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Due to their essential role in the pathogenesis of cancer, members of the Eph (erythropoietin-producing hepatoma cell line-A2) receptor tyrosine kinase family represent promising candidates for molecular imaging. Thus, the development and preparation of novel radiotracers for the noninvasive imaging of the EphB4 receptor via positron emission tomography (PET) is described. First in silico investigations with the indazolylpyrimidine lead compound which is known to be highly affine to EphB4 were executed to identify favorable labeling positions for an introduction of fluorine-18 to retain the affinity. Based on this, reference compounds as well as precursors were developed and labeled with carbon-11 and fluorine-18, respectively. For this purpose, a protecting group strategy was essential to generate for the prevention of unwanted methylation and to enable the introduction of fluorine-18. Further, a convenient radiolabeling strategy using [11C]methyl iodide was established which afforded the isotopically labeled radiotracer in 30-35% RCY (d.c.) which is identical with the original inhibitor molecule. A spiro ammonium precursor was prepared for radiolabeling with fluorine-18. Unfortunately, the labeling did not lead to the desired 18F-radiotracer under the chosen conditions.

In dem Projekt stehen die Aspekte der bauphysikalischen Nutzung von Bauteilen und deren Lebenszyklus im Vordergrund. So sollen mit Hilfe der RFID-Sensortechnik dynamische Informationen über den aktuellen Zustand einzelner Bauteile und Bausysteme erfasst und bewertet werden, um auch nach der Bauerstellung in der langjährigen Nutzungsphase eine Sicherung der Qualität durch ein "Hineinsehen" in die Bauteile mit Hilfe der RFID-Funk- und Sensor-Technik erreichen zu können.

We report the first GNO solar neutrino results for the measuring period GNOI, solar exposure time May 20, 1998 till January 12, 2000. In the present analysis, counting results for solar runs SR1 - SR19 were used till April 4, 2000. With counting completed for all but the last 3 runs (SR17 - SR19), the GNO I result is [65.8 +10.2 -9.6 (stat.) +3.4 -3.6 (syst.)]SNU (1sigma) or [65.8 + 10.7 -10.2 (incl. syst.)]SNU (1sigma) with errors combined. This may be compared to the result for Gallex(I-IV), which is [77.5 +7.6 -7.8 (incl. syst.)] SNU (1sigma). A combined result from both GNOI and Gallex(I-IV) together is [74.1 + 6.7 -6.8 (incl. syst.)] SNU (1sigma)., submitted to Physics Letters B, June 2000. PACS: 26.65. +t ; 14.60 Pq. Corresponding author: till.kirsten@mpi-hd.mpg.de ; bellotti@mi.infn.it

Objectives: Members of the Eph receptor tyrosine kinase family play an essential role in the pathogenesis of cancer and, therefore, they are promising candidates for noninvasive molecular imaging, e.g. by PET. Several potent Eph inhibitors are reported either based on high molecular weight compounds like peptides which block the extracellular domain or on small organic molecules which bind to the intramolecular ATP binding pocket of the appropriate receptor. To date, only peptide-based radiotracers containing Cu-64 or In-111 are known which are specific for Eph receptors [1]. Due to favourable chemical and biological properties, small organic inhibitors based on the benzodioxolylpyrimidine structural motif were developed in the past [2]. Unfortunately, these tracers showed only a moderate uptake in tumor cells (A375) and no uptake in vivo in the respective tumor (A375) bearing mice. To overcome these problems, a novel lead structure 1 (IC50 = 1.3 nM) was chosen based on a indazolylpyrazole core [3]. In silico studies were done to determine the best position for the introduction of fluorine-18. Further, the development and preparation of novel 11C/18F-radiotracers is described. First biological studies were accomplished regarding the stability of the new tracers to figure out the ex vivo and in vivo behavior. Methods: The first tracer prepared by isotopically labeling with [11C]methyl iodide. For this purpose and for the 18F-labeling, a protecting group strategy was developed for the regioselective labeling due to three secondary amino groups of this compound. In silico docking studies were performed using the X-ray structure of the EphB4 receptor including a similar inhibitor. Based on these results, two novel references and precursors were evaluated and prepared for the labeling with fluorine-18. Results: For both labeling purposes, a protecting group strategy based on the ethoxyethyl (EOE) group was applied. The EOE group was introduced to block the amino function of the indazole core and to avoid radiolabeling on this position. In the first labeling case, the 11C-labeling was accomplished in a remotely controlled synthesis module in three steps. The first step involved the preparation of [11C]methyl idodide from [11C]methane, the second step comprehended the radiolabeling of the EOE-protected precursor and the final step included the cleavage of the protecting group under acidic conditions leading to [11C]1. Attempts were made using docking experiments to evaluate the optimal position for the introduction of fluorine-18/-19. In the first case, the methyl group of the molecule was changed against the 3-fluoropropyl residue leading to 2. Secondly, one of the morpholine rings was replaced with the (3-fluoropropyl)piperazinyl moiety yielding 3. Based on these findings, a preparation route to precursors and references was successfully established. Conclusions: A novel 11C-radiotracer was prepared for the imaging of Eph receptors in cancer using a three step labeling procedure. For radiofluorination purposes, references (2 and 3) as well as precursors were prepared successfully. Radiolabeling and first promising biological studies are ongoing. Acknowledgements: Support by the Fonds der chemischen Industrie (FCI-Germany). References: [1] Xiong C, et al. (2011) J Nucl Med, 52, 241-8. [2] Mamat C, et al. (2012) ChemMedChem, 7, 1991-2003. Bardelle C, et al. (2010) Biorg Med Chem Lett, 20, 6242-5.

Ziel/Aim: Members of the Eph receptor tyrosine kinase family play an essential role in the pathogenesis of cancer and, therefore, are promising candidates for molecular imaging purposes, e.g. by PET. In this regard, radiochemical access to 11C-radiotracers derived from potent inhibitors (IC50 = 1.3 nM, calcd. logP = 3.42) targeting EphB4 kinase domain and bearing the indazolylpyrazole structural motif was developed. Methodik/Methods: The evaluation of a protecting group strategy based on the ethoxyethyl moiety (EOE) was necessary for the regioselective labeling with [11C]CH3I due to three secondary amino groups of the precursor. The labeling was accomplished in a remotely controlled synthesis module in three steps. The first step involved the preparation of [11C]CH3I from [11C]CH4, the second step comprehended the radiolabeling of the protected precursor and the final step included the cleavage of the protecting group. Ergebnisse/Results: The synthesis of the reference as well as the precursor was done starting from EOE protected indazole. Subsequent reaction with 2,4-diochloropyrimidine give the first substructure. For the preparation of the precursor, the first substructure was treated with 3,5-di(morpholino)aniline under Buchwald-Hartwig conditions. For the preparation of the reference, the first substructure was first methylated and then treated with 3,5-di(morpholino)aniline. The radiolabeling was done starting with ~ 1-1.5 GBq [11C]CH3I under basic conditions. After 2 min reaction time 1 M HCl was added and the mixture was maintained for 2 min. Approx. 200 MBq of the desired radiotracer could be obtained within 20 min after EOB (30-35% d.c. yield based on [11C]CH4). Schlussfolgerungen/Conclusions: The two-step radiolabeling of a novel indazolylpyrazole derivative with [11C]CH3I was successfully demonstrated. First stability tests showed beneficial behaviour ex vivo. Further biological studies for an application as radiotracer for functional tumor imaging are ongoing. Literatur/References: Mamat C, Mosch B et al. (2012) ChemMedChem 7:1991-2003.

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Polystyrene (PS) nanoparticles were prepared via a nanoprecipitation process. The influence of the pH of the buffer solution used during the immobilization process on the loading of Candida antarctica lipase B (Cal-B) and on the hydrolytic activity (hydrolysis of p-nitrophenyl acetate) of the immobilized Cal-B was studied. The pH of the buffer solution has no influence on enzyme loading, while immobilized enzyme activity is very dependent on the pH of adsorption. Cal-B immobilized on PS nanoparticles in buffer solution pH 6.8 performed higher hydrolytic activity than crude enzyme powder and Novozyme 435.

Recording of sub-MeV solar neutrinos ( ν pp , ν Be7 ) in the Gallium Neutrino Observatory (GNO) is essential in further defining the neutrino oscillation parameters (masses, mixings). Continued error reduction is crucial in this context. The data set GNO H is now completed. The result from 43 runs (May 1998 through January 2002) is 65 ± 7 SNU. The total record is now 108 runs (65 Gallex, 43 GNO [19 GNOI, 24 GNO II]), the combined result is 71 ± 6 SNU. The systematical error in GNO is reduced to ± 3.0 SNU. This substantial error reduction has been achieved mainly through internal counter calibrations, an improved Rn-correction, and the introduction of neural network data analysis. The physics potential of future sub-MeV neutrino studies demands further efforts. Work is underway towards even better 71 Ge counting efficiency by application of cryotechnics and towards a new and more precise 51 Cr neutrino source experiment (>2.5 MCi) for an improved determination of the cross section for ν-capture on 71 Ga.

GNO is the Gran Sasso experiment devoted to the measurement of the solar neutrino interaction rate in Gallium. It started to take solar data in 1998. Characteristics of the experimental apparatus are reported. The GNO I result from solar runs SR1-SR19 (corresponding to the period May 20, 1998 to January 12, 200) at 1 σ level is 65.8 −9.6 +10.2 ( stat. ) −3.6 +3.4 ( syst. ) or 65.8 −10.2 +10.7 SNU (with errors combined in quadrature). Future plans are also briefly presented.