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1.
Bioorg Med Chem ; 27(18): 4101-4109, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31371219

RESUMO

The design of conjugates displaying simultaneously high selectivity and high affinity for different subtypes of integrins is a current challenge. The arginine-glycine-aspartic acid amino acid sequence (RGD) is one of the most efficient short peptides targeting these receptors. We report herein the development of linear and cyclic fluoro-C-glycoside"RGD" conjugates, taking advantage of the robustness and hydrophilicity of C-glycosides. As attested by in vitro evaluation, the design of these C-glyco"RGD" with a flexible three-carbon triazolyl linker allows distinct profiles towards αIIbß3 and αvß3 integrins. Molecular-dynamics simulations confirm the suitability of cyclic C-glyco-c(RGDfC) to target αvß3 integrin. These C-glyco"RGD" could become promising biological tools in particular for Positron Emission Tomography imaging.

2.
EJNMMI Res ; 8(1): 51, 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29904818

RESUMO

BACKGROUND: Tracers triggering αvß3 integrins, such as certain RGD-containing peptides, were found promising in previous pilot studies characterizing high-grade gliomas. However, only limited comparisons have been performed with current PET tracers. This study aimed at comparing the biodistribution of 18F-fluorodeoxyglucose (18F-FDG) with that of 68Ga-NODAGA-RGD, an easily synthesized monomeric RGD compound with rapid kinetics, in two different rodent models of engrafted human glioblastoma. METHODS: Nude rodents bearing human U87-MG glioblastoma tumor xenografts in the flank (34 tumors in mice) or in the brain (5 tumors in rats) were analyzed. Kinetics of 68Ga-NODAGA-RGD and of 18F-FDG were compared with PET imaging in the same animals, along with additional autohistoradiographic analyses and blocking tests for 68Ga-NODAGA-RGD. RESULTS: Both tracers showed a primary renal route of clearance, although with faster clearance for 68Ga-NODAGA-RGD resulting in higher activities in the kidneys and bladder. The tumor activity from 68Ga-NODAGA-RGD, likely corresponding to true integrin binding (i.e., suppressed by co-injection of a saturating excess of unlabeled RGD), was found relatively high, but only at the 2nd hour following injection, corresponding on average to 53% of total tumor activity. Tumor uptake of 68Ga-NODAGA-RGD decreased progressively with time, contrary to that of 18F-FDG, although 68Ga-NODAGA-RGD exhibited 3.4 and 3.7-fold higher tumor-to-normal brain ratios on average compared to 18F-FDG in mice and rat models, respectively. Finally, ex-vivo analyses revealed that the tumor areas with high 68Ga-NODAGA-RGD uptake also exhibited the highest rates of cell proliferation and αv integrin expression, irrespective of cell density. CONCLUSIONS: 68Ga-NODAGA-RGD has a high potential for PET imaging of glioblastomas, especially for areas with high integrin expression and cell proliferation, although PET recording needs to be delayed until the 2nd hour following injection in order to provide sufficiently high integrin specificity.

3.
Bioorg Med Chem ; 25(20): 5603-5612, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28893600

RESUMO

This study describes the synthesis and radiosynthesis of eight new [18F]fluoro-inositol-based radiotracers in myo- and scyllo-inositol configuration. These radiotracers are equipped with a propyl linker bearing fluorine-18. This fluorinated arm is either on a hydroxyl group, i.e. O-alkylated inositols, or on the cyclohexyl backbone, i.e. C-branched derivatives. To modulate lipophilicity, inositols were synthesized in acetylated or hydroxylated form. Automated radiosynthesis was performed on the AllInOne module and the radiotracers were produced in good radiochemical yields (15-31.5% dc). Preliminary in vivo preclinical evaluation of these eight [18F]fluoro-inositols as Positron Emission Tomography (PET) imaging agents in a breast tumour-bearing mouse model was performed and compared with [18F]-2-fluoro-2-deoxy-d-glucose ([18F]FDG). Amongst the different inositols, [18F]myo-2 showed the highest tumour uptake 2.34±0.39%ID/g, revealing the potential of this tracer for monitoring breast cancer.


Assuntos
Radioisótopos de Flúor , Inositol/química , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Animais , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Modelos Animais de Doenças , Feminino , Radioisótopos de Flúor/normas , Humanos , Inositol/análogos & derivados , Inositol/síntese química , Camundongos , Estrutura Molecular
4.
Carbohydr Res ; 445: 61-64, 2017 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-28412594

RESUMO

α- and ß-C-allylglucopyranosides and hydroxy-, bromo- and azido-derivatives were prepared through allylation at C-1 of methyl 2,3,4,6-tetra-O-benzyl-D-glucopyranoside or 1-O-acetyl-2,3,4,6-tetra-O-benzyl-D-glucopyranose and subsequent chemical modifications of the alkene on the anomeric arm. However, we picked out some discordance between some recent published studies and our results. After a thorough work of characterization and NMR analysis, we unambiguously confirmed α and ß stereochemistry of the two series of compounds and fully described for the first time ß-C-propyl alcohol, bromide and azide of 2,3,4,6-tetra-O-benzyl-D-glucopyranose.


Assuntos
Alcenos/química , Glucose/química , Glucose/síntese química , Azidas/química , Brometos/química , Sequência de Carboidratos , Técnicas de Química Sintética , Estereoisomerismo
5.
Beilstein J Org Chem ; 12: 353-61, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26977196

RESUMO

Efficient routes were developed for the diastereoselective synthesis of new O-alkylated and C-branched inositols and their corresponding fluoro analogues. The key steps of the synthesis were the easy accessibility of different types of arms in term of configuration (myo and scyllo), the linking method and length, which could modulate the biological properties. These inositol derivatives, bearing an arm terminated either with a hydroxy group or a fluorine atom, could be interesting candidates for diastereoisomeric intermediates and biological evaluations, especially for PET imaging experiments.

6.
J Labelled Comp Radiopharm ; 59(2): 54-62, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26708055

RESUMO

This work describes the development of new 6-[(18) F]fluoro-carbohydrate-based prosthetic groups equipped with an azido arm that are able to participate in copper(I)-catalyzed cycloadditions for (18) F labeling of biomolecules under mild conditions. The radiolabeling in high radiochemical yields (up to 68 ± 6%) of these different prosthetic groups is presented. The flexibility of the azido arm introduced on the carbohydrate moieties allows efficient click reactions with different alkyne functionalized peptides such as gluthation or Arg-Gly-Asp derivatives in order to prepare glycopeptides. The radiosyntheses of (18) F-labeled glycopeptides proceed in high radiochemical yields (up to 76%) in an automated process with excellent radiochemical purity. The addition of a sugar moiety on peptides should enhance the bioavailability, pharmacokinetic, and in vivo clearance properties of these glycopeptides, compared with the unlabeled native peptide, and these properties are highly favorable for positron emission tomography imaging. A high uptake of (18) F-ß-gluco-c(RGDfC) is shown by positron emission tomography imaging in a subcutaneous abscess model in the rat, revealing the potential of this tracer to monitor integrin expression as a part of inflammation and/or angiogenesis processes.


Assuntos
Radioisótopos de Flúor/química , Glicopeptídeos/química , Compostos Radiofarmacêuticos/síntese química , Animais , Química Click/métodos , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Distribuição Tecidual
7.
Appl Radiat Isot ; 102: 87-92, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26002274

RESUMO

A fully automated production of the imaging agent sodium [(18)F]fluoride ([(18)F]NaF) on two different modules commercialized by Trasis®, the AllInOne and the miniAllInOne, is reported. Both modules allow to prepare [(18)F]NaF in good radiochemical yield (around 97%) in less than 4min with the same specifications. Quality control of [(18)F]NaF produced by this way was performed according to the US and European Pharmacopeia monograph requirements.


Assuntos
Radioisótopos de Flúor/química , Fluoreto de Sódio/síntese química
8.
Bioorg Med Chem ; 22(23): 6672-6683, 2014 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-25457125

RESUMO

'Click' glycosylation of cysteine-containing peptides were carried out in good yield by Copper(I)-catalyzed Azide-Alkyne Cycloaddition (CuAAC). For that peptides were functionalized though direct propargylation of the cysteine residue allowing their use in CuAAC with suitable free or protected azido sugars of gluco, manno and galacto configuration. Among these free and protected glycopeptides a series of 'glycoRGD' peptides were obtained and submitted to in vitro platelet aggregation tests, showing that the pseudoglycosylation of the adhesion sequence lowers the IC50 value and thus could improve the in vivo pharmacokinetic properties.


Assuntos
Química Click , Cisteína/química , Compostos Organometálicos/química , Pargilina/química , Peptídeos/síntese química , Alquinos/química , Azidas/química , Cobre/química , Ciclização , Glicosilação , Humanos , Estrutura Molecular , Compostos Organometálicos/síntese química , Pargilina/análogos & derivados , Peptídeos/química , Peptídeos/farmacologia , Agregação Plaquetária/efeitos dos fármacos
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