Radiochemische Separation von 45Ti und 52gMn zur Herstellung radiomarkierter Komplexe

With regard to special diagnostic applications, non-standard radionuclides often represent suitable alternatives to standard radionuclides like 11C and 18F due to their physical decay characteristics such as half-life (t1/2) and decay modes. Furthermore, non-standard positron emission tomography (PET) nuclides enable a novel design and synthesis of specific PET tracers to study a variety of biological processes. However, their clinical application in diagnostics is hampered by their limited availability owing to the lack of suitable radiochemical separation techniques. The positron emitter 45Ti (t½: 3.1 h, Iβ+ = 84.8 %, Eβ+max = 439 keV) is of high importance for imaging studies since Ti-complexes have shown therapeutic efficacy in cancer treatment as cytostatic agents. 45Ti can be easily produced at a small cyclotron by proton bombardment of a Sc target via the 45Sc(p,n)45Ti nuclear reaction. Unfortunately, efficient separation methods to isolate 45Ti from the irradiated target are still missing. Therefore, this work aimed to develop a novel separation technique to obtain 45Ti in high purity and radiochemical yield. The separation method was based on a thermochromatographic approach via the formation of volatile [45Ti]TiCl4 in a chlorine gas stream, enabling the separation from low volatile ScCl3. The separation apparatus and the individual steps were adjusted to enable trapping of [45Ti]Cl4 for further chemical conversions. The most relevant separation parameters like reaction temperature, volume flow, separation time, and chlorine concentration in the carrier gas were optimized to achieve efficient formation and trapping of [45Ti]TiCl4 in high separation yields. Finally, [45Ti]TiCl4 was obtained with a recovery yield of 76% ± 5% (n=5) (n.d.c. 48% ± 3% (n=5)) and a radionuclidic purity of >99%, facilitating subsequent labeling steps. To this end, [45Ti]TiCl4 was reacted with the complex ligand H4(2,4-salan) [6,6'-((ethane-1,2-diylbis((2-hydroxyethyl)azanediyl))-bis(methylene))-bis(2, 4-dimethyl-phenol)] or with H4(3,4-salane) [6,6'-((ethane-1,2-diylbis((2-hydroxyethyl)azanediyl))-bis(methylene))bis(3,4-dimethyl-phenol)] in THF to form the corresponding 45Ti complexes. Thus, [45Ti][Ti(2,4-salan)] and [45Ti][Ti(3,4-salan)] were afforded in radiochemical yields of 15% ± 7% (n=7) and 13% ± 6% (n=3), respectively. Furthermore, [45Ti][Ti(HBED)] was obtained from [45Ti]TiCl4 by reaction with the chelator N,N-bis(2-hydroxybenzyl)ethylenediamine-N,N-diacetic acid (HBED). However, radiochemical yield of the latter was poor (3% ± 1% (n=3)) after isolation by high performance liquid chromatography. The stability of the titanium complexes under physiological conditions was studied using human blood plasma. It was shown that [45Ti][Ti(HBED)] dissociates rapidly in buffered aqueous media, as well as human blood plasma. In contrast, [45Ti][Ti(2,4-salan)] seems to be more compatible for in vivo applications since it was stable in all tested media and blood plasma for two hours. The second part of this work focused on the non-standard radionuclide 52gMn. The application of isotopic mixtures of 52gMn and the non-radioactive 55Mn facilitates bimodal PET/MR imaging since Mn, due to its paramagnetic properties, is NMR-active. Bimodal PET/MR imaging synergistically combines the sensitivity and quantification of PET with the high spatial resolution of magnetic resonance imaging (MRI). Based on previous work at the INM-5, a bifunctional PSMA-specific ligand with a cyclohexyl-1,2-diaminoacetic acid function (CDTA) was prepared via copper(I)-catalyzed alkyne-azide cycloaddition with a total yield of 37 %. CDTA and divalent manganese form complexes exhibiting high in vivo stability and relaxivity, which are especially important for contrast imaging. Radiochemical yields for the carrier-added as well as the non-carrier-added Mn-complex were almost quantitative within 20 min. The carrier-added version of the Mn-complex has a high potential for bimodal imaging applications. The preliminary biological evaluation of [52gMn][Mn(CDTA-PSMA)] in a rat glioma model by ex vivo autoradiography demonstrated high accumulation in the peritumoral region of the brain tumor. Further studies using 45Ti-labeled PSMA-selective ligands are underway. Additionally, the 52gMn-labeled PSMA ligand will be examined in preclinical prostate cancer models

Systematic Screening of Drosophila Deficiency Mutations for Embryonic Phenotypes and Orphan Receptor Ligands

This paper defines a collection of Drosophila deletion mutations (deficiencies) that can be systematically screened for embryonic phenotypes, orphan receptor ligands, and genes affecting protein localization. It reports the results of deficiency screens we have conducted that have revealed new axon guidance phenotypes in the central nervous system and neuromuscular system and permitted a quantitative assessment of the number of potential genes involved in regulating guidance of specific motor axon branches. Deficiency “kits” that cover the genome with a minimum number of lines have been established to facilitate gene mapping. These kits cannot be systematically analyzed for phenotypes, however, since embryos homozygous for many deficiencies in these kits fail to develop due to the loss of key gene products encoded within the deficiency. To create new kits that can be screened for phenotype, we have examined the development of the nervous system in embryos homozygous for more than 700 distinct deficiency mutations. A kit of ∼400 deficiency lines for which homozygotes have a recognizable nervous system and intact body walls encompasses >80% of the genome. Here we show examples of screens of this kit for orphan receptor ligands and neuronal antigen expression. It can also be used to find genes involved in expression, patterning, and subcellular localization of any protein that can be visualized by antibody staining. A subset kit of 233 deficiency lines, for which homozygotes develop relatively normally to late stage 16, covers ∼50% of the genome. We have screened it for axon guidance phenotypes, and we present examples of new phenotypes we have identified. The subset kit can be used to screen for phenotypes affecting all embryonic organs. In the future, these deficiency kits will allow Drosophila researchers to rapidly and efficiently execute genome-wide anatomical screens that require examination of individual embryos at high magnification

Cultural trauma, counter-narratives, and dialogical intellectuals: the works of Murakami Haruki and Mori Tatsuya in the context of the Aum affair

In this article, we offer a new conceptualization of intellectuals as carriers of cultural trauma through a case study of the Aum Affair, a series of crimes and terrorist attacks committed by the Japanese new religious movement Aum Shinrikyō. In understanding the performative roles intellectuals play in trauma construction, we offer a new dichotomy between “authoritative intellectuals,” who draw on their privileged parcours and status to impose a distinct trauma narrative, and “dialogical intellectuals,” who engage with local actors dialogically to produce polyphonic and open-ended trauma narratives. We identify three dimensions of dialogical intellectual action: firstly, the intellectuals may be involved in dialogue with local participants; secondly, the intellectual products themselves may be dialogical in content; and thirdly, there might be a concerted effort on the part of the intellectuals to record and to disseminate dialogue between local participants. In the context of the Aum Affair, we analyze the works of Murakami Haruki and Mori Tatsuya as dialogical intellectuals while they sought, with the help of local actors’ experiences, to challenge and to alter the orthodox trauma narrative of Aum Shinrikyō as exclusively a social evil external to Japanese society and an enemy to be excluded from it. Towards the end of the article, we discuss the broader significance of this case study and suggest that in light of recent societal and technological developments, the role and scope of dialogical intellectuals as carriers of trauma are changing and possibly expanding

Radiochemische Separation von 45^{45}Ti und 52^{52}gMn zur Herstellung radiomarkierter Komplexe

With regard to special diagnostic applications, non-standard radionuclides often represent suitable alternatives to standard radionuclides like $\textit{11}$C and $\textit{18}$F due to their physical decay characteristics such as half-life (t$_{1/2}$) and decay modes. Furthermore, non-standard positron emission tomography (PET) nuclides enable a novel design and synthesis of specific PET tracers to study a variety of biological processes. However, their clinical application in diagnostics is hampered by their limited availability owing to the lack of suitable radiochemical separation techniques. The positron emitter $^{45}$Ti (t$_{½}$: 3.1 h, I$_{β+}$ = 84.8 %, E$_{β+max}$ = 439 keV) is of high importance for imaging studies since Ti-complexes have shown therapeutic efficacy in cancertreatment as cytostatic agents. $^{45}$Ti can be easily produced at a small cyclotron by proton bombardment of a Sc target via the $^{45}$Sc(p,n)$^{45}$Ti nuclear reaction. Unfortunately, efficient separation methods to isolate $^{45}$Ti from the irradiated targetare still missing. Therefore, this work aimed to develop a novel separation technique to obtain $^{45}$Ti in high purity and radiochemical yield. The separation method was based on a thermochromatographic approach via the formation of volatile [$^{45}$Ti]TiCl$_{4}$ in a chlorine gas stream, enabling the separation from low volatile ScCl$_{3}$. The separation apparatus and the individual steps were adjusted to enable trapping of [$^{45}$Ti]Cl$_{4}$ for further chemical conversions. The most relevant separation parameters like reaction temperature, volume flow, separation time, and chlorine concentration in the carrier gas were optimized to achieve efficient formation and trapping of [$^{45}$Ti]TiCl$_{4}$ in high separation yields. Finally, [$^{45}$Ti]TiCl$_{4}$ was obtained with a recovery yield of 76% ± 5%(n=5) (n.d.c. 48% ± 3% (n=5)) and a radionuclidic purity of >99%, facilitating subsequent labeling steps. To this end, [$^{45}$Ti]TiCl$_{4}$ was reacted with the complex ligand H$_{4}$(2,4-salan) [6,6'- ((ethane-1,2-diylbis((2-hydroxyethyl)azanediyl))-bis(methylene))-bis(2,4-dimethylphenol)] or with H$_{4}$(3,4-salane) [6,6'-((ethane-1,2-diylbis((2-ydroxyethyl)azanediyl))- bis(methylene))bis(3,4-dimethyl-phenol)] in THF to form the corresponding $^{45}$Ti complexes. Thus, [$^{45}$Ti][Ti(2,4-salan)] and [$^{45}$Ti][Ti(3,4-salan)] were afforded in radiochemical yields of 15% ± 7% (n=7) and 13% ± 6% (n=3), respectively. Furthermore, [$^{45}$Ti][Ti(HBED)] was obtained from [$^{45}$Ti]TiCl$_{4}$ by reaction with the chelator N,N-bis(2-hydroxybenzyl)ethylenediamine-N,N-diacetic acid (HBED). [...

Thermochromatographic separation of 45Ti and subsequent radiosynthesis of [45Ti]salan

Due to its favorable decay properties, the non-standard radionuclide 45Ti is a promising PET isotope for tumor imaging. Additionally, titanium complexes are widely used as anti-tumor agents and 45Ti could be used to study their in vivo distribution and metabolic fate. However, although 45Ti can be obtained using the 45Sc(p,n)45Ti nuclear reaction its facile production is offset by the high oxophilicity and hydrolytic instability of Ti4+ ions in aqueous solutions, which complicate recovery from the irradiated Sc matrix. Most available 45Ti recovery procedures rely on ion exchange chromatography or solvent extraction techniques which are time-consuming, produce large final elution volumes, or, in case of solvent extraction, cannot easily be automated. Thus a more widespread application of 45Ti for PET imaging has been hampered. Here, we describe a novel, solvent-free approach for recovery of 45Ti that involves formation of [45Ti]TiCl4 by heating of an irradiated Sc target in a gas stream of chlorine, followed by thermochromatographic separation of the volatile radiometal chloride from co-produced scandium chloride and trapping of [45Ti]TiCl4 in a glass vial at − 78 °C. The recovery of 45Ti amounted to 76 ± 5% (n = 5) and the radionuclidic purity was determined to be > 99%. After trapping, the [45Ti]TiCl4 could be directly used for 45Ti-radiolabeling, as demonstrated by the successful radiosynthesis of [45Ti][Ti(2,4-salan)]

Apprehensive parents: a qualitative study of parents seeking immediate primary care for their children

Background: Children are more frequent users of out-of-hours primary care than other age groups, although their medical problems are less urgent. Aim: To gain insight into the health-seeking behaviour of parents who ask for immediate medical attention for their children. Design of study: Qualitative analysis of interviews and telephone calls. Setting: A general practice out-of-hours cooperative that caters for approximately 300 000 people in The Netherlands. Method: A semi-structured interview was conducted with 27 parents who had consulted their own GP or an out-of-hours facility for primary care because they wanted urgent medical attention for their child who was sick. Forty-four telephone calls from parents seeking medical care for a child were analysed. Results: Recognising symptoms in a child started with the observation of a deviation from the child's normal appearance or behaviour. Parents decided to contact medical services when they felt they lost control of the situation. Most parents consulted because they wanted to rule out or prevent serious disease, not because of the condition itself; not wanting to take a risk with their child was an important motivation. In an attempt to rule out serious disease at home, parents also attempted diagnostic procedures they had copied from professionals. Conclusion: Worry of parents and their health-seeking behaviour can be seen as an expression of the central role of risk regulation in modern society. Doctors need to realise their own contribution to the way parents want to rule out serious disease in their children. Improving parents' knowledge will not solve the problem of inappropriate use of out-of-hours facilities