Evaluation of an internal cyclotron target for the production of 211At via the 209Bi (α,2n)211At reaction

doi:10.1016/0969-8043(95)00285-5

Applied Radiation and Isotopes

Volume 47, Issue 2, February 1996, Pages 135-143

https://doi.org/10.1016/0969-8043(95)00285-5 Get rights and content

Abstract

Astatine-211 is a 7.2 h half-life α-emitting radionuclide which has shown great promise for targeted radiotherapy. It is generally produced by cyclotron bombardment of bismuth metal targets with 28 MeV α-particles via the ²⁰⁹Bi(α,2n)²¹¹At reaction. In order to provide ²¹¹At activity levels anticipated for clinical investigations, an internal target system has been designed and evaluated. The system has a grazing-angle configuration and leading- and trailing-edge monitors. Both aluminum and copper target backings were evaluated. With approx. 28MeV α-particles, the ²¹¹At production efficiency was 41 ± 7 MBq/μA·h, compared with 10.6 ± 1.2 MBq/μA·h for an external target. Radionuclidic purity of ²¹¹At was high with no evidence of ²¹⁰At.

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Cited by (91)

Optimized cyclotron production of 211At: The challenge of 210Po-characterization
2023, Radiation Physics and Chemistry
The yield of ²¹¹At is currently limited by the restriction of the incident He²⁺-beam energy of the ²⁰⁹Bi(α,2n)²¹¹At reaction to ≈28 MeV avoiding the co-production of ²¹⁰At with its daughter ²¹⁰Po through ²⁰⁹Bi(α,3n)²¹⁰At. In parallel, ²¹⁰Po is directly produced as well through the ²⁰⁹Bi(α,x)²¹⁰Po reaction at a energies as low as 26.7 MeV. Cross-sectional data predict a significant increase of the ²¹¹At-yield at higher energies indicating that this approach warrants optimization. The strategy of using higher energies means that potential solutions to handle ²¹⁰Po during production, target processing and labelling, including the potential ²¹⁰Po-related toxicity in (pre-) clinical studies have to be studied. Here we present the results of the ²¹⁰Po quantification after a non-destructive target characterization.
Two 25 μm thick Bi targets were irradiated at the Scanditronix MC 32, Rigshospitalet Copenhagen at 28.8 MeV and 29.8 MeV. For both targets the theoretical yield of ²¹¹At, ²¹⁰At and the directly produced ²¹⁰Po was estimated in a 25 layered 1 μm Bi model using the available cross-sectional data. The ²¹¹At and ²¹⁰At yields were measured with a HPGe-detector 30 min post EOB. After sufficient decay Pb foils and a²¹⁰Po calibration source were used to calibrate an iQID α-camera and an AMBER α-spectrometer prior to the non-destructive quantification of ²¹⁰Po.
Calculations predict a 28% and 1600% increased yield per μA of respectively ²¹⁰At and ²¹¹At for targets irradiated at 28.8 and 29.8 MeV respectively. At the same time the ²¹⁰Po activity increased by 350% up to a total activity of 24.14 kBq from which 60% is attributable to the direct reaction.
Measured ²¹¹At and ²¹⁰At activities show an increase of 49% and 1900% per μA for the 29.8 MeV target whereas quantification of ²¹⁰Po with both α-detection systems validates the predicted activities.
The results obtained in this study confirm a significantly increased yield of ²¹¹At at higher incident He²⁺- beam energies but also indicate the importance of directly produced ²¹⁰Po, which impacts the assessment of ²¹⁰Po prior to target processing.
Production of radionuclides: Cyclotrons and reactors
2022, Nuclear Medicine and Molecular Imaging: Volume 1-4
Molecular imaging techniques like PET and SPECT as well as endoradiotherapy, especially radioimmunotherapy, have marked a story of success in nuclear medicine in recent years. The broad spectrum of radiopharmaceuticals needed to cover the diverse requirements of individual applications, directly depends on the availability of a variety of radionuclides with different physical and chemical properties to meet these demands. This review highlights actual radionuclide developments for diagnostics and therapy. For either cyclotron or reactor produced nuclides nuclear physical properties are given together with the actual most promising production routes. Advantages and disadvantages are presented.
Besides the well-known PET nuclides ¹⁸F, ¹¹C, ¹³N and ¹⁵O, particularly longer-lived nuclides, mostly radiometals have emerged and already have become an integral part in preclinical and clinical research. Examples presented are ⁶⁴Cu, ⁶⁸Ga, ⁸⁹Zr, ⁸⁶Y and ¹²⁴I. There are more in the pipeline to prove their value in the future, like ⁵²Mn, ⁶¹Cu, ⁴³Sc, ⁴⁴Sc or ^94mTc. For the SPECT nuclides ^99mTc and ¹²³I production at a small cyclotron was successfully developed. Availability of the alpha emitters ²¹¹At and ²²⁵Ac could significantly be improved. As examples for reactor produced nuclides ⁸⁹Sr, ⁹⁰Y, ⁹⁹Mo, ¹³¹I, ¹⁵³Sm, ¹⁶⁶Ho, ¹⁷⁷Lu, ¹⁸⁶Re and ¹⁸⁸Re are described. Additionally, ⁴⁷Sc, ⁷⁷As and ¹⁶¹Tb offer a promising perspective. This outline shall demonstrate the versatility of available radionuclides for a broad spectrum of application.
Excitation functions for 209Bi reactions induced by threshold to 50 MeV energy alpha particles
2021, Applied Radiation and Isotopes
Citation Excerpt :
In recent years Lead–Bismuth Eutectic is used as a coolant for Generation IV reactors [Gromov et al., 1997]. Many research groups have studied cross-sections of charged particles such as proton and alpha particles induced reactions for 209Bi [Ramler et al., 1959; Larsen et al., 1996; Henriksen et al., 2001; Groppi et al., 2005; Hermanne et al., 2005; Lebeda et al., 2005; Schultz et al., 2006]. However there is a scarcity of experimental data and the reported results [Hermanne et al., 2005] indicate that most of the theoretical plots fail to match with the corresponding experimental cross-section reported in EXFOR database or as in the case of [Mokhtari et al., 2017] the general trend of the calculated 209Bi(p,xn) excitation functions follow the experimental data.
Excitation functions for ²⁰⁹Bi(α,2n)²¹¹At, ²⁰⁹Bi(α,3n)²¹⁰At and ²⁰⁹Bi(α,4n)²⁰⁹At reactions were calculated using TALYS-1.95 nuclear code from threshold to 50 MeV by invoking suitable options for level densities, nucleon-nucleus optical model potentials and alpha optical model potentials. Statistical factors were used to verify the quality of matching between theoretical model calculations and the experimental data from the EXFOR database. The TTY of ²¹¹At calculated using the excitation function of ²⁰⁹Bi(a,2n)²¹¹At reaction is compared with existing experimental studies from literature The results of the present study are important for the validation of nuclear model approaches with increased predictive power for ²⁰⁹Bi(α,xn) reactions for the production of ²¹¹At.
Production, purification and availability of 211At: Near term steps towards global access
2021, Nuclear Medicine and Biology
Citation Excerpt :
The efficiency of 211At isolation from the cyclotron target both in terms of yield and time depends in large part on the methods utilized for performing the cyclotron irradiation including the size, thickness and mass of the bismuth target and its backing plate, and the backing plate material. In addition, the length of the irradiation as well as the intensity of the beam current can also play a significant role [33]. Two strategies have been used successfully for 211At purification – dry distillation and wet harvesting – with the choice between the two depending on technical considerations such as target dimensions and subsequent labeling chemistry as well as on personal preference of the investigator [45].
The promising characteristics of the 7.2-h radiohalogen ²¹¹At have long been recognized; including having chemical properties suitable for labeling targeting vectors ranging from small organic molecules to proteins, and the emission of only one α-particle per decay, providing greater control over off-target effects. Unfortunately, the impact of ²¹¹At within the targeted α-particle therapy domain has been constrained by its limited availability. Paradoxically, the most commonly used production method – via the ²⁰⁹Bi(α,2n)²¹¹At reaction – utilizes a widely available natural material (bismuth) as the target and straightforward cyclotron irradiation methodology. On the other hand, the most significant impediment to widespread ²¹¹At availability is the need for an accelerator capable of generating ≥28 MeV α-particles with sufficient beam intensities to make clinically relevant levels of ²¹¹At. In this review, current methodologies for the production and purification of ²¹¹At – both by the direct production route noted above and via a ²¹¹Rn generator system – will be discussed. The capabilities of cyclotrons that currently produce ²¹¹At will be summarized and the characteristics of other accelerators that could be utilized for this purpose will be described. Finally, the logistics of networks, both academic and commercial, for facilitating ²¹¹At distribution to locations remote from production sites will be addressed.
Evaluation of astatine-211-labeled octreotide as a potential radiotherapeutic agent for NSCLC treatment
2018, Bioorganic and Medicinal Chemistry
Octreotide is a somatostatin (SST) analogue currently used in the treatment of neuroendocrine tumors (NETs) with high binding affinity for the somatostatin receptor-2 (SSTR2) that is also overexpressed in non-small cell lung cancer cell (NSCLC). Alpha-particle-emitting astatine-211 (²¹¹At) is a promising radionuclide with appropriate physical and chemical properties for use in targeted anticancer therapies. To obtain an additional pharmacological agent for the treatment of NSCLC, we present the first investigation of the possible use of ²¹¹At-labeled octreotide as a potential alpha-radionuclide therapeutic agent for NSCLC treatment. ²¹¹At-SPC-octreotide exhibited observable higher uptake in lung, spleen, stomach and intestines than in other tissues. Through histological examination, ²¹¹At-SPC-octreotide demonstrated much more lethal effect than control groups (PBS, octreotide and free ²¹¹At). These promising preclinical results suggested that ²¹¹At labeled octreotide deserved to be further developed as a new anticancer agent for NSCLC.
Radiopharmaceutical chemistry of targeted radiotherapeutics, part 4: Strategies for 211At labeling at high activities and radiation doses of 211At α-particles
2017, Nuclear Medicine and Biology
Alpha particles are radiation of high energy and short range, properties that can lead to radiolysis-mediated complications in labeling chemistry at the high radioactivity levels required for clinical application. In previous papers in this series, we have shown that radiation dose has a profound effect on the astatine species that are present in the labeling reaction and their suitability for the synthesis of N-succinimidyl 3-[²¹¹At]astatobenzoate. The purpose of this study was to evaluate the effects of adding N-chlorosuccinimide (NCS) to the methanol solution used for initial isolation of ²¹¹At after distillation, a process referred to as ²¹¹At stabilization, on ²¹¹At chemistry after exposure to high radiation doses.
High performance liquid chromatography was used to evaluate the distribution of ²¹¹At species present in methanol in the 500–65,000 Gy radiation dose range and the synthesis of SAB from N-succinimidyl 3-(tri-n-butylstannyl)benzoate in the 500–120,000 Gy radiation dose range using different ²¹¹At timeactivity combinations under conditions with/without ²¹¹At stabilization.
In the absence of NCS stabilization, a reduced form of astatine, At(2), increased with increasing radiation dose, accounting for about half the total activity by about 15,000 Gy, while with stabilization, At(2) accounted for <10% of ²¹¹At activity even at doses >60,000 Gy. SAB yields without stabilization rapidly declined with increasing dose, falling to ~20% at about 5000 Gy while with stabilization, yields >80% were obtained with ²¹¹At solutions stored for more than 23 h and receiving radiation doses >100,000 Gy.
Adding NCS to the methanol solution used for initial isolation of ²¹¹At is a promising strategy for countering the deleterious effects of radiolysis on ²¹¹At chemistry.
This strategy could facilitate the ability to perform ²¹¹At labeling at sites remote from its production and at the high activity levels required for clinical applications.

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Applied Radiation and Isotopes

Abstract

References (23)

The development of a [²¹¹At]-astatinated endoradiotherapeutic drug: part II. Therapeutic results for transplanted adenocarcinoma of the rectum in mice and associated studies

Int. J. Radiat. Oncol. Biol. Phys.

Preparation of a biologically stable and immunogenically competent astatinated protein

Int. J. Nucl. Med. Biol.

A microdosimetric model of astatine-211 labeled antibodies for radioimmunotherapy

Int. J. Radiat. Oncol. Biol. Phys.

Cyclotron isotopes and radiopharmaceuticals—CCCV. Astatine-211

Int. J. Appl. Radiat. Isot.

α-particle radiotherapy with ²¹¹At-labeled monodisperse polymer particles, ²¹¹At-labeled IgG proteins, and free ²¹¹At in a murine intraperitoneal tumor model

Gynecol. Oncol.

Modeling of dose to tumor and normal tissue from intraperitoneal radioimmunotherapy with alpha and beta emitters

Int. J. Radiat. Oncol. Biol. Phys.

Preparation and evaluation of para-[²¹¹At]astatobenzoyl labeled anti-renal cell carcinoma antibody A6H F(ab′)₂. In vivo distribution comparison with para-[¹²⁵I]iodobenzoyl labeled A6H F(ab′)₂

Nucl. Med. Biol.

Astatination of proteins using a N-succinimidyl tri-n-butylstanyl benzoate intermediate

Appl. Radiat. Isot.

Artificially radioactive elements 85

Phys. Rev.

The ENSDF Radioactivity Data Base for IBM-PC and Computer Network Access

Cited by (91)

Optimized cyclotron production of <sup>211</sup>At: The challenge of <sup>210</sup>Po-characterization

Production of radionuclides: Cyclotrons and reactors

Excitation functions for <sup>209</sup>Bi reactions induced by threshold to 50 MeV energy alpha particles

Production, purification and availability of <sup>211</sup>At: Near term steps towards global access

Evaluation of astatine-211-labeled octreotide as a potential radiotherapeutic agent for NSCLC treatment

Radiopharmaceutical chemistry of targeted radiotherapeutics, part 4: Strategies for <sup>211</sup>At labeling at high activities and radiation doses of <sup>211</sup>At α-particles

Radiochemistry and radionuclide applicationEvaluation of an internal cyclotron target for the production of 211At via the 209Bi (α,2n)211At reaction

Abstract

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Nucl. Med. Biol.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Appl. Radiat. Isot.

Gynecol. Oncol.

Int. J. Radiat. Oncol. Biol. Phys.

Nucl. Med. Biol.

Appl. Radiat. Isot.

Artificially radioactive elements 85

Phys. Rev.

The ENSDF Radioactivity Data Base for IBM-PC and Computer Network Access

Radiochemistry and radionuclide application
Evaluation of an internal cyclotron target for the production of ²¹¹At via the ²⁰⁹Bi (α,2n)²¹¹At reaction