Synthesis and preclinical evaluation of BOLD-100 radiolabeled with ruthenium-97 and ruthenium-103.

BOLD-100 (formerly IT-139, KP1339), a well-established chemotherapeutic agent, is currently being investigated in clinical trials for the treatment of gastric, pancreatic, colorectal, and bile duct cancer. Despite numerous studies, the exact mode of action is still the subject of discussions. Radiolabeled BOLD-100 could be a powerful tool to clarify pharmacokinetic pathways of the compound and to predict therapy responses in patients using nuclear molecular imaging prior to the therapy. In this study, the radiosyntheses of carrier-added (c.a.) [97/103Ru]BOLD-100 were performed with the two ruthenium isotopes ruthenium-103 (103Ru; ß-, γ) and ruthenium-97 (97Ru; EC, γ), of which in particular the latter isotope is suitable for imaging by single-photon emission computed tomography (SPECT). To identify the best tumor-to-background ratio for diagnostic imaging, biodistribution studies were performed with two different injected doses of c.a. [103Ru]BOLD-100 (3 and 30 mg kg-1) in Balb/c mice bearing CT26 allografts over a time period of 72 h. Additionally, ex vivo autoradiography of the tumors (24 h p.i.) was conducted. Our results indicate that the higher injected dose (30 mg kg-1) leads to more unspecific accumulation of the compound in non-targeted tissue, which is likely due to an overload of the albumin transport system. It was also shown that lower amounts of injected c.a. [103Ru]BOLD-100 resulted in a relatively higher tumor uptake and, therefore, a better tumor-to-background ratio, which are encouraging results for future imaging studies using c.a. [97Ru]BOLD-100.

Terbium-149 production: a focus on yield and quality improvement towards preclinical application.

Terbium-149 (T1/2 = 4.1 h, Eα = 3.98 MeV (16.7%), 28 µm range in tissue) is a radionuclide with potential for targeted alpha therapy. Due to the negligible emission of α-emitting daughter nuclides, toxicity to healthy tissue may be reduced in comparison with other α-particle emitters. In this study, terbium-149 was produced via 1.4 GeV proton irradiation of a tantalum target at the CERN-ISOLDE facility. The spallation products were mass separated and implanted on zinc-coated foils and, later, radiochemically processed. Terbium-149 was separated from the co-produced isobaric radioisotopes and the zinc coating from the implantation foil, using cation-exchange and extraction chromatographic techniques, respectively. At the end of separation, up to 260 MBq terbium-149 were obtained with > 99% radionuclidic purity. Radiolabeling experiments were performed with DOTATATE, achieving 50 MBq/nmol apparent molar activity with radiochemical purity > 99%. The chemical purity was determined by inductively coupled plasma-mass spectrometry measurements, which showed lead, copper, iron and zinc only at ppb level. The radiolabeling of the somatostatin analogue DOTATATE with [149Tb]TbCl3 and the subsequent in vivo PET/CT scans conducted in xenografted mice, showing good tumor uptake, further demonstrated product quality and its ability to be used in a preclinical setting.

Production of 129mXe and 131mXe via neutron activation of 128Xe and 130Xe at ILL-RHF and NCBJ-MARIA high-flux reactors.

The long-lived xenon isomers 129mXe and 131mXe are of interest for the GAMMA-MRI project, which aims at developing a novel imaging modality based on magnetic resonance of polarized unstable tracers. Here, we present the steps leading to and following the production of these two isomers via neutron irradiation of highly-enriched 128Xe and 130Xe gas samples at two high-flux reactors, the High-Flux Reactor (Réacteur à haut flux, RHF) at the Institut Laue-Langevin (ILL) and the MARIA reactor at the National Centre for Nuclear Research (NCBJ). We describe the experimental setups and procedures used to prepare the stable xenon samples, to open the irradiated samples, and to transfer xenon isomers into reusable transport vials. The activity of 129mXe and 131mXe was measured to be in the range of tens of MBq per sample of 0.8(1)mg, and was proportional to thermal neutron flux density. A small activity of unstable contaminants was also visible in the samples, but their level is not limiting for the GAMMA-MRI project's objectives. In addition, the minimum thermal neutron flux density required to produce 129mXe and 131mXe sufficient for the project could be also determined.

Further Evidence for Shape Coexistence in

Isomers close to doubly magic _{28}^{78}Ni_{50} provide essential information on the shell evolution and shape coexistence near the Z=28 and N=50 double shell closure. We report the excitation energy measurement of the 1/2^{+} isomer in _{30}^{79}Zn_{49} through independent high-precision mass measurements with the JYFLTRAP double Penning trap and with the ISOLTRAP multi-reflection time-of-flight mass spectrometer. We unambiguously place the 1/2^{+} isomer at 942(10) keV, slightly below the 5/2^{+} state at 983(3) keV. With the use of state-of-the-art shell-model diagonalizations, complemented with discrete nonorthogonal shell-model calculations which are used here for the first time to interpret shape coexistence, we find low-lying deformed intruder states, similar to other N=49 isotones. The 1/2^{+} isomer is interpreted as the bandhead of a low-lying deformed structure akin to a predicted low-lying deformed band in ^{80}Zn, and points to shape coexistence in ^{79,80}Zn similar to the one observed in ^{78}Ni. The results make a strong case for confirming the claim of shape coexistence in this key region of the nuclear chart.

Determination of the Terbium-152 half-life from mass-separated samples from CERN-ISOLDE and assessment of the radionuclide purity.

Terbium-152 is one of four terbium radioisotopes that together form a potential theranostic toolbox for the personalised treatment of tumours. As 152 Tb decay by positron emission it can be utilised for diagnostics by positron emission tomography. For use in radiopharmaceuticals and for activity measurements by an activity calibrator a high radionuclide purity of the material and an accurate and precise knowledge of the half-life is required. Mass-separation and radiochemical purification provide a production route of high purity 152Tb. In the current work, two mass-separated samples from the CERN-ISOLDE facility have been assayed at the National Physical Laboratory to investigate the radionuclide purity. These samples have been used to perform four measurements of the half-life by three independent techniques: high-purity germanium gamma-ray spectrometry, ionisation chamber measurements and liquid scintillation counting. From the four measurement campaigns a half-life of 17.8784(95) h has been determined. The reported half-life shows a significant difference to the currently evaluated half-life (ζ-score = 3.77), with a relative difference of 2.2 % and an order of magnitude improvement in the precision. This work also shows that under controlled conditions the combination of mass-separation and radiochemical separation can provide high-purity 152Tb.

Half-life determination of 155Tb from mass-separated samples produced at CERN-MEDICIS.

Terbium-155 has been identified for its potential for single-photon emission computed tomography (SPECT) in nuclear medicine. For activity measurements, an accurate and precise half-life of this radionuclide is required. However, the currently evaluated half-life of 5.32(6) d with a relative standard uncertainty of 1.1% determines the precision possible. Limited literature for the half-life measurements of this radionuclide is available and all reported investigations are prior to 1970. Further measurements are therefore needed to confirm the accuracy and improve the precision of the half-life for its use in the clinical setting. Two samples produced and mass separated at the CERN-MEDICIS facility have been measured at the National Physical Laboratory by two independent techniques: liquid scintillation counting and high-purity germanium gamma-ray spectrometry. A half-life of 5.2346(36) d has been determined from the weighted mean of the half-lives determined by the two techniques. The half-life reported in this work has shown a relative difference of 1.6% to the currently evaluated half-life and has vastly improved the precision.

PET in vivo generators 134Ce and 140Nd on an internalizing monoclonal antibody probe.

The in vivo-generator radionuclides 140Nd (t1/2 = 3.4 d) and 134Ce (t1/2 = 3.2 d) were used to trace a urokinase-type plasminogen activator (uPA)-targeting mouse monoclonal antibody, ATN-291, in U87 MG xenograft tumor-bearing mice. ATN-291 is known to internalize on the uPA/uPA-receptor pair, making it an appropriate targeting vector for investigating the fate of in vivo generator daughters on internalizing probes. Ante-mortem and post-mortem PET imaging at 120 h post-injection gave no indication of redistribution of the positron emitting daughter nuclides 134La and 140Pr from tumor tissue (p > 0.5). The lack of redistribution indicates that the parent radionuclides 134Ce and 140Nd could be considered as long-lived PET-diagnostic matches to therapeutic radionuclides like 177Lu, 161Tb and 225Ac when internalizing bioconjugates are employed.

Neutron Capture on the s-Process Branching Point

The neutron capture cross sections of several unstable nuclides acting as branching points in the s process are crucial for stellar nucleosynthesis studies. The unstable ^{171}Tm (t_{1/2}=1.92 yr) is part of the branching around mass A∼170 but its neutron capture cross section as a function of the neutron energy is not known to date. In this work, following the production for the first time of more than 5 mg of ^{171}Tm at the high-flux reactor Institut Laue-Langevin in France, a sample was produced at the Paul Scherrer Institute in Switzerland. Two complementary experiments were carried out at the neutron time-of-flight facility (n_TOF) at CERN in Switzerland and at the SARAF liquid lithium target facility at Soreq Nuclear Research Center in Israel by time of flight and activation, respectively. The result of the time-of-flight experiment consists of the first ever set of resonance parameters and the corresponding average resonance parameters, allowing us to make an estimation of the Maxwellian-averaged cross sections (MACS) by extrapolation. The activation measurement provides a direct and more precise measurement of the MACS at 30 keV: 384(40) mb, with which the estimation from the n_TOF data agree at the limit of 1 standard deviation. This value is 2.6 times lower than the JEFF-3.3 and ENDF/B-VIII evaluations, 25% lower than that of the Bao et al. compilation, and 1.6 times larger than the value recommended in the KADoNiS (v1) database, based on the only previous experiment. Our result affects the nucleosynthesis at the A∼170 branching, namely, the ^{171}Yb abundance increases in the material lost by asymptotic giant branch stars, providing a better match to the available pre-solar SiC grain measurements compared to the calculations based on the current JEFF-3.3 model-based evaluation.

Shape Coexistence at Zero Spin in

The low-spin structure of the semimagic ^{64}Ni nucleus has been considerably expanded: combining four experiments, several 0^{+} and 2^{+} excited states were identified below 4.5 MeV, and their properties established. The Monte Carlo shell model accounts for the results and unveils an unexpectedly complex landscape of coexisting shapes: a prolate 0^{+} excitation is located at a surprisingly high energy (3463 keV), with a collective 2^{+} state 286 keV above it, the first such observation in Ni isotopes. The evolution in excitation energy of the prolate minimum across the neutron N=40 subshell gap highlights the impact of the monopole interaction and its variation in strength with N.

Establishment of a clinical SPECT/CT protocol for imaging of 161Tb.

BACKGROUND: It has been proposed, and preclinically demonstrated, that 161Tb is a better alternative to 177Lu for the treatment of small prostate cancer lesions due to its high emission of low-energy electrons. 161Tb also emits photons suitable for single-photon emission computed tomography (SPECT) imaging. This study aims to establish a SPECT protocol for 161Tb imaging in the clinic. MATERIALS AND METHODS: Optimal settings using various γ-camera collimators and energy windows were explored by imaging a Jaszczak phantom, including hollow-sphere inserts, filled with 161Tb. The collimators examined were extended low-energy general purpose (ELEGP), medium-energy general purpose (MEGP), and low-energy high resolution (LEHR), respectively. In addition, three ordered subset expectation maximization (OSEM) algorithms were investigated: attenuation-corrected OSEM (A-OSEM); attenuation and dual- or triple-energy window scatter-corrected OSEM (AS-OSEM); and attenuation, scatter, and collimator-detector response-corrected OSEM (ASC-OSEM), where the latter utilized Monte Carlo-based reconstruction. Uniformity corrections, using intrinsic and extrinsic correction maps, were also investigated. Image quality was assessed by estimated recovery coefficients (RC), noise, and signal-to-noise ratio (SNR). Sensitivity was determined using a circular flat phantom. RESULTS: The best RC and SNR were obtained at an energy window between 67.1 and 82.1 keV. Ring artifacts, caused by non-uniformity, were removed with extrinsic uniformity correction for the energy window between 67.1 and 82.1 keV, but not with intrinsic correction. Analyzing the lower energy window between 48.9 and 62.9 keV, the ring artifacts remained after uniformity corrections. The recovery was similar for the different collimators when using a specific OSEM reconstruction. Recovery and SNR were highest for ASC-OSEM, followed by AS-OSEM and A-OSEM. When using the optimized parameter setting, the resolution of 161Tb was higher than for 177Lu (8.4 ± 0.7 vs. 10.4 ± 0.6 mm, respectively). The sensitivities for 161Tb and 177Lu were 7.41 and 8.46 cps/MBq, respectively. CONCLUSION: SPECT with high resolution is feasible with 161Tb; however, extrinsic uniformity correction is recommended to avoid ring artifacts. The LEHR collimator was the best choice of the three tested to obtain a high-resolution image. Due to the complex emission spectrum of low-energy photons, window-based scatter correction had a minor impact on the image quality compared to using attenuation correction only. On the other hand, performing attenuation, scatter, and collimator-detector correction clearly improved image quality. Based on these data, SPECT-based dosimetry for 161Tb-labeled radiopharmaceuticals is feasible.

15 years of the model study course in medicine at the Ruhr University Bochum.

The Faculty of Medicine of the Ruhr University Bochum (RUB) introduced a model study course in medicine (MSM) in the winter semester 2003. For 9 consecutive years, 42 out of 280 first year students at the Ruhr University Bochum had the opportunity to begin their studies in the model study course in medicine. The places were allocated amongst the applicants internally through a raffle. The MSM was consistently problem-, practice- and patient-oriented and largely did away with lectures, broke with the distinction between a pre-clinical and clinical phase and tested basic knowledge in equivalent integrated exams focusing on clinical application. Following a comparative evaluation of the standard degree course (RSM) and the MSM, the faculty merged the two degree courses into the Integrated Reformed Medical Curriculum (IRMC), which has been on offer since 2013 and is characterized by a topic-oriented hybrid curriculum. This article examines experiences relating to the origins, conception and introduction of the MSM.

Production and separation of 163Ho for nuclear physics experiments.

This paper describes the production and chemical separation of the 163Ho isotope that will be used in several nuclear physics experiments aiming at measuring the neutrino mass as well as the neutron cross section of the 163Ho isotope. For this purpose, several batches of enriched 162Er have been irradiated at the Institut Laue-Langevin high flux reactor to finally produce 6 mg or 100 MBq of the desired 163Ho isotope. A portion of the Er/Ho mixture is then subjected to a sophisticated chemical separation involving ion exchange chromatography to isolate the Ho product from the Er target material. Before irradiation, a thorough analysis of the impurity content was performed and its implication on the produced nuclide inventory will be discussed.

Direct Measurement of the Mass Difference of (163)Ho and (163)Dy Solves the Q-Value Puzzle for the Neutrino Mass Determination.

The atomic mass difference of (163)Ho and (163)Dy has been directly measured with the Penning-trap mass spectrometer SHIPTRAP applying the novel phase-imaging ion-cyclotron-resonance technique. Our measurement has solved the long-standing problem of large discrepancies in the Q value of the electron capture in (163)Ho determined by different techniques. Our measured mass difference shifts the current Q value of 2555(16) eV evaluated in the Atomic Mass Evaluation 2012 [G. Audi et al., Chin. Phys. C 36, 1157 (2012)] by more than 7σ to 2833(30(stat))(15(sys)) eV/c(2). With the new mass difference it will be possible, e.g., to reach in the first phase of the ECHo experiment a statistical sensitivity to the neutrino mass below 10 eV, which will reduce its present upper limit by more than an order of magnitude.

HOLMES: The electron capture decay of [Formula: see text]Ho to measure the electron neutrino mass with sub-eV sensitivity.

The European Research Council has recently funded HOLMES, a new experiment to directly measure the neutrino mass. HOLMES will perform a calorimetric measurement of the energy released in the decay of [Formula: see text]Ho. The calorimetric measurement eliminates systematic uncertainties arising from the use of external beta sources, as in experiments with beta spectrometers. This measurement was proposed in 1982 by A. De Rujula and M. Lusignoli, but only recently the detector technological progress allowed to design a sensitive experiment. HOLMES will deploy a large array of low temperature microcalorimeters with implanted [Formula: see text]Ho nuclei. The resulting mass sensitivity will be as low as 0.4 eV. HOLMES will be an important step forward in the direct neutrino mass measurement with a calorimetric approach as an alternative to spectrometry. It will also establish the potential of this approach to extend the sensitivity down to 0.1 eV. We outline here the project with its technical challenges and perspectives.

Measurement of the first ionization potential of astatine by laser ionization spectroscopy.

The radioactive element astatine exists only in trace amounts in nature. Its properties can therefore only be explored by study of the minute quantities of artificially produced isotopes or by performing theoretical calculations. One of the most important properties influencing the chemical behaviour is the energy required to remove one electron from the valence shell, referred to as the ionization potential. Here we use laser spectroscopy to probe the optical spectrum of astatine near the ionization threshold. The observed series of Rydberg states enabled the first determination of the ionization potential of the astatine atom, 9.31751(8) eV. New ab initio calculations are performed to support the experimental result. The measured value serves as a benchmark for quantum chemistry calculations of the properties of astatine as well as for the theoretical prediction of the ionization potential of superheavy element 117, the heaviest homologue of astatine.

Magnetic dipole moment of the doubly-closed-shell plus one proton nucleus 49Sc.

The nucleus 49Sc, having a single f(7/2) proton outside doubly magic 48Ca (Z=20, N=28), is one of the very few isotopes which makes possible testing of the fundamental theory of nuclear magnetism. The magnetic moment has been measured by online ß NMR of nuclei oriented at milli-Kelvin temperatures to be (+)5.616(25) µ(N). The result is discussed in terms of a detailed theory of the structure of the magnetic moment operator, showing excellent agreement with calculated departure from the f(7/2) Schmidt limit extreme single-particle value. The measurement completes the sequence of moments of Sc isotopes with even numbers of f(7/2) neutrons: the first such isotopic chain between two major shells for which a full set of moment measurements exists. The result further completes the isotonic sequence of ground-state moments of nuclei with an odd number of f(7/2) protons coupled to a closed subshell of f(7/2) neutrons. Comparison with a recent shell-model calculation of the latter sequence is made.

Early onset of ground state deformation in neutron deficient polonium isotopes.

In-source resonant ionization laser spectroscopy of the even-A polonium isotopes (192-210,216,218)Po has been performed using the 6p(3)7s (5)S(2) to 6p(3)7p (5)P(2) (λ=843.38 nm) transition in the polonium atom (Po-I) at the CERN ISOLDE facility. The comparison of the measured isotope shifts in (200-210)Po with a previous data set allows us to test for the first time recent large-scale atomic calculations that are essential to extract the changes in the mean-square charge radius of the atomic nucleus. When going to lighter masses, a surprisingly large and early departure from sphericity is observed, which is only partly reproduced by beyond mean field calculations.

New type of asymmetric fission in proton-rich nuclei.

A very exotic process of ß-delayed fission of 180Tl is studied in detail by using resonant laser ionization with subsequent mass separation at ISOLDE (CERN). In contrast to common expectations, the fission-fragment mass distribution of the post-ß-decay daughter nucleus 180Hg (N/Z=1.25) is asymmetric. This asymmetry is more surprising since a mass-symmetric split of this extremely neutron-deficient nucleus would lead to two 90Zr fragments, with magic N=50 and semimagic Z=40. This is a new type of asymmetric fission, not caused by large shell effects related to fragment magic proton and neutron numbers, as observed in the actinide region. The newly measured branching ratio for ß-delayed fission of 180Tl is 3.6(7) × 10(-3)%, approximately 2 orders of magnitude larger than in an earlier study.

Nuclear spins and magnetic moments of 71,73,75Cu: inversion of pi2p3/2 and pi1f5/2 levels in 75Cu.

We report the first confirmation of the predicted inversion between the pi2p3/2 and pi1f5/2 nuclear states in the nu(g)9/2 midshell. This was achieved at the ISOLDE facility, by using a combination of in-source laser spectroscopy and collinear laser spectroscopy on the ground states of 71,73,75Cu, which measured the nuclear spin and magnetic moments. The obtained values are mu(71Cu)=+2.2747(8)mu(N), mu(73Cu)=+1.7426(8)mu(N), and mu(75Cu)=+1.0062(13)mu(N) corresponding to spins I=3/2 for 71,73Cu and I=5/2 for 75Cu. The results are in fair agreement with large-scale shell-model calculations.