Cross section measurements of ¹⁵¹Eu(³He,5n) reaction: new opportunities for medical alpha emitter ¹⁴⁹Tb production

Abstract

Method for production of alpha emitter ¹⁴⁹Tb by irradiation of ¹⁵¹Eu with 70 MeV ³He nuclei is proposed. For the first time, the cross sections for the formation of isotopes ^{149,150,151,152}Tb were measured experimentally using a stack foil technique in the ³He particles energy range 70 → 12 MeV. The thick target yield of ¹⁴⁹Tb is 39 MBq/μAh, or 230 MBq/μA ¹⁴⁹Tb at saturation. The optimal energy range from the point of view of radioisotopic purity is 70 → 40 MeV. At these conditions about 150 MBq/μA ¹⁴⁹Tb can be produced in 8 hours irradiation, which is sufficient for therapeutic applications. The main impurities are ¹⁵⁰Tb (~100% in activity) and ¹⁵¹Tb (~30% in activity). The proposed method surpasses its counterparts by the high content of the target isotope in the natural mixture and the simplicity of the radiochemical separation of ¹⁴⁹Tb from the bulk target material.

Introduction

Targeted alpha-radiotherapy is considered one of the most promising ways for cancer treatment^1–3. Alpha particles have 2-3 orders of magnitude greater linear energy transfer (LET) than beta particles¹, therefore the application of alpha emitters allows to target small objects such as micrometastases and single cancer cells more effectively as compared to beta-emitting radionuclides used today. For this purpose, a number of radiopharmaceuticals are considered⁴, in which molecules with a small weight (²²⁵Ac-PSMA-617)⁵, peptides (²¹³Bi-DOTATOC)⁶, or antibodies (²¹³Bi-HuM195mAb)⁷ are used as a vector. However, the use of targeted alpha radiotherapy is limited primarily by the limited availability of suitable alpha emitters. Radionuclide ¹⁴⁹Tb is considered one of the few candidates for targeted alpha-radiotherapy⁸. It has a half-life of 4.12 hours and emits alpha particles with an energy of 3.97 MeV (17%). It also decays by electron capture (76%) and positron emission (7%) Unlike ²²⁵Ac, ¹⁴⁹Tb does not have daughter alpha emitters in the decay chain, which means that the recoil effect during radioactive decay should not lead to excessive dose burden. The methods for radiolabeling of biomolecules by using bifunctional chelators based on DOTA, DTPA and others have been well developed for rare earth elements (REE). This is a clear advantage of ¹⁴⁹Tb over ²¹¹At and ²²³Ra.

¹⁴⁹Tb is one of four medically relevant terbium isotopes⁸. The beta emitter ¹⁶¹Tb is considered therapeutic radionuclide that exceeds ¹⁷⁷Lu⁹ in its nuclear properties and ¹⁵²Tb can be used for PET. ¹⁵⁵Tb is suitable for molecular imaging and Auger therapy¹⁰. The availability of several isotopes with various nuclear properties allows using isotope pairs for theranostics thus enhancing the perspectives of the medical application of the isotopes of terbium. ¹⁴⁹Tb can also be considered a theranostic radionuclide. Its positron radiation allows visualizing the distribution of the radiopharmaceutical using PET¹¹. In vivo experiments¹² showed that ¹⁴⁹Tb-rituximab can effectively kill single lymphoma cells. The efficacy of ¹⁴⁹Tb-DOTA-folate conjugate against carcinoma has also been shown in animal studies¹³.

Various reactions have been proposed for the production of ¹⁴⁹Tb, in particular, under the action of protons¹⁴ and heavy ions^15–17 (Table 1); a review can be found in^18–20. However, the production of this radionuclide is associated with serious difficulties. In the preclinical studies mentioned above, ¹⁴⁹Tb was obtained in the spallation reaction by irradiating the tantalum target with a proton beam of 1.0–1.4 GeV energy and online mass-separation of isotopes in the ISOLDE (CERN) facility. As a result, 25 MBq of radionuclide had been obtained at the time of radiolabeling. It was proposed²¹ to obtain ¹⁴⁹Tb by irradiation of ¹⁵¹Eu targets with ³He nuclei and the thick target yields in the energy range 70 → 40 MeV were experimentally determined. Preliminary results showed that ¹⁴⁹Tb yields can be high enough to produce therapeutic amounts of a radionuclide. This work is a further study of ³He induced reactions on ¹⁵¹Eu and the first experimental measurement of their cross sections.

Table 1.

Main routes of ¹⁴⁹Tb production.

Reaction	Projectile energy, MeV	Yield, MBq/μAh	Reference
152Gd(p,4n)149Tb	70 → 30	2600	14
151Eu(3He,5n)149Tb	70 → 40	19.4 (for Eu2O3)	21
142Nd(12C,5n)149Dy → 149Tb	108	3.3	15
141Pr(12C,4n)149Tb	71.5	0.086	16
natTa(p,x)149Tb	1000–1400	~3000 (100 g/cm2 target)	20

Results

The radioactive isotopes of terbium and gadolinium are formed in the irradiation of a stack of thin (100 μg/cm²) ¹⁵¹Eu targets by ³He nuclei with incoming energy of 70 ± 1 MeV. ^{147, 148, 149, 150, 151}Tb and ^{147, 149}Gd were identified (Table 2) in gamma-ray spectra (Fig. 1a) of irradiated targets. The alpha activity of irradiated targets was due to ¹⁴⁹Tb (Fig. 1b) and to a small extent to ¹⁵¹Tb. It is not possible to see ¹⁵¹Tb peak due to low alpha decay branching (9.5∙10⁻³%), for more spectral data see Supplementary Information.

Table 2.

Activation products identified in irradiated targets.

Nuclide	Half life	Principal contributing reaction	Q-value MeV	Decay mode	Eγ, keV	Iγ, %
147Tb	1.7 h	151Eu(3He,7n)147Tb	−45.48	EC (100%)	694.4 keV	43.0
148Tb	60 m	151Eu(3He,6n)148Tb	−37.62	EC (100%)	784.4 keV	84.4
149Tb	4.118 h	151Eu(3He,5n)149Tb	−28.59	EC (83.3%) α (16.7%)	352.2 keV	29.43
150Tb	3.48 h	151Eu(3He,4n)150Tb	−20.90	EC (100%) α (<0.05%)	638.1 keV	72.0
151Tb	17.609 h	151Eu(3He,3n)151Tb	−12.31	EC (100%) α (0.0095%)	108.1 keV 251.9 keV 287.4 keV	24.3 26.3 28.3
152Tb	17.5 h	151Eu(3He,2n)152Tb	−5.15	EC (100%) α (<7E-7%)	344.3 keV	65.0
147Gd	38.06 h	151Eu(3He,p6n)147Gd 147Tb → 147Gd	−40.08	EC (100%)	229.3 keV	63.0
149Gd	9.28 d	151Eu(3He, p4n)149Gd 149Tb → 149Gd	−24.17	EC (100%) α (4.3E-4%)	149.7 keV	48.2

Figure 1.

Typical gamma-ray spectrum (a) and alpha particle spectrum (b) of ¹⁵¹Eu target on Ti support irradiated by ³He nuclei with incident energy ~50 MeV, measured at ~11 cm distance during 10 minutes 5 h after the end of bombardment (EOB) for (a) and measured at ~2 cm distance during 2 minutes 5 h after the EOB for (b).

The cross sections of nuclear reactions leading to the corresponding terbium isotopes were calculated based on the radioactivity measurements of the irradiated targets. The experimentally obtained excitation functions for the main nuclear reactions are presented in Fig. 2a. By integrating the excitation functions, the physical yields were calculated in the energy range E₀ → 0, where the incident beam energy E₀ varied from 70 to a minimum value of ~12 MeV (Fig. 2b).

Figure 2.

Measured excitation functions for ¹⁵¹Eu(³He,xn)^154-xTb reactions (a) and physical thick target yields for reactions ¹⁵¹Eu(³He,xn)^154-xTb (b), calculated using measured excitation functions.

Discussion

The physical yield of the ¹⁵¹Eu(³He,5n) ¹⁴⁹Tb reaction in the range 70 → 30 MeV was 38.7 ± 7.7 MBq/μAh, that allows one to produce up to 230 MBq/μA on a ¹⁵¹Eu metal target up on saturation. In previous work²¹, thick targets from pressed ¹⁵¹Eu oxide were irradiated. Our yields based on the experimentally cross sections (Fig. 2a) are in good agreement with obtained in²¹. The saturation yield was 125.0 ± 25.0 MBq/μA for the range 70 → 40 MeV for the target from Eu₂O₃²¹ and 161.7 ± 32.3 MBq/μA in this work, recalculated for the same target.

Besides terbium isotopes, peaks of ^147,149Gd were also detected in the gamma-ray spectra of irradiated targets. They can be formed both by direct reactions and as a result of the decay of ¹⁴⁷Tb and ¹⁴⁹Tb, respectively. The relative contribution of these processes to the work was not determined. The ¹⁴⁸Gd lines were not observed in the spectrum, apparently, due to the low specific activity of this radionuclide.

As follows from the excitation functions shown in Fig. 2a the proposed method does not allow to obtain a product free of radioisotope impurities ¹⁵⁰Tb and ¹⁵¹Tb. They reduce the specific activity of the product and thereby can affect the efficiency of labeling, as well as lead to an undesirable dose burden on the patient. However, both of these impurities have a relatively short half-life. It should also be noted that LET for alpha particles is two orders of magnitude higher than for electrons. Therefore, therapeutic doses of alpha emitters are usually significantly lower than those of the electron emitters. This means that impurity of 150 and 151 isotopes of the same radioactivity will cause a significantly lower damaging biological effect in targeted delivery.

In part, the problem of radioisotope impurities can be solved by selecting a suitable range of incident particle energies. The maximum production cross sections for ¹⁴⁹Tb are ~47 MeV, and for ¹⁵⁰Tb ~ 35 MeV, ¹⁵¹Tb ~ 23 MeV. By changing the lower limit of the energy of the incident particles, one can reduce the amount of impurities, but the yield of the target radionuclide also decreases (Fig. 3). It is proposed to use the range of 70 → 40 MeV as a reasonable compromise between the amount and the purity of the product. Moreover, the activity of the target product ¹⁴⁹Tb after eight hours will be 150 MBq/µA, which is only 10% less than the maximum possible. At the same time, the content of impurities reduces more than twice in comparison with the range 70 → 30 MeV.

Figure 3.

The yield of ¹⁴⁹Tb and radioisotopic impurities content calculated for 8 h irradiation of metal ¹⁵¹Eu target.

A possible route to obtain ¹⁴⁹Tb is to use the nuclear reaction ¹⁵²Gd(p,4n)¹⁴⁹Tb. Its cross section reaches a maximum value of ~250 millibarn at a proton energy of 42 MeV, which inherently provides an opportunity for obtaining of this radionuclide in sufficient quantities for medical use¹⁴. The yield of this reaction is two orders of magnitude higher than proposed in our work. However, the practical implementation of this path is associated with serious difficulties. The main disadvantage of the proton pathway is the low content of the ¹⁵²Gd target isotope in the natural mixture (0.20%) compared to ¹⁵¹Eu (47.8%). Unfortunately, the cross sections for the formation of terbium isotopes with mass numbers of 150 and 151 are not given¹⁴. Therefore, the question of the content of radioisotope impurities and the optimal range of beam energy remains unsolved. However, it is apparent that in this case, the formation of radioisotope impurities of ^150,151Tb is inevitable. Another competitive advantage of our method is the further radiochemical processing of the europium target. Europium is one of the few rare earth metals that can be reduced in aqueous solutions to an oxidation state of +2. This makes it possible to quickly and efficiently separate the target radionuclide from the bulk of the target material and traces of gadolinium, and such a technique has already been developed²².

Also, the possibility of using ¹²C^15,18 beams and other heavy ions²³ to produce ¹⁴⁹Tb, was repeatedly considered. In this case, both a direct way to obtain by the reaction ¹⁴¹Pr(¹²C,4n)¹⁴⁹Tb is possible, as well as an indirect one: ¹⁴²Nd(¹²C,5n)¹⁴⁹Dy → ¹⁴⁹Tb. The latter looks more promising. According to Zaitseva et al.¹⁵, this way can yield tens of GBq for irradiation at a beam current of 50-100 μA. Upon 1.25 hours irradiation of 12 mg/cm² thick natural neodymium target with a beam of ¹²C ions with an energy of 108 MeV and a particle current of 1 μA 2.6 MBq of ¹⁴⁹Tb were produced. However, no information concerning radioisotopic impurities is given. Irradiation of targets from praseodymium gives a significantly lower activity of ¹⁴⁹Tb¹⁶. The weak point of these methods is the lack of accelerators giving intense ¹²C ion beams.

Methods

Target preparation and irradiation

¹⁵¹Eu of 97.5 ± 0.1% of enrichment in oxide form was used. The material was provided by the National stable isotopes reserve. It contains 0.02% Nd, 0.02% Gd, <0.01% Sm impurities. ¹⁵¹Eu targets were prepared by electrodeposition from isopropanol solution on 2 μm thick titanium foil (Fig. 4). Enriched europium oxide powder was dissolved in 4 M nitric acid and evaporated near dryness, then triply evaporated with water, the residue was dissolved in a minimal volume of ethyl alcohol and diluted with isopropanol and placed in an electrolytic cell. Electrodeposition was carried out at a constant current density of 0.058 A/dm² for 2.5 hours at a voltage 100–250 V. The precipitated layer was heated on a hot plate to 400 °C. The thickness of ¹⁵¹Eu layer was ~100 μg/cm² that is thin enough to allow the measurement of ¹⁴⁹Tb alpha particles emitted from the target. The content of Eu on the target was controlled by X-ray fluorescence analysis. To excite X-ray fluorescence, a standard 120 MBq ¹⁰⁹Cd O-ring source was used. Characteristic x-ray radiation was recorded with Canberra semiconductor Si (Li) detector with an energy resolution of 145 eV for 6.4 keV Fe line. The spectra were analyzed using the WinAxil Canberra software. As a reference 149 μg/cm² europium sample with a diameter of 21 mm was used. It was prepared by evaporation of a standard solution of europium nitrate in isopropanol on a filter paper substrate. Thickness inhomogeneity was controlled using x-ray excitation in the target material through collimator moving along the target.

Figure 4.

¹⁵¹Eu target with a thickness of 100 μg/cm², electrodeposited on a 2 μm Ti support.

Up to 10 ¹⁵¹Eu/Ti target foils were irradiated in one run using the conventional stack foils technique. Apart from the target foils, the stack also contained 9 μm Al and 13 μm Cu monitors for controlling the beam parameters, and aluminum degraders (53–159 μm), so that the energy ³He on each subsequent target was 2–3 MeV less than on the previous one.

The assembled target was irradiated at the U-150 isochronous cyclotron of the National Research Center “Kurchatov Institute”. The initial energy of ³He particle beam was 70 ± 1 MeV in the first run and 45 ± 1 MeV in the second. The beam energy was determined by the cyclotron settings and additionally was controlled by the monitoring reactions on Al, Ti, and Cu (see Supplementary Information). The beam current averaged 1 μA irradiation time 1 h. The passed charge was determined by the activation of aluminum monitors, based on the IAEA recommended cross section for ²⁷Al(³He,x)²⁴Na reaction²⁴. If necessary, a correction was done in order to take into account the change in the current value during irradiation. In total, two irradiations were performed; the thicknesses of the degraders were selected so that the energy range of ³He particles overlaps in both experiments. In Fig. 2a shows the combined result of two irradiations.

Radioactivity measurements

The radioactivity of the activation products was measured by two methods: α-spectrometry and γ-spectrometry. Gamma-ray spectrometry was carried out on a spectrometer with a high purity germanium detector ORTEC GEM 35P4 Series, the energy resolution of 850 eV for 122 keV line and of 1.5 keV for 1.33 MeV. The measurement was carried out in two geometries at a distance of 11 cm and 6 cm so that the dead time did not exceed 6–7%. Efficiency calibration for the selected measurement conditions was carried out using certified reference point sources ¹³⁷Cs, ²⁴¹Am, ⁶⁰Co, ¹⁵²Eu with an activity of 10 to 100 kBq. Spectra were processed using Spectra Line 1.4.2792 software (LSRM Company, Russia).

Registration of alpha particles was chosen as the main method for the radioactivity measurements for ¹⁴⁹Tb since the efficiency of registration under the experimental conditions was approximately two orders of magnitude higher than that of gamma rays. Also, the main gamma line of ¹⁴⁹Tb can interfere with the natural background radiation line 351.9 keV (²¹⁴Pb). Alpha spectrometry was performed without radiochemical separation, registering α particles emitted from the irradiated target surface on an ORTEC Alpha Suite Alpha Duo instrument with ULTRA Ion Implanted Silicon Charged Particle Radiation Detector with an energy resolution of up to 20 keV. The detection efficiency of alpha particles was determined using certified reference sources of ²³⁹Pu and ²²⁶Ra.

Cross-sections calculations and uncertainty budget

The cross sections of nuclear reactions were calculated by activation equation²⁵. Nuclear data were used from IAEA database²⁶. Energy losses were calculated by SRIM 2008.04 code²⁷.

The overall experimental uncertainty was calculated as the square root of the sum of the squares of the individual relative uncertainties. The following uncertainty values of the individual components were taken: detector efficiency - 5–7%, photopeak areas uncertainty varied 1–10% depending on counting statistics, determination of Eu targets thickness and composition - 10%, and nuclear decay data 3%. The overall experimental cross sections uncertainties amounted to about 20%.

Calculating energy uncertainties, it was assumed that the initial beam energy varies within ± 1 MeV (an estimate based on the cyclotron settings). The uncertainty of the thickness of the degraders was estimated at 1 μm by multiple weighing, of copper and titanium foils at 0.1 μm. Based on these data, the possible limits of the energy loss of the beam along the path to each foil were calculated by SRIM 2008.04 code.

Conclusions

Thus, the use of the ¹⁵¹Eu(³He,5n)¹⁴⁹Tb reaction is an effective solution to the problems associated with the production of this very promising radionuclide. In our experiments, low-intensity beams were used, however, up to 20 µA values can be achieved at the Kurchatov Institute isochronous cyclotron U-150. This means that up to 3.0 GBq can be obtained in eight-hour irradiation, which is sufficient for clinical use. Although the therapeutic quantity has yet to be established for ¹⁴⁹Tb-based preparations, one can estimate from other alpha emitters. For example, for ²¹³Bi this value is 10–50 MBq/kg; for ²²⁵Ac - 20–150 kBq/kg. For ²²³Ra, the recommended dose is 55 kBq/kg. Dosages for ²¹²Pb (as [²¹²Pb]Pb-TCMC-trastuzumab) are 7.4–21.1 MBq/m², or about 200-500 kBq/kg²⁸. It can be assumed that the latter value is closest to therapeutic doses of ¹⁴⁹Tb. That is, for a single patient, an estimated 10–50 MBq.

The advantage of the method is the availability of target material and the relatively simple radiochemical processing of the irradiated europium. The main drawback is the very limited availability of high-intensity ³He beams worldwide.

This method, like other methods not related to electromagnetic mass separation, does not allow one to obtain ¹⁴⁹Tb free of impurities from short-lived neighboring radioisotopes. The possibility of clinical application of such a product has yet to be proven.

Author contributions

Conception, design of the work: A.A. Ogloblin, R.A. Aliev, V.A. Zagryadskiy, A.N. Moiseeva; Preparation of materials: N.V. Aksenov, N.S. Gustova, M.G. Voronuk, G.Ya. Starodub, V.N. Unezhev and S.T. Latushkin; Collected and analyzed data: A.N. Moiseeva, R.A. Aliev and V.A. Zagryadskiy; Wrote majority of the manuscript: A.N. Moiseeva and R.A. Aliev. Reviewed and edited the manuscript: all authors.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on request.

Competing interests

The authors declare no competing interests.

Supplementary information

is available for this paper at 10.1038/s41598-020-57436-6.