSO₄, are practically insoluble in water. Actually, our samples showed a nearly zero recovery of free ²²⁶Ra²⁺ when the Ra matrix was suspended in water or 1 M HCl, providing additional evidence that Ra is in the sulfate. However, when Chelex-100 was allowed to sit long term, a remarkable recovery occurred as trace amounts of Ra²⁺ were gradually liberated from the sulfate as the chelation sites tightly held Ra²⁺. Sonication seemed to effectively pulverize or rake out a solid Ra matrix that stayed in a small cavity. Both of these situations increased the contact chance of the Ra matrix to the Chelex-100 resin. The recovery rate of ²²⁶Ra was 30–50% for a week, but quantitative after a month.

Electrodeposition and Activation of ²²⁶Ra

The deposition rate of ²²⁶Ra was satisfactory. It ranged from 94 to 97%, as evaluated by the balance of the ²²⁶Ra activity between the initial and the post-deposition electrolyte (Table 1). The deposited ²²⁶Ra layer, which contained some amount of carrier Ba, was practically insoluble upon washing after the deposition process. The washing fractions of pure water showed a very small activity of ²²⁶Ra (1–2% of the initial value).

Since we handled ²²⁶Ra in a small amount of 400–1000 µg (µCi), the conical design of the cathode effectively enriched the Ra layer at the center of the target (Fig. 3(a)). The gap between the top of the cathode cone and the Pt anode was the shortest distance for efficient growth of the Ra layer at the center of the cone. Because the beam was generally focused at the center of the target, thick areas of the projectile and the target were expected to match and contribute to efficient activation.

A magnified image of the cathode surface showed that many precipitants were grown, spreading in random spots (Fig. 3(b)). The uneven Ra-deposition was mainly attributed to the small amount of ²²⁶Ra. An uneven target would decrease the ²²⁵Ac yield compared to an ideal surface with the same amount (activity) of ²²⁶Ra because incoming projectiles trajected at a thin area of ²²⁶Ra do not contribute to activating the target. Hence, we evaluated the deposition covering rate by a digital imaging processor (ImageJ, NIH, MD, USA [13]) to estimate a practical cross-section and our activation efficiency. Briefly, a magnified image of the target surface was acquired after electrodeposition, and the raw image was converted to an eight-bit monochrome, where white is the Ra deposition and black is the background (Fig. 3(c)). Then the coverage rate was calculated. Several parameters were set automatically to the determined default values. For run #2, which had a sample with a target of ~ 1000 µCi-²²⁶Ra, the estimated coverage ratio was 64%. Hence, an ²²⁵Ac yield of approximately 1/3 that of the theoretical value would be acceptable in the confirmed range up to 1-mg Ra. Increasing ²²⁶Ra should alter the coverage profile, which is a subject in our future scale-up production study.

Table 1 shows the production results (three runs). Our ²²⁶Ra target prepared on the cathode surface can be regarded as a thin target of 1.0–1.5 mg/cm². The estimated cross-section (σ) for the ²²⁶Ra(p,2n)²²⁵Ac was 353 mb at 15.6 MeV [Online Resource 4]. Previous studies showed much higher values of about 710 mb at 16.8 MeV [9], > 600 mb at 16.0 MeV calculated by ALICE code [9], and 522 mb at 16.0 MeV by TENDL-2019 [15]. However, only about 2/3 of our target’s surface was unevenly covered with ²²⁶Ra. Hence, the above σ can be multiplied by 1.56 (= 1/0.64), for example. Consequently, corrected values of 552 mb and 14 mb were obtained as the estimated cross-sections for the ²²⁶Ra(p,2n)²²⁵Ac and ²²⁶Ra(p,n)²²⁶Ac in our practical condition, respectively (cf. 34 mb for the (p,n)-channel at 16 MeV, [15]). Because the Ac separation efficiency, beam profile, or Ba/Ra ratio may introduce errors in the evaluation, quantitative corrections of such factors could not be applied in this study. Although these uncertainties were not included in the above estimation, the corrected cross-sections agreed well with the calculated values by both ALICE and TENDL codes as well as the practical value of the previous study.

Separation

The primal separation of the ²²⁵Ac sample contained ²²⁶Ac and other radionuclidic impurities [Fig. 4(a)]. Similar to ²²⁶Ra, ²²⁶Ac is a 4n + 2 series radionuclide, which generated many descendants during the cooling period. Hence, repeated separation as a secondary purification removed the 4n + 2 impurities to yield high-quality ²²⁵Ac. Regarding our activation condition, although ²²⁴Ac (EC 91%, α 9%, T_1/2 = 2.8 h) should be co-produced via the ²²⁶Ra(p,3n)-channel (E_TH = 13.6 MeV), the half-life of ²²⁴Ac was too short to be detected at the end of separation at 4 d from EOB. However, a couple of ²²⁴Ac descendants with favorable gamma emissions in the 4n series, ²¹²Bi (T_1/2 = 61 min, 727 keV, 6.7%) and ²⁰⁸Tl (T_1/2 = 3.1 min, 2615 keV, 99%), were the major distributions in both the washing fraction and leftover in separation materials. Moreover, trace amounts were detected in the purified ²²⁵Ac sample, providing evidence for the generation of ²²⁴Ac. The presence of ²¹²Bi and ²⁰⁸Tl in the ²²⁵Ac fraction was acceptable because Bi showed partial similarity to Ac in our separation conditions. On the other hand, ²¹²Pb (T_1/2 = 10.6 h, 239 keV, 44%), a parent nuclide for ²¹²Bi, was not detected in the purified ²²⁵Ac samples. All the 4n series-nuclides with the potential to be the parent for ²¹²Pb (²²⁴Ac–²¹⁶Po, except ²²⁴Ra) have shorter half-lives than ²¹²Pb, and ²²⁴Ra was removed along with ²²⁶Ra. Hence, only the 4n + 2 series can be considered as the byproducts to be focused on in the separation process.

Other notable by-products were ¹³⁵La (EC, T_1/2 = 19.5 h) and ¹⁴⁰La (β, T_1/2 = 1.68 d). The former presumably originated from a possible carrier of natural Ba in the legacy Ra needle via the ¹³⁵Ba(p,n)-channel. However, the half-life of ¹³⁵La is much shorter than that of ²²⁵Ac. Thus, an appropriate cooling time would gradually decrease the impact of ¹³⁵La on the ²²⁵Ac even though the legacy Ra was not chemically purified. On the other hand, since the heaviest stable isotope of Ba is ¹³⁸Ba, the atomic mass of ¹⁴⁰La seemed to be too rich to be generated by proton activation, suggesting that fission on ²²⁶Ra may occur in our activation condition. In addition, ¹⁴⁰Ba (β, T_1/2 = 12.6 d), a parent nuclide for ¹⁴⁰La, could also be generated as another fission product. Unfortunately, direct confirmation for the presence of ¹⁴⁰Ba was impossible in our sample, because most of characteristic gamma lines for ¹⁴⁰Ba were close to those of ²¹⁴Bi (RaC) and the chemical similarity between Ba and Ra, that always interfered to evaluate small amount of ¹⁴⁰Ba in large amounts of ²²⁶Ra with its descendants. However, the primal separation of the ²²⁵Ac fraction would practically eliminate ¹⁴⁰Ba along with ²²⁶Ra due to chemical similarity. Indeed, orphan ¹⁴⁰La found in the ²²⁵Ac fraction showed an acceptable half-life of 1.67 ± 0.10 d, and then decayed to a non-detectable level on the gamma spectrum by cooling for 2–3 weeks. This finding suggests that the carrier Ba in Ra needles is not critical for the quality of ²²⁵Ac, and no need for Ra purification from carrier Ba would be a practical advantage.

For example, we cooled the samples for 19–20 days after EOB or 2 weeks from the end of separation. The spectra of the cooled samples were similar to that for an authentic ²²⁵Ac originating from a ²²⁹Th/²²⁵Ac generator [Figs. 4(b) and 4(c)]. The alpha spectrum of our ²²⁵Ac product also showed the same profile as the reference (Fig. 5). Notably, neither ²²⁶Ra (Eα = 4.78 MeV, 94%) nor ²¹⁰Po (Eα = 5.30 MeV, 100%) was detected. Hence, the double separation with an appropriate cooling period gave pure ²²⁵Ac with a quality comparable to generator-made ²²⁵Ac.

Recovery of ²²⁶Ra for recycling

We developed a closed circuit for Ra recycling to minimize the loss of the ²²⁶Ra inventory (Figs. 2 and 6). This process effectively reduced long-lived radioactive wastes. After single-runs of this circuit, we evaluated the ²²⁶Ra leftover in each measurable material (i.e., the Ra recovery fraction), separation materials (cartridges), and reservoirs. The Ra recovery fraction contained 90–98% of ²²⁶Ra, and other materials were negligible (e.g., < 1–2 µg (µCi) when handled with a 1000-µg ²²⁶Ra batch). It should be noted that the Ra leftover depended on the volume of the residual liquid presented in the dead-space or on the surface. In addition, any deposition/leftover on the target box could not be estimated due to its high radioactivity. Consequently, about a 10% discrepancy in the activity distribution can be explained by this reason. Since the target box was used repeatedly, the practical loss of ²²⁶Ra would be negligible.

Radionuclidic purity – impact of ²²⁶Ac in ²²⁵Ac

²²⁶Ac disintegrates by the pathways of β decay (83%), EC (17%), and trace α decay (6×10^− 3), which breed ²²⁶Th (α, T_1/2 = 30.6 min), ²²⁶Ra, and ²²²Fr (β, T_1/2 = 14.2 min), respectively. Among these, the longest half-life of ²²⁶Ra would be the biggest concern when considering the preparation of ²²⁵Ac-labeled injections. According to an ICRP Publication [16], the human body contains an estimated 31 pg (1.13 Bq) of ²²⁶Ra, where 27 pg (0.99 Bq) is accumulated in the skeletal system (87%) and 2.3 pg (0.084 Bq)/day comes from dietary intake. Although any discussion on the radiation safety related to both ²²⁶Ac and ²²⁶Ra is beyond the scope of this study, we estimate the possible amount for ²²⁶Ra generation as a decay product of ²²⁶Ac that would be informative to discuss further clinical applications of ²²⁵Ac as well as to consider the appropriate cooling time to address the acceptable quality on the ²²⁵Ac product.

For simplicity, assuming a case where ²²⁶Ac is the sole impurity in a 10-MBq ²²⁵Ac product, a radionuclidic purity (RNP) of 68% (3.2-MBq (86-µCi) ²²⁶Ac in ²²⁵Ac) would finitely generate the same activity of ²²⁶Ra in the whole body or a RNP 97.6% product (0.24-MBq (6.4-µCi) ²²⁶Ac in ²²⁵Ac) would be equal to that from a dietary path. At the end of the primal separation (4 d from EOB), the activity ratio of ²²⁶Ac/²²⁵Ac in our samples ranged 1.4–2.3%, which is comparable to that in our dietary intake. As shown in Fig. 4(b), the secondary separation effectively increases the ²²⁵Ac RNP, which reached > 99% within 2–3 weeks.

In addition, it would be worthwhile to mention that ²²⁷Ac (β 98.6%, α 1.38%; T1/2 = 21.8 y), a major by-product in a spallation pathway from ²³²Th target, would be a good reference to consider long-life alpha-emitting by-products. In the radioactivity-based estimation at the time of injection, ²²⁷Ac is equivalent to 0.7% of ²²⁵Ac [17] that would generate ²²³Ra (T_1/2 = 11.4 d) through the alpha decay of ²²⁷Th (T_1/2 = 18.7 d). A calculation on T_max (time for reaching the maximum activity) for ²²⁷Th and ²²³Ra are 164 d and 189 d, respectively, and the activity of ²²³Ra would reach > 98% of the initial activity of ²²⁷Ac at T_max. On the other hand, since ²²⁶Ac has a shorter half-life than that of ²²⁷Ac, the estimated T_max for ²²⁶Ra is 23 d and at the T_max activity for ²²⁶Ra would be 3.6×10^− 5% of the initial activity of ²²⁶Ac. However, these Ra activities generated from respective parents would be overestimated because above estimation did not take any biological excretion or metabolic paths into account. ²²⁶Ra possibly generated from ²²⁶Ac inside the body is seemed to be much smaller than ²²³Ra from ²²⁷Ac, and the activity of ²²⁶Ra is a competitive magnitude to the naturally presented ²²⁶Ra in our body; suggesting that any radiation risks caused by ²²⁶Ac would be negligible or exceedingly small, if the RNP of ²²⁵Ac is within or close to the range of our results.

Because the physical decay loss of ²²⁵Ac during the cooling period is a critical issue for the ²²⁵Ac industry, we plan to evaluate the biological impact of ²²⁶Ac as a future feasibility study related to our ²²⁵Ac product.

We obtained ²²⁵Ac from an electrodeposited ²²⁶Ra target. The ²²⁵Ac purified with two separation columns showed an acceptable quality. The repeated separation process with appropriate cooling produced highly pure ²²⁵Ac and byproducts were not detected.

The characteristics of the purified ²²⁵Ac are similar to those of commercially available ²²⁵Ac originating from a generator system. Thus, the proposed production method has potential as an alternative pathway to address the increasing demand for ²²⁵Ac. The production results showed a linear increase of ²²⁵Ac yield by increasing ²²⁶Ra prepared, thus a clinical requirement of ²²⁵Ac yield can be achieved by increasing the amount of ²²⁶Ra, beam intensity, and irradiation period.

ACKNOWLEDGEMENTS

The authors are grateful to our cyclotron staff for providing excellent beams. We also express our gratitude to Mikio Matsumoto, Hidetake Ishizu, Shogo Akabori, Kasumi Arai, and Takuya Shiina for their technical support. We thank Steffen Happel (TrisKem International) and Atsushi B Tsuji for the fruitful discussion.

FUNDING

This work was supported by JSPS KAKENHI [Grant Numbers JP26461814 (K.N.), JP17K10384 (K.N.), and JP20K08096 (K.N.)] and by AMED [Grant Number JP17pc0101014 (T.H.)].

CONFLICTS OF INTERESTS

The authors have no potential conflicts of interest to report.

ETHICS APPROVAL

This is a radioisotope production study without any biological materials, and no ethical approval is required.

CONSENT TO PARTICIPATE

There is no participant in this study, and consent is not required.

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TABLE 1 Production results

Run	#1	#2	#3
Beam condition (Ep=15.6 MeV)	20 µA x 3 h	20 µA x 5 h	20 µA x 5 h
Ra-deposition
²²⁶Ra, initial electrolyte	14.5 MBq (391 µCi)	36.4 MBq (984 µCi)	38.8 MBq (1.05 mCi)
²²⁶Ra, deposited	13.5 MBq (366 µCi)	35.4 MBq (956 µCi)	37.5 MBq (1.01 mCi)
Deposition rate (%)	94	97	97
Nuclides of interest* in the primally purified sample (kBq, decay corrected to EOB)
²²⁵Ac (150 keV, 0.6%)	522	2.23 x10³	2.43 x10³
²²⁶Ac (230 keV, 26.9%)	111	451	488
²²⁶Ra (186 keV, 3.64%)	not detected	not detected	not detected
²¹⁴Pb (352 keV, 35.6%)	not detected	not detected	not detected
²¹⁴Bi (609 keV, 45.5%)	5.2	13.5	33.3
¹³⁵La (481 keV, 1.52%)	84.5	333	344
¹⁴⁰La (487 keV, 43.9%)	0.0571	0.165	0.231

* Nuclear data presented in parenthesis [14], were used for quantification.

Quantification was performed on a 4096-ch well calibrated HPGe, where the uncertainty and detection limit were 9% and 3.7 Bq (1.2×10^–3% of ²²⁵Ac in the most sensitive case), respectively.

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Cyclotron Production of 225Ac from an electroplated 226Ra Target

Status:

Journal Publication

Version 1

Abstract

Purpose

Methods

Results

Conclusion

Figures

Introduction

Materials And Methods

Materials

Methods

General

Ra recovery from legacy needles

Target box design and target preparation

Activation

Separation of ²²⁵Ac from the target matrix

Recycle mode for Ra

Results

Ra liberation from legacy needles

Electrodeposition and Activation of ²²⁶Ra

Separation

Recovery of ²²⁶Ra for recycling

Discussion

Radionuclidic purity – impact of ²²⁶Ac in ²²⁵Ac

Conclusion

Declarations

References

Tables

Supplementary Files

Status:

Journal Publication

Version 1

Cyclotron Production of 225Ac from an electroplated 226Ra Target

Status:

Journal Publication

Version 1

Abstract

Purpose

Methods

Results

Conclusion

Figures

Introduction

Materials And Methods

Materials

Methods

General

Ra recovery from legacy needles

Target box design and target preparation

Activation

Separation of 225Ac from the target matrix

Recycle mode for Ra

Results

Ra liberation from legacy needles

Electrodeposition and Activation of 226Ra

Separation

Recovery of 226Ra for recycling

Discussion

Radionuclidic purity – impact of 226Ac in 225Ac

Conclusion

Declarations

References

Tables

Supplementary Files

Status:

Journal Publication

Version 1

Separation of ²²⁵Ac from the target matrix

Electrodeposition and Activation of ²²⁶Ra

Recovery of ²²⁶Ra for recycling

Radionuclidic purity – impact of ²²⁶Ac in ²²⁵Ac