共查询到20条相似文献,搜索用时 15 毫秒
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Roland T. Ullrich Thomas Zander Bernd Neumaier Mirjam Koker Takeshi Shimamura Yannic Waerzeggers Christa L. Borgman Samir Tawadros Hongfeng Li Martin L. Sos Heiko Backes Geoffrey I. Shapiro Jürgen Wolf Andreas H. Jacobs Roman K. Thomas Alexandra Winkeler 《PloS one》2008,3(12)
Background
Inhibition of the epidermal growth factor receptor (EGFR) has shown clinical success in patients with advanced non-small cell lung cancer (NSCLC). Somatic mutations of EGFR were found in lung adenocarcinoma that lead to exquisite dependency on EGFR signaling; thus patients with EGFR-mutant tumors are at high chance of response to EGFR inhibitors. However, imaging approaches affording early identification of tumor response in EGFR-dependent carcinomas have so far been lacking.Methodology/Principal Findings
We performed a systematic comparison of 3′-Deoxy-3′-[18F]-fluoro-L-thymidine ([18F]FLT) and 2-[18F]-fluoro-2-deoxy-D-glucose ([18F]FDG) positron emission tomography (PET) for their potential to identify response to EGFR inhibitors in a model of EGFR-dependent lung cancer early after treatment initiation. While erlotinib-sensitive tumors exhibited a striking and reproducible decrease in [18F]FLT uptake after only two days of treatment, [18F]FDG PET based imaging revealed no consistent reduction in tumor glucose uptake. In sensitive tumors, a decrease in [18F]FLT PET but not [18F]FDG PET uptake correlated with cell cycle arrest and induction of apoptosis. The reduction in [18F]FLT PET signal at day 2 translated into dramatic tumor shrinkage four days later. Furthermore, the specificity of our results is confirmed by the complete lack of [18F]FLT PET response of tumors expressing the T790M erlotinib resistance mutation of EGFR.Conclusions
[18F]FLT PET enables robust identification of erlotinib response in EGFR-dependent tumors at a very early stage. [18F]FLT PET imaging may represent an appropriate method for early prediction of response to EGFR TKI treatment in patients with NSCLC. 相似文献3.
Torsten Kniess Ralf Bergmann Manuela Kuchar Jörg Steinbach Frank Wuest 《Bioorganic & medicinal chemistry》2009,17(22):7732-7742
The radiosynthesis and radiopharmacological evaluation of 3-[4′-[18F]fluorobenzylidene]indolin-2-one, a derivative of tyrosine kinase inhibitor SU5416, is described. The radiosynthesis was accomplished by Knoevenagel condensation of 4-[18F]fluorobenzaldehyde with oxindole in a remotely controlled synthesis module. The reaction conditions were optimized through screening the influence of different bases on the radiochemical yield. The radiotracer was obtained after a two-step labelling procedure in 4% decay-corrected radiochemical yield at a specific activity of 48–61 GBq/μmol within 90 min. The radiochemical purity after semi-preparative HPLC purification exceeded 98%.The biodistribution was studied in Wistar rats. After distribution the radiotracer was rapidly accumulated in the adrenals, liver and kidneys, however, it was cleared from these and the most other organs. Only the adipose tissue remained the activity over 60 min. Unexpected high transient uptake was observed in the brain, pancreas, heart and lung. The fast clearance of 3-[4′-[18F]fluorobenzylidene]indolin-2-one was caused by excretion, approximately one half each was renal and biliary excreted and the other part cleared by metabolic processes. In arterial blood plasma two more polar metabolites were found by radio-HPLC. After 20 min post-injection, only 12% of intact radiotracer has been detected. Consequently, in small animal PET studies with FaDu tumour bearing mice no specific uptake in the tumours could be observed. 相似文献
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《International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology》1987,14(2):119-122
No-carrier-added (NCA) (±)-N-(3-[18F]Fluoropropyl)-N-normetazocine (2) was synthesized by N-alkylation of (±)-N-normetazocine (1) with NCA 1-[18F]fluoro-3-iodopropane in an overall radiochemical yield of 10% (EOB) with a mass of 3.5 nmol in a synthesis time of 90 min from end of bombardment (EOB). PET studies of 2 in a baboon did not indicate specificity for opiate receptor sites alone: The activity declined rapidly in the striatum the frontal cortex and the cerebellum. The baboon total arterial plasma radioactivity clearance was very rapid and the metabolism of compound 2 in plasma was also very rapid. These results suggest that compound 2 is not a suitable radioligand for imaging opiate receptors in the human brain by positron tomography. 相似文献
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《International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology》1991,18(5):539-545
The metabolic fate of 2′-deoxy-5-[18F]fluorouridine ([18F]FdUrd), a useful positron emission tomography (PET) tracer of nucleic acid metabolism in tumors, was investigated in mice and humans. A rapid increase in labeled catabolites was found in mouse and human plasma. In mouse FM3A mammary carcinoma, the corresponding catabolites were also detected in addition to metabolites which were activated by the nucleic acid metabolism. From a biodistribution study of β-[3H]alanine, α-[18F]fluoro-β-alanine, a major catabolite, was assumed to be taken up twice as much by tumor than by the brain. Nucleic acid metabolism in brain tumors by [18F]FdUrd-PET may be assessed using normal brain regions as a reference. 相似文献
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Simon Ingate Ana San-Félix Erik De Clercq Jan Balzarini Maríia-José Camarasa 《Nucleosides, nucleotides & nucleic acids》2013,32(3-5):299-301
Abstract Derivatives of TSAO-T based upon pentofuranose sugars with the L-configuration have been prepared and evaluated as inhibitors of HIV-1 induced cytopathicity. 相似文献
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《International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology》1992,19(2):149-158
This report critically appraises methods for the synthesis of 6-[18F]fluoro-l-3,4-dihydroxyphenylalanine (6-FDOPA) that are based on labelling by non-regioselective electrophilic fluorination, regioselective fluorodemetalation or nucleophilic substitution. Recommendations for the standardization of labelling procedures, the optimization of radiochemical yield and the assurance of product quality and safety are given. Studies of the metabolism of 6-FDOPA in vivo are also reviewed to emphasize the importance of the biochemical component of the development of this tracer for positron emission tomography (PET). 相似文献
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Etsuko Kawashima Yukio Aoyama Mohamed F. Radwan Masayoshi Miyahara Takeshi Sekine Masatsune Kainosho 《Nucleosides, nucleotides & nucleic acids》2013,32(3-5):333-336
Abstract The four (2′S)-[2′-2H]-2′-deoxynucleosides (>90 atom % 2H), were synthesized from the corresponding ribonucleosides involving six steps of reactions, i.e., oxidation of their 2′-hydroxyl group, stereoselective reductive deuteration of the resulting 2′-ketonucleoside intermediates with NaB2H4 in EtOH-H2O or EtOH, triflation, bromination with LiBr, highly stereoselective Bu3SnH-Et3B reduction of the resulting bromide, and, finally, unmasking. 相似文献
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David A. Berry Linda L. Wotring John C. Drach Leroy B. Townsend 《Nucleosides, nucleotides & nucleic acids》2013,32(1-3):405-420
Abstract Chemical modification of the 4-nitrile group in 5-amino-1-(2,3,5-tri-O-benzyl-β-D-ribofuranosyl)pyrazole-4-carbonitrile (1) afforded 5-amino-4-(5-methyl-1,2,4-oxadiazol-3-yl)-1-(2,3,5-tri-O-benzyl-β-D-ribofuran osyl)pyrazole (3). The methylation of 3, via a three step procedure, gave 5-methylamino-4-(5-methyl-1,2,4-oxadiazol-3-yl)-1-(2,3,5-tri-O-benzyl-β-D-ribofuranosyl)pyrazole (3a). The mononuclear heterocyclic rearrangement (m.h.r) of 3 and 3a, provided a convenient route to the novel azapentalene adenosine analogs 3-amino-6-(β-D-ribofuranosyl)pyrazolo[3,4-c]pyrazole (6) and 3-amino-1-methyl-6-(β-D-ribofuranosyl)pyrazolo[3,4-c]pyrazole (6a), respectively. Compound 6 exhibited no cytotoxicity when screened in vitro against either mouse L1210 leukemic cells or human foreskin fibroblasts. Nor was it active against human cytomegalovirus. Compound 6a was designed and prepared to investigate the possibility that the lack of biological activity of 6 might be due to annular tautomerization limiting the ability of 6 to serve as a substrate for the activating enzyme adenosine kinase. This hypothesis was neither supported nor disproved by the results, as compound 6a was also inactive in both the antiproliferative and antiviral test systems. 相似文献
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Nakagawa T Nishi Y Kondo A Shirai Y Honda C Asahi M Tanimoto T 《Carbohydrate research》2011,346(13):1792-1800
6(I),6(IV)-Di-O-[α-l-fucopyranosyl-(1→6)-2-acetamido-2-deoxy-β-d-glucopyranosyl]-cyclomaltoheptaose (βCD) {6(I),6(IV)-di-O-[α-l-Fuc-(1→6)-β-d-GlcNAc]-βCD (5)} and 6-O-[α-l-fucopyranosyl-(1→6)-2-acetamido-2-deoxy-β-d-glucopyranosyl]-βCD {6-O-[α-l-Fuc-(1→6)-β-d-GlcNAc]-βCD (6)} were chemically synthesized using the corresponding authentic compounds, bis(2,3-di-O-acetyl)-pentakis(2,3,6-tri-O-acetyl)-βCD as the glycosyl acceptor and 2,3,4-tri-O-benzyl-α-l-fucopyranosyl-(1→6)-3,4-di-O-acetyl-2-deoxy-2-(2,2,2-trichloroethoxycarbonylamino)-d-glucopyranosyl trichloroacetimidate as the fuco-glucosaminyl donor. NMR confirmed that α-l-Fuc-(1→6)-d-GlcNAc was bonded by β-linking to the βCD ring. To evaluate biological efficiency, the biological activities of the new branched βCDs were examined. The cell detachment activity of 5 was lower than that of 6 in real-time cell sensing (RT-CES) assay, indicating that 5 has lower toxicity. In SPR analysis, 5 had a higher special binding with AAL, a fucose-recognizing lectin. These results suggest that 5 could be an efficient drug carrier directed at cells expressing fucose-binding proteins. 相似文献
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Eliot T. McKinley Ping Zhao Robert J. Coffey M. Kay Washington H. Charles Manning 《PloS one》2014,9(9)
Biomarkers that predict response to targeted therapy in oncology are an essential component of personalized medicine. In preclinical treatment response studies that featured models of wild-type KRAS or mutant BRAF colorectal cancer treated with either cetuximab or vemurafenib, respectively, we illustrate that [18F]-FLT PET, a non-invasive molecular imaging readout of thymidine salvage, closely reflects pro-survival responses to targeted therapy that are mediated by PI3K-mTOR activity. Activation of pro-survival mechanisms forms the basis of numerous modes of resistance. Therefore, we conclude that [18F]-FLT PET may serve a novel and potentially critical role to predict tumors that exhibit molecular features that tend to reflect recalcitrance to MAPK-targeted therapy. Though these studies focused on colorectal cancer, we envision that the results may be applicable to other solid tumors as well. 相似文献
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Yoshikazu Uto Yohei Kiyotsuka Yuko Ueno Yuriko Miyazawa Hitoshi Kurata Tsuneaki Ogata Tsuneo Deguchi Makiko Yamada Nobuaki Watanabe Masahiro Konishi Nobuya Kurikawa Toshiyuki Takagi Satoko Wakimoto Keita Kono Jun Ohsumi 《Bioorganic & medicinal chemistry letters》2010,20(2):746-754
Cyclization of the benzoylpiperidine in lead compound 2 generated a series of novel and highly potent spiropiperidine-based stearoyl-CoA desaturase (SCD)-1 inhibitors. Among them, 1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4′-piperidine] (19) demonstrated the most powerful inhibitory activity against SCD-1, not only in vitro but also in vivo (C57BL/6 J mice). With regard to the pharmacological evaluation, 19 showed powerful reduction of the desaturation index in the plasma of C57BL/6 J mice on a non-fat diet after a 7-day oral administration (q.d.) without causing notable abnormalities in the eyes or skin up to the highest dose (3 mg/kg) in our preliminary analysis. 相似文献
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《Médecine Nucléaire》2014,38(6):439-448
ObjectivesPositron emission tomography with 16α-[18F]fluoro-17β-œstradiol (PET-[18F]FES) is used to evaluate the in vivo tissue density in estrogen receptor (ER). We report here the first cases in the diagnosis of endometriosis.Patients and methodsFour patients with clinical and morphological signs (pelvic ultrasound ± MRI) consistent with endometriosis were enrolled in this National Grant PHRC ENDOTEP. They underwent a PET-[18F]FES scan before laparoscopy (macroscopic and histological analysis, immuno-histochemical ER expression).ResultsIn the four patients, the diagnosis of endometriosis was confirmed on the typical macroscopic appearance of laparoscopy plus histological analysis of at least one lesion. No uptake of [18F]FES by endometriosis lesions was observed in the first three patients with estrogen-progestin therapy. The fourth patient, untreated and in the first part of the menstrual cycle when performing PET-[18F]FES, had however an increased [18F]FES uptake of one lesion of endometriosis confirmed by laparoscopy.ConclusionWe report here the first case of [18F]FES uptake by an endometriosis lesion. With the ENDOTEP trial, the performance of PET-[18F]FES for the diagnosis of endometriosis will be evaluated in patients who are not receiving hormone therapy. 相似文献
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Abstract A theoretical conformational study of dextran, a (l?6)-linked α-D-glucan polysaccharide, has been made to allow an explicit comparison with earlier results on pustulan, the corresponding (1 ?6)-linked β-D-glucan. The nonbonded, torsional and hydrogen bond contributions to potential energy were calculated as a function of rotational angles φ, ψ, and ω The (φ, ψ, ω)-space of the disaccharide and of helices contain many local energy minima with very small energy differences. A comparison of (1?6)-α-D-glucans with (1?6)-β-D-glucans indicates significant differences in conformational behavior. Specifically, our results shed light on the fact that dextran does not gel, whereas pustulan does. The difference in tendency to gel may be related to the fact that dextran has no particularly favored conformations with structural regularity whereas pustulan does. 相似文献
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The C-nucleoside analogs 6-chloro-3-β-d-erythrofuranosyl-l-phenylpyrazolo-[3,4-b]quinoxaline (5) and 3-β-d-erythrofuranosy]-l-p-tolylpyrazolo[3,4-b]quinoxaline (10) were prepared by dehydration of the polyhydroxyalkyl chain of 6(7)-chlorolo-phenyl-3-(d-arabino-tetritol-l-yl)-pyrazolo(3,4-b]quinoxaline and 3-(d-arbino-tetritol-l-yl)-l-p-tolylpyrazolo[3,4-b]quinoxaline, respectively. The structure and anomeric configuration of 5 and 10 were determined by high-resolution, n.m.r. spectroscopy. The mass spectra and biological activities of some of these compounds are discussed. 相似文献
18.
S Spieser K Mazeau M.C Brochier C Gey J.P Utille F.R Taravel 《Glycoconjugate journal》1998,15(5):511-521
The title compound is a cyclic oligosaccharide having six glucopyranose residues linked alternatively by -(14) and -(16) glycosidic linkages. Like cyclodextrin analogues it is expected to exhibit an internal cavity and to form inclusion complexes with other species. In order to investigate its conformational preferences, an extensive conformational search was carried out using a combination of Metropolis Monte-Carlo (MMC) procedure in the glycosidic torsion angle space and molecular mechanics procedures. To this end a specific program (METROCYCLIX) was developed. To reduce the MMC search, conformational maps of parent disaccharides were considered as starting entries. Fully minimized conformations were gathered into families using a clustering technique based on RMS fitting over the glycosidic torsion angle values. A wide range of local energy minima were identified in spite of ring closure conditions that constrained the structure of the oligosaccharide. Low energy conformers were stabilized by intramolecular interactions between distant residues. From the Bolzmann population of the best structures derived from the clustering results, various average properties were calculated and compared with experimental data obtained by high resolution NMR. Interpretation of these experimental values (heteronuclear coupling constants, rotating frame nuclear Overhauser effects, relaxation times) relies on the use of Karplus like equations (coupling constants) and analysis of the full relaxation rate matrix treatment (ROE). The quality of the molecular modelling strategy used is assessed by the agreement obtained between calculated and measured observables. 相似文献
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Ahmed Kamal Paidakula Suresh M. Janaki Ramaiah T. Srinivasa Reddy Ravi Kumar Kapavarapu Bolla Narasimha Rao Syed Imthiajali T. Lakshminarayan Reddy S.N.C.V.L. Pushpavalli Nagula Shankaraiah Manika Pal-Bhadra 《Bioorganic & medicinal chemistry》2013,21(17):5198-5208
A series of 4β-[4′-(1-(aryl)ureido)benzamide]podophyllotoxin congeners (11a–l) were synthesized and evaluated for their cytotoxic activity against six human cancer cell lines. Some of the compounds like 11a, 11h, 11k and 11l showed significant anti-proliferative activity in Colo-205 cells and were superior to etoposide. The flow-cytometric analysis studies indicated that these compounds show strong G1 cell cycle arrest, as well exhibited improved inhibitory activities on DNA topoisomerase I and IIα enzymes. These compounds induce apoptosis by up regulating caspase-3 protein as observed by ELISA and Western blotting analysis. In addition, a brief structure–activity relationship studies within the series along with docking results of representative compounds 11a, 11h, 11k, 11l were presented. 相似文献
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Yuji Haga Toshihiro Sakamoto Takunobu Shibata Katsumasa Nonoshita Makoto Ishikawa Takuya Suga Hirobumi Takahashi Toshiyuki Takahashi Hidekazu Takahashi Makoto Ando Takashi Murai Akira Gomori Zenjun Oda Hidefumi Kitazawa Yuko Mitobe Maki Kanesaka Tomoyuki Ohe Hisashi Iwaasa Yasuyuki Ishii Akane Ishihara Takehiro Fukami 《Bioorganic & medicinal chemistry》2009,17(19):6971-6982
A series of trans-3-oxospiro[(aza)isobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide derivatives were synthesized to identify potent NPY Y5 receptor antagonists. Of the compounds, 21j showed high Y5 binding affinity, metabolic stability and brain and cerebrospinal fluid (CSF) penetration, and low susceptibility to P-glycoprotein transporters. Oral administration of 21j significantly inhibited the Y5 agonist-induced food intake in rats with a minimum effective dose of 1 mg/kg. This compound was selected for proof-of-concept studies in human clinical trials. 相似文献