Ulli Koster

The acceleration and storage of radioactive ions for a neutrino factory

The term beta-beam has been coined for the production of a pure beam of electron neutrinos or their antiparticles through the decay of radioactive ions circulating in a storage ring. This concept requires radioactive ions to be accelerated to a Lorentz gamma of 150 for 6 He and 60 for 18 Ne. The neutrino source itself consists of a storage ring for this energy range, with long straight sections in line with the experiment(s). Such a decay ring does not exist at CERN today, nor does a high -intensity proton source for the production of the radioactive ions. Nevertheless, the existing CERN accelerator infrastructure could be used as this would still represent an important saving for a betabeam facility. This paper outlines the first study, while some of the more speculative ideas will need further investigations.

A Unique Matched Quadruplet of Terbium Radioisotopes for PET and SPECT and for α- and β−-Radionuclide Therapy: An In Vivo Proof-of-Concept Study with a New Receptor-Targeted Folate Derivative

Terbium offers 4 clinically interesting radioisotopes with complementary physical decay characteristics: 149Tb, 152Tb, 155Tb, and 161Tb. The identical chemical characteristics of these radioisotopes allow the preparation of radiopharmaceuticals with identical pharmacokinetics useful for PET (152Tb) and SPECT diagnosis (155Tb) and for α- (149Tb) and β−-particle (161Tb) therapy. The goal of this proof-of-concept study was to produce all 4 terbium radioisotopes and assess their diagnostic and therapeutic features in vivo when labeled with a folate-based targeting agent. Methods: 161Tb was produced by irradiation of 160Gd targets with neutrons at Paul Scherrer Institute or Institut Laue-Langevin. After neutron capture, the short-lived 161Gd decays to 161Tb. 149Tb, 152Tb, and 155Tb were produced by proton-induced spallation of tantalum targets, followed by an online isotope separation process at ISOLDE/CERN. The isotopes were purified by means of cation exchange chromatography. For the in vivo studies, we used the DOTA–folate conjugate cm09, which binds to folate receptor (FR)–positive KB tumor cells. Therapy experiments with 149Tb-cm09 and 161Tb-cm09 were performed in KB tumor–bearing nude mice. Diagnostic PET/CT (152Tb-cm09) and SPECT/CT (155Tb-cm09 and 161Tb-cm09) studies were performed in the same tumor mouse model. Results: Carrier-free terbium radioisotopes were obtained after purification, with activities ranging from approximately 6 MBq (for 149Tb) to approximately 15 GBq (for 161Tb). The radiolabeling of cm09 was achieved in a greater than 96% radiochemical yield for all terbium radioisotopes. Biodistribution studies showed high and specific uptake in FR-positive tumor xenografts (23.8% ± 2.5% at 4 h after injection, 22.0% ± 4.4% at 24 h after injection, and 18.4% ± 1.8% at 48 h after injection). Excellent tumor-to-background ratios at 24 h after injection (tumor to blood, ∼15; tumor to liver, ∼5.9; and tumor to kidney, ∼0.8) allowed the visualization of tumors in mice using PET (152Tb-cm09) and SPECT (155Tb-cm09 and 161Tb-cm09). Compared with no therapy, α- (149Tb-cm09) and β−-particle therapy (161Tb-cm09) resulted in a marked delay in tumor growth or even complete remission (33% for 149Tb-cm09 and 80% for 161Tb-cm09) and a significantly increased survival. Conclusion: For the first time, to our knowledge, 4 terbium radionuclides have been tested in parallel with tumor-bearing mice using an FR targeting agent. Along with excellent tumor visualization enabled by 152Tb PET and 155Tb SPECT, we demonstrated the therapeutic efficacy of the α-emitter 149Tb and β−-emitter 161Tb.

The low-energy β− and electron emitter 161Tb as an alternative to 177Lu for targeted radionuclide therapy

INTRODUCTION The low-energy β(-) emitter (161)Tb is very similar to (177)Lu with respect to half-life, beta energy and chemical properties. However, (161)Tb also emits a significant amount of conversion and Auger electrons. Greater therapeutic effect can therefore be expected in comparison to (177)Lu. It also emits low-energy photons that are useful for gamma camera imaging. METHODS The (160)Gd(n,γ)(161)Gd→(161)Tb production route was used to produce (161)Tb by neutron irradiation of massive (160)Gd targets (up to 40 mg) in nuclear reactors. A semiautomated procedure based on cation exchange chromatography was developed and applied to isolate no carrier added (n.c.a.) (161)Tb from the bulk of the (160)Gd target and from its stable decay product (161)Dy. (161)Tb was used for radiolabeling DOTA-Tyr3-octreotate; the radiolabeling profile was compared to the commercially available n.c.a. (177)Lu. A (161)Tb Derenzo phantom was imaged using a small-animal single-photon emission computed tomography camera. RESULTS Up to 15 GBq of (161)Tb was produced by long-term irradiation of Gd targets. Using a cation exchange resin, we obtained 80%-90% of the available (161)Tb with high specific activity, radionuclide and chemical purity and in quantities sufficient for therapeutic applications. The (161)Tb obtained was of the quality required to prepare (161)Tb-DOTA-Tyr3-octreotate. CONCLUSIONS We were able to produce (161)Tb in n.c.a. form by irradiating highly enriched (160)Gd targets; it can be obtained in the quantity and quality required for the preparation of (161)Tb-labeled therapeutic agents.

ISOLDE target and ion source chemistry

For the production of radioactive ion beams by means of the ISOL (isotope separation on-line) method in which the nuclei of interest are stopped in a thick target, chemistry plays a crucial role. It serves to separate the nuclear reaction products in atomic or molecular form from the bulk target and to transfer them efficiently to an ion source. This article gives an overview of ISOLDE radiochemical methods where targets (liquid metals, solid metals, carbides and oxides) and ion sources are optimized with respect to efficiency, speed and chemical selectivity. Rather pure beams of non-metals and volatile metals can be obtained with a temperature-controlled transfer line acting as thermo-chromatograph. For less volatile metals the temperature of the target and ion source units needs to be kept as high as possible, but a selective ion source can be used: positive surface ionization for metals with ionization potentials below about 6 eV and the RILIS (resonance ionization laser ion source) technique for most other metals.

Investigation of evaporation characteristics of polonium and its lighter homologues selenium and tellurium from liquid Pb-Bi-eutecticum

Summary The evaporation behaviour of polonium and its lighter homologues selenium and tellurium dissolved in liquid Pb-Bi-eutecticum (LBE) has been studied at various temperatures in the range from 482 K up to 1330 K under Ar/H2 and Ar/H2O-atmospheres using γ-ray spectroscopy. Polonium release in the temperature range of interest for technical applications is slow. Within short term (1 h) experiments measurable amounts of polonium are evaporated only at temperatures above 973 K. Long term experiments reveal that a slow evaporation of polonium occurs at temperatures around 873 K resulting in a fractional polonium loss of the melt around 1% per day. Evaporation rates of selenium and tellurium are smaller than those of polonium. The presence of H2O does not enhance the evaporation within the error limits of our experiments. The thermodynamics and possible reaction pathways involved in polonium release from LBE are discussed.

Folate Receptor Targeted Alpha-Therapy Using Terbium-149

Terbium-149 is among the most interesting therapeutic nuclides for medical applications. It decays by emission of short-range α-particles (Eα = 3.967 MeV) with a half-life of 4.12 h. The goal of this study was to investigate the anticancer efficacy of a 149Tb-labeled DOTA-folate conjugate (cm09) using folate receptor (FR)-positive cancer cells in vitro and in tumor-bearing mice. 149Tb was produced at the ISOLDE facility at CERN. Radiolabeling of cm09 with purified 149Tb resulted in a specific activity of ~1.2 MBq/nmol. In vitro assays performed with 149Tb-cm09 revealed a reduced KB cell viability in a FR-specific and activity concentration-dependent manner. Tumor-bearing mice were injected with saline only (group A) or with 149Tb-cm09 (group B: 2.2 MBq; group C: 3.0 MBq). A significant tumor growth delay was found in treated animals resulting in an increased average survival time of mice which received 149Tb-cm09 (B: 30.5 d; C: 43 d) compared to untreated controls (A: 21 d). Analysis of blood parameters revealed no signs of acute toxicity to the kidneys or liver in treated mice over the time of investigation. These results demonstrated the potential of folate-based α-radionuclide therapy in tumor-bearing mice.

Spatially correlated and coincidence detection of fission fragments with the pixel detector Timepix

Charged-particle coincidence correlated measurements such as angular correlations between rare and main fission fragments measured with conventional detectors provide only partial and limited information (energy cutoff, narrow range of studied ion Z numbers). Many of these drawbacks arise from the standard solid state detectors used so far which can be solved simultaneously by usage of highly segmented single-quantum counting pixel detectors. The Timepix pixel device, which is equipped with energy and time sensitivity capability per pixel, provides high granularity, wide dynamic range and per pixel threshold. This detector operated with integrated USB-readout interfaces such as the USB 1.0 and FITPix devices and the data acquisition software tool Pixelman, both developed for the pixel detectors of the Medipix-family, enables a variety of instrumental configurations, visualization, real-time event-by-event selection as well as vacuum and portability of operation for flexible measurements on different targets and setups. These features combined with event track analysis provide enhanced signal to noise ratio with a high suppression of background and unwanted events. The detector provides multi-parameter information (position, energy and time) for basically all types of ionizing particles in a wide dynamic range of energy (pixel energy threshold ≈ 4 keV), interaction/arrival time (timepix clock step ≥ 100 ns) and position (pixel size = 55 μm). High selectivity is achieved by spatial and time correlation in the same sensor. In addition, several detectors can be run in coincidence. The open and close exposition (shutter) time as well as the readout DAQ can be fully synchronized. For this purpose, we have assembled a modular multi-parameter, tunable and extendable coincidence detector array system based on two and more Timepix devices which can be coupled with supplementary detectors (solid state ΔE detectors and/or ionization chambers) for enhanced ion selectivity. We describe the individual configurations and techniques together with the experiments carried out at several neutron beam/source facilities. We summarize the results and capabilities of application.

Future prospects for SPECT imaging using the radiolanthanide terbium-155 — production and preclinical evaluation in tumor-bearing mice

INTRODUCTION We assessed the suitability of the radiolanthanide (155)Tb (t1/2=5.32 days, Eγ=87 keV (32%), 105keV (25%)) in combination with variable tumor targeted biomolecules using preclinical SPECT imaging. METHODS (155)Tb was produced at ISOLDE (CERN, Geneva, Switzerland) by high-energy (~1.4 GeV) proton irradiation of a tantalum target followed by ionization and on-line mass separation. (155)Tb was separated from isobar and pseudo-isobar impurities by cation exchange chromatography. Four tumor targeting molecules - a somatostatin analog (DOTATATE), a minigastrin analog (MD), a folate derivative (cm09) and an anti-L1-CAM antibody (chCE7) - were radiolabeled with (155)Tb. Imaging studies were performed in nude mice bearing AR42J, cholecystokinin-2 receptor expressing A431, KB, IGROV-1 and SKOV-3ip tumor xenografts using a dedicated small-animal SPECT/CT scanner. RESULTS The total yield of the two-step separation process of (155)Tb was 86%. (155)Tb was obtained in a physiological l-lactate solution suitable for direct labeling processes. The (155)Tb-labeled tumor targeted biomolecules were obtained at a reasonable specific activity and high purity (>95%). (155)Tb gave high quality, high resolution tomographic images. SPECT/CT experiments allowed excellent visualization of AR42J and CCK-2 receptor-expressing A431 tumors xenografts in mice after injection of (155)Tb-DOTATATE and (155)Tb-MD, respectively. The relatively long physical half-life of (155)Tb matched in particular the biological half-lives of (155)Tb-cm09 and (155)Tb-DTPA-chCE7 allowing SPECT imaging of KB tumors, IGROV-1 and SKOV-3ip tumors even several days after administration. CONCLUSIONS The radiolanthanide (155)Tb may be of particular interest for low-dose SPECT prior to therapy with a therapeutic match such as the β(-)-emitting radiolanthanides (177)Lu, (161)Tb, (166)Ho, and the pseudo-radiolanthanide (90)Y.

New neutron long-counter for delayed neutron investigations with the LOHENGRIN fission fragment separator

Some neutrons are emitted from fission products seconds to minutes after fission occurs. The knowledge of these delayed neutrons is essential in the field of nuclear energy. But the probabilities to emit such delayed neutrons (Pn) are not always well known. A summary of different databases and compilations of Pn values is presented to show these discrepancies and uncertainties. The usual methods used to determine these nuclear data are then reviewed with an emphasis on biases and systematic errors to be avoided. To measure precise Pn values, a new neutron LOng-counter with ENergy Independant Efficiency (LOENIE) has been built for the LOHENGRIN separator facility installed at Institut Laue Langevin (FRANCE). Its characteristics and first results obtained are presented.

Preparation and characterisation of an 39Ar sample and study of the 39Ar(nth, α)36S reaction

Abstract The 39 Ar ( n th , α ) 36 S reaction has been studied for the first time. A sample containing 2.85×10 14 39 Ar atoms was produced at the ISOLDE facility at CERN. The number of 39 Ar atoms in the layer was determined by measuring the 39 Ar β -activity using a primary standardisation method. Subsequently, the sample was irradiated with thermal neutrons at the High Flux Reactor of the Institut Laue–Langevin. An upper limit of 0.29 b was obtained for the 39 Ar ( n th , α ) 36 S reaction cross-section.