Radiosynthesis of L-[18F]fluorotryptophan by isotopic exchange on carbonyl-activated precursors

In the past a variety of 18F-labeled aromatic amino acids have been developed, primarily for tumor diagnostics with positron-emission-tomography. Recently tryptophan got high attention, since evidence came up that some tumors exhibit an elevated consumption of it. So far, this amino acid could only be radiofluorinated by unsatisfactory approaches. In the work here, a simpler, 3-step method for a nucleophilic radiosynthesis of L-4-[18F]fluorotryptophan was developed. For this a carbonyl activated precursor was radiofluorinated by isotopic exchange, followed by removal of the activating formyl group by reductive decarbonylation and subsequent hydrolysis of the protecting groups under acidic conditions. First, the influence of positions of fluorine and of the formyl group on the isotopic exchange was examined in several fluoro-1H-indolecarbaldehydes where different protecting groups were attached to the indole nitrogen. Further, a decarbonylation reaction with Rh(PPh3)3 on those molecules was carried out and optimized. The best results regarding radiochemical yield and chemical stability were obtained with 1-benzyl-4-fluoro-1H-indole-5-carbaldehyde. Based on these results a concept for the synthesis of precursors for L-6-[18F]fluorotryptophan and L-4-[18F]fluorotryptophan was developed. Hereby the compounds benzyl (2S,5S)-2-tert-butyl-5-[(1-benzyl-4-fluoro-5-formyl-1H–indol–3-yl)methyl]–3–methyl–4–oxoimidazolidine-1-carboxylate and benzyl (2S,5S)–2–tert–butyl–5-[(1–Boc–4–fluoro–5–formyl-1H–indol–3 yl) methyl]-3-methyl-4-oxoimidazolidine-1-carboxylate were prepared following 11-step linear synthetic pathways with overall yields of about 8 % and an enantiomeric purity of > 99 %. While the radiosynthesis of L-6-[18F]fluorotryptophan was not successful due to the failing hydrolysis of the benzyl group, L-4-[18F]fluorotryptophan was prepared by the three step radiosynthesis, consisting of an isotopic exchange, a reductive decarbonylation with Rh(PPh3)3 and the hydrolysis of the protecting groups with HCl, yielding an enantiomeric purity of > 99 %. After optimization of this procedure L-4-[18F]fluorotryptophan was isolated in a radiochemical yield of ca. 13 % and a molar activity of > 70 MBq/mmol within about 115 min. Hence, a new and more efficient nucleophilic radiosynthesis of L-4-[18F]fluoro-tryptophan was developed which is now available for preclinical evaluation

Optical bullets and double bullet complexes in dissipative systems

We show that optical light bullets can coexist with double bullet complexes in nonlinear dissipative systems. Coexistence occurs for a relatively large range of the system parameters, and is associated with either marginal stability or bistable existence of the two dissipative soliton species. In the case of marginal stability, spontaneous transformations of single bullets into double bullet complexes are observed. Among the bistable cases, we show how both clockwise and anticlockwise rotating double bullet complexes can be formed out of the phase-controlled interaction of two single bullets. The internal dynamics of pulsating double bullet complexes, with oscillations in both the spatial separation between the two bullets and the bullet shape in time domain is also detailed. © 2006 The American Physical Society.The work of J.M.S.C. was supported by the M.E.y C. under Contract No. BFM2003-00427 and FIS2006-03376.Peer Reviewe

Combined Coronary CT-Angiography and TAVI-Planning: A Contrast-Neutral Routine Approach for Ruling-Out Significant Coronary Artery Disease

Background: Significant coronary artery disease (CAD) is a common finding in patients undergoing transcatheter aortic valve implantation (TAVI). Assessment of CAD prior to TAVI is recommended by current guidelines and is mainly performed via invasive coronary angiography (ICA). In this study we analyzed the ability of coronary CT-angiography (cCTA) to rule out significant CAD (stenosis ≥ 50%) during routine pre-TAVI evaluation in patients with high pre-test probability for CAD. Methods: In total, 460 consecutive patients undergoing pre-TAVI CT (mean age 79.6 ± 7.4 years) were included. All patients were examined with a retrospectively ECG-gated CT-scan of the heart, followed by a high-pitch-scan of the vascular access route utilizing a single intravenous bolus of 70 mL iodinated contrast medium. Images were evaluated for image quality, calcifications, and significant CAD; CT-examinations in which CAD could not be ruled out were defined as positive (CAD+). Routinely, patients received ICA (388/460; 84.3%; Group A), which was omitted if renal function was impaired and CAD was ruled out on cCTA (Group B). Following TAVI, clinical events were documented during the hospital stay. Results: cCTA was negative for CAD in 40.2% (188/460). Sensitivity, specificity, PPV, and NPV in Group A were 97.8%, 45.2%, 49.6%, and 97.4%, respectively. Median coronary artery calcium score (CAC) was higher in CAD+-patients but did not have predictive value for correct classification of patients with cCTA. There were no significant differences in clinical events between Group A and B. Conclusion: cCTA can be incorporated into pre-TAVI CT-evaluation with no need for additional contrast medium. cCTA may exclude significant CAD in a relatively high percentage of these high-risk patients. Thereby, cCTA may have the potential to reduce the need for ICA and total amount of contrast medium applied, possibly making pre-procedural evaluation for TAVI safer and faster

Pulmonary cancers across different histotypes share hybrid tuft cell/ionocyte-like molecular features and potentially druggable vulnerabilities

Tuft cells are chemosensory epithelial cells in the respiratory tract and several other organs. Recent studies revealed tuft cell-like gene expression signatures in some pulmonary adenocarcinomas, squamous cell carcinomas (SQCC), small cell carcinomas (SCLC), and large cell neuroendocrine carcinomas (LCNEC). Identification of their similarities could inform shared druggable vulnerabilities. Clinicopathological features of tuft cell-like (tcl) subsets in various lung cancer histotypes were studied in two independent tumor cohorts using immunohistochemistry (n = 674 and 70). Findings were confirmed, and additional characteristics were explored using public datasets (RNA seq and immunohistochemical data) (n = 555). Drug susceptibilities of tuft cell-like SCLC cell lines were also investigated. By immunohistochemistry, 10–20% of SCLC and LCNEC, and approximately 2% of SQCC expressed POU2F3, the master regulator of tuft cells. These tuft cell-like tumors exhibited “lineage ambiguity” as they co-expressed NCAM1, a marker for neuroendocrine differentiation, and KRT5, a marker for squamous differentiation. In addition, tuft cell-like tumors co-expressed BCL2 and KIT, and tuft cell-like SCLC and LCNEC, but not SQCC, also highly expressed MYC. Data from public datasets confirmed these features and revealed that tuft cell-like SCLC and LCNEC co-clustered on hierarchical clustering. Furthermore, only tuft cell-like subsets among pulmonary cancers significantly expressed FOXI1, the master regulator of ionocytes, suggesting their bidirectional but immature differentiation status. Clinically, tuft cell-like SCLC and LCNEC had a similar prognosis. Experimentally, tuft cell-like SCLC cell lines were susceptible to PARP and BCL2 co-inhibition, indicating synergistic effects. Taken together, pulmonary tuft cell-like cancers maintain histotype-related clinicopathologic characteristics despite overlapping unique molecular features. From a therapeutic perspective, identification of tuft cell-like LCNECs might be crucial given their close kinship with tuft cell-like SCLC

Beiträge zur Chemie von niedervalenten Bleiverbindungen - Synthese und Untersuchungen zur Reaktivität sterisch abgeschirmter, niedervalenter Organobleihydride

Dissertation ist geseprrt bis 22. Juli 2022 !Mit der erst kürzlich veröffentlichten Isolierung des ersten zweiwertigen Organobleihydrids, konnte die letzte fehlende niedervalente Hydridverbindung der Gruppe 14 erhalten werden. Im Rahmen dieser Arbeit wurde die Darstellung und Reaktivität von zweiwertigen Bleihydriden untersucht. Dabei wurde zunächst die Synthese des Organobleihydrids [Ar*PbH]2 (Ar* = 2,6-Trip2C6H3, Trip = 2,4,6-iPr-C6H2) optimiert. Anschließend wurde die Reaktivität des [Ar*PbH]2 gegenüber organischen Molekülen, Übergangsmetallkomplexen, Verbindungen der Gruppe 14 und Lewis-Säuren untersucht. Das sterisch weniger anspruchsvolle [Ar’PbH]2 (Ar‘ = 2,6-Mes2C6H3, Mes = 2,4,6-Me-C6H2) konnte ebenfalls dargestellt werden. Aufgrund der Instabilität auch bei tiefen Temperaturen konnte dieses Bleihydrid jedoch nicht isoliert werden. Aus diesem Grund wurde [Ar’PbH]2 in situ erzeugt und direkt mit Verbindungen der Gruppe 14 oder Lewis-Säuren umgesetzt. Als weiteres zweiwertiges Bleihydrid konnte das DippNacNacPbH (NacNac = HC(C(CH3)N-Dipp)2, Dipp = 2,6-Diisopropylphenyl) synthetisiert werden. Das monomere Organobleihydrid zerfällt nach wenigen Minuten bei –40 °C. Durch die in situ Erzeugung war die Umsetzung mit einem niedervalenten Zinnhydrid erfolgreich. Zuletzt wurde die Reaktivität der Allyle Ar*EC4H7 (E = Sn, Pb) gegenüber Benzonitril untersucht. Mit zwei Äquivalenten des Nitrils konnte ein Pyridin-Ring am Tetrylen erhalten werden. Bemerkenswert ist, dass sich hierbei die Dreifachbindung eines Benzonitrils löst

Modifications of the humic acid fraction in a soil treated with composted municipal refuse

8 pages, 3 figures, 3 tables, 21 references.The effects on the humic acid fraction of a soil after three years of compost application in a field experiment has been studied. Most of the analytical parameters, such as elementary composition, functional group contents, ratios and spectral characteristics seem to be quite useless for evaluating differences between the structure of the humic acids isolated from soil before and after the application of compost. However, chemical degradations reveal that representative components of the organic matter from compost such as fatty acid series were retained in loosely linked forms in the humic acid fraction of the soil.Peer reviewe

Año cristiano santoral completo extractado de los principales autores católicos; [tomo XII]

Sign.: 1-208, 216AntepContiene: Diciembr