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We show the synthesis of an in vivo stable mercury compound with functionality suitable for radiopharmaceuticals. The designed cyclic bisarylmercury was based on the water tolerance of organomercurials, higher bond dissociation energy of Hg−Ph to Hg−S, and the experimental evidence that acyclic structures suffer significant cleavage of one of the Hg−R bonds. The bispidine motif was chosen for its in vivo stability, chemical accessibility, and functionalization properties. Radionuclide production results in 197(m)HgCl2(aq), so the desired mercury compound was formed via a water‐tolerant organotin transmetallation. The Hg‐bispidine compound showed high chemical stability in tests with an excess of sulfur‐containing competitors and high in vivo stability, without any observable protein interaction by human serum assay, and good organ clearance demonstrated by biodistribution and SPECT studies in rats. In particular, no retention in the kidneys was observed, typical of unstable mercury compounds. The natHg analogue allowed full characterization by NMR and HRMS., Stable and versatile: The cyclic bisarylmercury bispidine structure shows exceptional stability against sulfur compounds known to usually react very easily with mercury. Aside from its novelty in mercury chemistry, the in vivo stability paired with the functionalizability of this motif is an important step forward in the development of useful radiomercury pharmaceuticals.

Specific oncology diagnostics requires new types of the selective radiopharmaceuticals, particularly those suitable for the molecular PET imaging. The aim of this work is to present a new, specific PET-immunodiagnostic radiopharmaceutical based on the monoclonal antibody IgG M75 targeting human carbonic anhydrase IX labelled with 64Cu (T½ = 12.70h) and its in vitro and in vivo evaluation. The antibody IgG M75 was conjugated with a non-commercial copper-specific chelator "phosphinate" and then labelled with the positron emitter 64Cu. Stability of the labelled conjugated was tested in human serum. The immunoreactivity of the labelled conjugate was evaluated in vitro on a suitable cell cultures of the colorectal carcinoma (HT-29) and its imaging properties were estimated in vivo on a mouse model with inoculated colorectal carcinoma HT-29 imaged on a µPET/CT. The tested radioimmunoconjugate was obtained in a specific activity of 0.25-0.5 MBq/µg. In vitro uptake experiments revealed specific binding to the HT-29 cells (45 ± 2.8% of the total added activity) and the measured KD value was found to be 9.2nM. Imaging clearly demonstrated significant uptake of the labelled monoclonal antibody in the tumour at 18h post administration. The radioimmunoconjugate 64Cu-PS-IgG M75 seems to be a suitable candidate for PET diagnostics of hypoxic tumours expressing human carbonic anhydrase IX.

Background Prostate specific membrane antigen (PSMA) is a type II membrane protein widely expressed on the surface of prostate cancer cells. One of its functions is to act as a receptor mediating the ligand internalization. This PSMA property is employed in the diagnostics and therapy of prostate cancer. Over the years, small molecules with high affinity for PSMA have been developed and labelled with positron emitters (e.g. 68Ga, 18F, 11C, 64Cu, or 86Y). One of these radiolabelled ligands, [68Ga] PSMA-11, is one of the most widespread tracers for PET imaging of the prostate cancer. Many techniques have been proposed and tested for the 68Ga labelling of PSMA-11. The aim of our work was to design a labelling method of PSMA-11 that minimizes number of the used chemicals and steps, providing quantitative labelling yield at laboratory temperature and may be easily automated. Methodology A68Ge/68Ga generator eluate in 0.1 M HCl was loaded on an activated Oasis MCX cartridge, and the cartridge was then thoroughly washed with water. The radionuclide 68Ga was eluted from the cartridge with 0.1 M NaHCO3 (pH = 8.5, n = 36) or with the same solution with pH adjusted to 7.2–9.0 (n = 38). Precursor PSMA-11 was mixed directly with the cartridge eluate of 68Ga in 0.1 M NaHCO3 of given pH. For the stability test, samples of 68GaPSMA-11 in 0.1 M NaHCO3 (pH 8.5) were mixed in ratio 1 : 1 with the following solutions: 0.1 M NaHCO3 (pH 8.5), human serum, PBS and 0.9% NaCl. In order to estimate an effect of the time elapsed between 68Ga elution from the cartridge in 0.1 M NaHCO3 (pH 8.5) and the labelling onset of PSMA-11, the latter was initiated 0, 5, 10 and 20 min post elution and radiochemical yield was monitored. All the PSMA-11 labelled samples were subjected to radiochemical purity test using HPLC. The whole process starting from generator elution up to HPLC analysis commencement took 10–15 min. Results Recovery of 68Ga from cartridge Oasis MCX using 0.1 M NaHCO3 at pH 8.5 was 71.5 ± 1.4%. Thirty six PSMA-11 samples (10 μg in reaction mixture) were labelled at pH 8.5 with total average radiochemical yield of 98 ± 2%. Recovery of 68Ga from cartridge Oasis MCX using 0.1 M NaHCO3 at variable pH of 7.2–9.0 was 62.5 ± 1.8% showing certain decrease with decreasing pH. A total of 138 samples of PSMA-11 were labelled with 68 Ga at variable pH (7.2–9.0) and four different amounts of PSMA-11 (1, 2.5, 5 and 10 μg) resulting in the labelling yields of 54.0 ± 5.3%, 88.2 ± 3.2%, 99.4 ± 0.3% and 99.9 ± 0.1%, respectively. Irrespective of the pH, the radiolabelling yield was quantitative for the molar ratio PSMA-11: 68Ga > 5000 : 1 in the reaction mixture. Stability tests in 0.1 M NaHCO3 (pH 8.5), human serum, PBS and 0.9% NaCl revealed no observable release of 68Ga from the 68Ga-PSMA-11 complex within 3 h. Similarly, the delay between the 68Ga elution from the Oasis MCX cartridge in 0.1 M NaHCO3 (pH 8.5) and start of the labelling of PSMA-11 labelling has no effect on the radiochemical yield. Conclusion A new method of labelling PSMA-11 ligand with 68Ga in 0.1 M NaHCO3 using Oasis MCX cartridges was proposed, developed and tested. The results demonstrated that it is rapid, simple, reproducible and easy to automate.

In the framework of the Co-ordinated Research Project of the IAEA, we measured in detail cross-sections of the nuclear reactions natMo(p,x)93gTc, 93mTc, 93m+gTc, 94gTc, 94mTc, 95gTc, 95mTc, 96m+gTc, 97mTc, 99mTc, 90Mo, 93mMo, 99Mo, 88gNb, 88mNb, 89gNb, 89mNb, 90m+gNb, 90m+gNbcum, 91mNb, 92mNb, 95gNb, 95mNb, 95m+gNb, 96Nb, 97m+gNb, 88m+gZrcum and 89m+gZrcum in the energy range of 6.9–35.8 MeV. The data for formation of 97mTc, 88gNb, 88mNb and 89mNb are reported for the first time. The obtained results were compared to the prediction of the nuclear reaction model code TALYS adopted from the TENDL-2015 library and to the previously published cross-sections. The thick target yields for all the radionuclides were calculated from the measured data. We suggest recommended cross-sections and thick target yields for the 100Mo(p,2n)99mTc, 100Mo(p,x)99Mo and natMo(p,x)96m+gTc nuclear reactions deduced from the selected experimental data.

We measured cross-sections of the deuteron-induced reactions on 89 Y in the energy range of 3.9–19.5 MeV. Excitation functions for formation of 88 Zr, 89m Zr, 89 Zr, 88 Y, 90m Y and 87m Sr were determined and compared with previously published data and prediction of the TALYS code. Thick target yields for production of 88 Zr, 89 Zr cum , 88 Y, 90m Y and 87m Sr were calculated from the measured cross-sections. Achievable activity versus radionuclidic purity of medically relevant 89 Zr is discussed and compared with the production via the 89 Y(p,n) reaction. Parallel use of titanium and aluminium beam monitors revealed systematic difference between the recommended cross-sections of both monitoring reactions and provided new cross-section data for formation of 24 Na, 27 Mg, 43 Sc, 44m Sc, 44 Sc, 46 Sc, 47 Sc and 48 Sc. The cross-sections for the nat Ti(d,x) 46 Sc reactions agree very well with recently proposed recommended values.

The production and separation of no-carrier-added 197(m)Hg for imaging and therapy research based on the 197Au(p,n)197(m)Hg reaction was recently reported. However, large-scale production requires the development of a rapid, reliable method for Hg/Au separation. Ideally, a solid phase sorbent is used to bind at least one of the two metal ions reversibly, allowing for the product elution into a small volume. Di(2-ethylhexyl)orthophosphoric acid (HDEHP) im-pregnated onto an inert support as the so called LN resin (LaNthanides) was examined for this application.

Drug delivery systems based on thermoresponsive polymers might serve as suitable carriers for local radiotherapy. We have, therefore, designed and synthesized a radioiodine-labellable thermoresponsive polymer. The polymer was synthesized by copolymerization of N -isopropylacrylamide with N -methacryloyl tyrosinamide in tetrahydrofuran, and then labelled by 131 I. The solution of this labelled polymer in dimethylsulfoxide (4.4 MBq/ml; 1.8 wt% polymer) was applied to femoral muscle of male Balb/C mice (50 μl per animal). The biodistribution and excretion of radioactivity was followed in 2 h and 1, 7, 14, 28 and 42 d post injection ( n =6 per time point). As expected, the labelled polymer was left on the application site (ca 90% 2 h post injection), decreasing slowly to ca 80% within 14 d. At 28 d post injection, ca 70% of the injected activity was still found on the application site, decreasing to ca 60% at 42 d. No organ-specific accumulation of the radioactivity released from the application site, including thyroid, was observed. Majority of the released radioactivity was excreted via urine and faeces. This preliminary study suggests that thermoresponsive polymers could be used as an effective delivery system for localized radiotherapy.

I. E. Marko [Universite catholique de Louvain, Belgium]—Novel Orthoesters in Organic Synthesis. S. J. Harwood [GlaxoSmithKline, UK]—The Synthesis of Stable Labelled Ketamine. Th. Moenius, R. Salter, B. Wietfeld, P. Burtscher, C. Zueger [Novartis, Switzerland]—C-13, C-14, N-15 Labelling of the 4-Cyanobenzyl bromide – A Versatile Labelling Building Block. J. Clayden [University of Manchester, UK]—Synthesis and Stereocontrol with Lithiated Amides. R. Salter, K. Bordeaux, P. Burtscher, Y. Metz, Th. Moenius, I. Rodriguez, R. Ruetsch, R. Voges, C. Zueger [Novartis, Switzerland]—Isotopic Labelling of STI571 and its Metabolites in the Development of Gleevec®. J. M. Gardiner, W. Stimpson, N. Panchal [University of Manchester, UK], J. Herbert, G. J. Ellames [Sanofi-Aventis, UK]—Synthesis of Labelled Carbohydrates. M. Beller [Rostock University, Germany]—Homogeneous Catalysis – A Powerful Tool for the Synthesis of Pharmaceuticals. J. Kozempel, J. Kadeřavek, L. Lesetický, O. Lebeda [University of Prague, Czech]—Preparation of Ortho-radiohalogenated Phenylazides and Triazenes, Versatile Building Blocks for Indirect Labelling. K. Wahala, P. Kiuru, E. Leppala, M. Pohjoispaa, K. Parikka, B. Raffaelli [University of Helsinki, Finland]—Controlled Polydeuteration of Estrogenic Compounds. J. M. Herbert [Sanofi-Aventis, UK]—Catalyst Stability in Iridium-mediated Isotope Exchange. C. G. M. Janssen, W.L.M. Verluyten, M. Vliegen [Johnson & Johnson Pharmaceutical, Belgium]—Pd/C Catalysed Hydrogenolytic H/T Exchange in Solvents, Effects on Solvents and Product in a Bromine-tritium Exchange Reaction. P. Mading, F. Fuchtner, R. Bergmann, J. Pietzsch, C. Hultsch, F. Wust [Forschungszentrum Rossendorf, Germany]—A New Module-Assisted Synthesis of the Versatile, Bifunctional Labelling Agent [18F]SFB: From Radiochemistry to Applications. M. Scheunemann, J. Vercouillie, St. Fischer, J. Steinbach [Institut fur Interdisziplinare Isotopenforschung Leipzig, Germany], D. Sorger, U. Grosmann, O. Sabri, R. Schliebs [University Leipzig, Germany]—Syntheses and First Biological Evaluation of 18F Labelled Bicyclic Analogues of Vesamicol as Potential VAChT Imaging Agents.

The mono-energetic conversion electrons from the decay of 83 m Kr represent a unique tool for energy calibration and systematic studies of the tritium beta spectrum measured in neutrino mass determination experiments. For this reason, the corresponding parent isotope was produced in reactions nat Kr(p,xn) 83 Rb. The behaviour of 83 Rb ( T 1 / 2 = 86.2 d ) and its daughter product 83 m Kr ( T 1 / 2 = 1.83 h ) was examined, when the 83 Rb was trapped in a cation-exchanger chromatographic paper or in zeolite. Using gamma spectroscopy measurements, recommendations for the production of a 83 Rb/ 83 m Kr radionuclide generator based on these cation-exchangers and suitable for the neutrino mass determination experiment KATRIN were deduced.

The alpha emitter (211)At is a radionuclide with good potential for use in the therapy of smaller tumours and metastases. However, limited availability of this radionuclide hinders development of this application and the research of astatine chemistry in general. In this general context we have designed and tested a new internal target system. A thin bismuth layer (3-5 microm) was evaporated onto a light target backing (7.5 g) and irradiated at 0.5-1.5 degrees angles with 29.5 MeV alpha particles beam of intensity up to 30 microA. The backing was then released from the target holder and used directly for astatine separation via dry distillation. Astatine condensed on the Teflon capillary walls was then eluted into 150-250 microl of methanol. The saturation yield was found to be ca. 400 MBq/microA, and the radionuclidic purity of (211)At acceptable for medical applications (activity ratio (210)At/(211)At

Introduction The commercial viability of cyclotron-produced 99m Tc as an alternative to generator-produced 99m Tc depends on several factors. These include: production yield, ease of target processing and recycling of 100 Mo, radiochemical purity, specific activity as well as the presence of other radionuclides, particularly various Tc radioisotopes that cannot be separated chemically and will remain in the final clinical preparation. These Tc radionuclidic impurities are derived from nuclear interactions of the accelerated protons with other stable Mo isotopes present in the enriched 100 Mo target. The aim of our study was to determine experimentally the yields of Tc radioisotopes produced from these stable Mo isotopes as a function of incident beam energy in order to predict radionuclidic purity of 99m Tc produced in highly enriched 100 Mo targets of known isotopic composition. Methods Enriched molybdenum targets of 95 Mo, 96 Mo, 97 Mo, 98 Mo and 100 Mo were prepared by pressing powdered metal into an aluminum target support. The thick targets were bombarded with 10 to 24MeV protons using the external beam line of the U-120M cyclotron of the Nuclear Physics Institute, Řež. The thick target yields of 94 Tc, 94m Tc, 95 Tc, 95m Tc, 96m+g Tc and 97m Tc were derived from their activities measured by γ spectrometry using a high purity Ge detector. These data were then used to assess the effect of isotopic composition of highly enriched 100 Mo targets on the radionuclidic purity of 99m Tc as a function of proton beam energy. Estimates were validated by comparison to measured activities of Tc radioisotopes in proton irradiated, highly enriched 100 Mo targets of known isotopic composition. Results The measured thick target yields of 94 Tc, 94m Tc, 95 Tc, 95m Tc, 96m+g Tc and 97m Tc correspond well with recently published values calculated via the EMPIRE-3 code. However, the measured yields are more favourable with regard to achievable radionuclidic purity of 99m Tc. Reliability of the measured thick target yields was demonstrated by comparison of the estimated and measured activities of 94 Tc, 95 Tc, 95m Tc, and 96m+g Tc in highly enriched 100 Mo (99%) targets that showed good agreement, with maximum differences within estimated uncertainties. Radioisotopes 94m Tc and 97m Tc were not detected in the irradiated 100 Mo targets due to their low activities and measurement conditions; on the other hand we detected small amounts of the short-lived positron emitter 93 Tc ( T ½ =2.75h). In addition to 99m Tc and trace amounts of the various Tc isotopes, significant activities of 96 Nb, 97 Nb and 99 Mo were detected in the irradiated 100 Mo targets. Conclusions Radioisotope formation during the proton irradiation of Mo targets prepared from different, enriched stable Mo isotopes provides a useful data base to predict the presence of Tc radionuclidic impurities in 99m Tc derived from proton irradiated 100 Mo targets of known isotopic composition. The longer-lived Tc isotopes including 94 Tc ( T ½ =4.883h), 95 Tc ( T ½ =20.0h), 95m Tc ( T ½ =61 d), 96m+g Tc ( T ½ =4.24 d) and 97m Tc ( T ½ =90 d) are of particular concern since they may affect the dosimetry in clinical applications. Our data demonstrate that cyclotron production of 99m Tc, using highly enriched 100 Mo targets and 19–24MeV incident proton energy, will result in a product of acceptable radionuclidic purity for applications in nuclear medicine.

The isomer 83mKr with its half-life of 1.83 h is an ideal calibration source for a liquid noble gas dark matter experiment like the XENON project. However, the risk of contamination of the detector with traces of the much longer lived mother isotop 83Rb (86.2 d half-life) has to be ruled out. In this work the release of 83Rb atoms from a 1.8 MBq 83Rb source embedded in zeolite beads has been investigated. To do so, a cryogenic trap has been connected to the source for about 10 days, after which it was removed and probed for the strongest 83Rb gamma-rays with an ultra-sensitive Germanium detector. No signal has been found. The corresponding upper limit on the released 83Rb activity means that the investigated type of source can be used in the XENON project and similar low-background experiments as 83mKr generator without a significant risk of contaminating the detector. The measurements also allow to set upper limits on the possible release of the isotopes 84Rb and 86Rb, traces of which were created alongside the production of 83Rb at the Rez cyclotron., Comment: 11 pages, 7 figures, submitted to Journal of Instrumentation

A difficult task with many particle detectors focusing on interactions below ~100 keV is to perform a calibration in the appropriate energy range that adequately probes all regions of the detector. Because detector response can vary greatly in various locations within the device, a spatially uniform calibration is important. We present a new method for calibration of liquid xenon (LXe) detectors, using the short-lived 83m-Kr. This source has transitions at 9.4 and 32.1 keV, and as a noble gas like Xe, it disperses uniformly in all regions of the detector. Even for low source activities, the existence of the two transitions provides a method of identifying the decays that is free of background. We find that at decreasing energies, the LXe light yield increases, while the amount of electric field quenching is diminished. Additionally, we show that if any long-lived radioactive backgrounds are introduced by this method, they will present less than 67E-6 events/kg/day in the next generation of LXe dark matter direct detection searches, 9 pages, 9 figures. Accepted to Review of Scientific Instruments

A new simplified approach for the preparation of 211 At-labelled compounds is presented. The labelling procedure is carried out entirely in a Teflon capillary which also serves as a cryotrap. Two organic astatine compounds were synthesized by this method: 5-[ 211 At]astato-2′-deoxyuridine (AUdR) and N -succinimidyl-4-[ 211 At]astatobenzoate (SAB), starting from their respective stannylated precursors. The first reaction was performed in aqueous solution and the latter in an organic solvent using Iodogen as the oxidant in both cases. Overall radiochemical yields were approximately 75% for AUdR and approximately 70% for SAB.

The separation of krypton and xenon is of particular importance for the field of direct dark matter search with liquid xenon detectors. The intrinsic contamination of the xenon with radioactive (85)Kr makes a significant background for these kinds of low count-rate experiments and has to be removed beforehand. This can be achieved by cryogenic distillation, a technique widely used in industry, using the different vapor pressures of krypton and xenon. In this paper, we present an investigation on the separation performance of a single stage distillation system using a radioactive (83m)Kr-tracer method. The separation characteristics under different operation conditions are determined for very low concentrations of krypton in xenon at the level of (83m)Kr/Xe = 1.9 ⋅ 10(-15), demonstrating, that cryogenic distillation in this regime is working. The observed separation is in agreement with the expectation from the different volatilities of krypton and xenon. This cryogenic distillation station is the first step on the way to a multi-stage cryogenic distillation column for the next generation of direct dark matter experiment XENON1T.

The alpha emitter 211At is a prospective radionuclide for the therapy of smaller tumours and metastases. However, the chemical properties of 211At together with the fact that it is available only in trace amounts, makes the labelling of prospective astatine carriers rather complicated. In this context we have studied a new class of possible astatine carriers--nanoparticle systems, which tend to concentrate themselves in some types of tumours by means of the EPR effect. Additionally, such nanoparticles have the advantage that they may be chemically modified by the attachment of a tumour-seeking agent, and also directly applied to the target site. In order to reach high labelling yields, and in order to protect the nanoparticles from rapid degradation by the immune system, silver-containing particles covalently coated by poly(ethylene oxide) were developed and tested. The effect of the different reducing and oxidizing agents on the labelling yield was also determined. It was found that labelling yields were almost quantitative and well reproducible under reducing conditions, while under oxidizing conditions they dropped to ca. 50%. In the absence of any reducing or oxidizing agent, the labelling yields were randomly distributed between a range of 50% and 97%. The labelled nanoparticles were stable even in a large surplus of competing chloride ions.

We describe a novel thermoresponsive polymeric drug delivery system based on poly(N-isopropylacrylamide) with isotopically labellable end groups [l-tyrosinamide or diethylenetriaminepentaacetic acid (DTPA)] designed for local radiotherapy. The polymers are readily soluble in isotonic aqueous sodium chloride at room temperature and the phase separation is complete at body temperature as proved by DSC measurements. Sufficent binding capacity for radionuclides and chemical stability are demonstrated on 125I and 90Y-labelled polymers.

summary A new polymeric drug delivery system designed for possible local chemoradiotherapy using injectable thermoresponsive polymer with radionuclide and doxorubicin, which serves as an antiproliferative agent and hydrophobic moiety controlling bioerosion in the same time, was synthesized and characterized. Doxorubicin is bound to the polymer carrier by a newly developed N -glycosylamine bond.

The KATRIN experiment is designed for a direct and model-independent determination of the effective electron anti-neutrino mass via a high-precision measurement of the tritium $\beta$-decay endpoint region with a sensitivity on $m_\nu$ of 0.2$\,$eV/c$^2$ (90% CL). For this purpose, the $\beta$-electrons from a high-luminosity windowless gaseous tritium source traversing an electrostatic retarding spectrometer are counted to obtain an integral spectrum around the endpoint energy of 18.6$\,$keV. A dominant systematic effect of the response of the experimental setup is the energy loss of $\beta$-electrons from elastic and inelastic scattering off tritium molecules within the source. We determined the \linebreak energy-loss function in-situ with a pulsed angular-selective and monoenergetic photoelectron source at various tritium-source densities. The data was recorded in integral and differential modes; the latter was achieved by using a novel time-of-flight technique. We developed a semi-empirical parametrization for the energy-loss function for the scattering of 18.6-keV electrons from hydrogen isotopologs. This model was fit to measurement data with a 95% T$_2$ gas mixture at 30$\,$K, as used in the first KATRIN neutrino mass analyses, as well as a D$_2$ gas mixture of 96% purity used in KATRIN commissioning runs. The achieved precision on the energy-loss function has abated the corresponding uncertainty of $\sigma(m_\nu^2), Comment: 12 figures, 18 pages; to be submitted to EPJ C