References of "Van den Eynde, Benoit"
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See detailFully automated radiosynthesis of N1-[18F]fluoroethyl-tryptophan and study of its biological activity as a new potential substrate for indoleamine 2,3-dioxygenase PET imaging
Henrottin, Jean ULg; Lemaire, Christian ULg; Egrise, Dominique et al

in Nuclear Medicine & Biology (2016)

Introduction: Indoleamine 2,3-dioxygenase (IDO) catalyzes the initial step in the catabolism of L-tryptophan along the kynurenine pathway and exerts immunosuppressive properties in inflammatory and tumor ... [more ▼]

Introduction: Indoleamine 2,3-dioxygenase (IDO) catalyzes the initial step in the catabolism of L-tryptophan along the kynurenine pathway and exerts immunosuppressive properties in inflammatory and tumor tissues by blocking locally T-lymphocyte proliferation. Recently, 1-(2-[19F]fluoroethyl)-DL-tryptophan (1-[19F]FE-DL-Trp) was reported as a good and specific substrate of this enzyme. Herein, the radiosynthesis of its radioactive isotopomer (1-[18F]FE-DL-Trp, DL-[18F]5) is presented along with in vitro enzymatic and cellular uptake studies. Methods: The one-pot n.c.a. radiosynthesis of this novel potential PET imaging tracer, including HPLC purification and formulation, has been fully automated on a FASTlabTM synthesizer. Chiral separation of both isomers and their formulation were implemented on a second cassette. In vitro enzymatic and cellular uptake studies were then conducted with the D-, L- and DL-radiotracers. Results: The radiolabeling of the tosylate precursor was performed in DMF (in 5 min; RCY: 57% (d.c.), n=3). After hydrolysis, HPLC purification and formulation, DL-[18F]5 was obtained with a global radiochemical yield of 18±3% (not decay corrected, n=7, in 80 min) and a specific activity of 600±180 GBq/µmol (n=5). The subsequent separation of L- and D-enantiomers was performed by chiral HPLC and both were obtained after formulation with a RCY (d.c.) of 6.1% and 5.8%, respectively. In vitro enzymatic assays reveal that L-[18F]5 is a better substrate than D-[18F]5 for human IDO. In vitro cellular assays show an IDO-specific uptake of the racemate varying from 30% to 50% of that of L-[18F]5, and a negligible uptake of D-[18F]5. Conclusion: In vitro studies show that L-[18F]5 is a good and specific substrate of hIDO, while presenting a very low efflux. These results confirm that L-[18F]5 could be a very useful PET radiotracer for IDO expressing cells in cancer imaging. [less ▲]

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See detailN1-Fluoroalkyltryptophan analogues: synthesis and in vitro study as potential substrates for indoleamine 2,3-dioxygenase
Henrottin, Jean ULg; Zervosen, Astrid ULg; Lemaire, Christian ULg et al

in ACS Medicinal Chemistry Letters (2015)

ABSTRACT: Indoleamine 2,3-dioxygenase (hIDO) is an enzyme that catalyzes the oxidative cleavage of the indole ring of L-tryptophan through the kynurenine pathway, thereby exerting immunosuppressive ... [more ▼]

ABSTRACT: Indoleamine 2,3-dioxygenase (hIDO) is an enzyme that catalyzes the oxidative cleavage of the indole ring of L-tryptophan through the kynurenine pathway, thereby exerting immunosuppressive properties in inflammatory and tumoral tissues. The syntheses of 1-(2-fluoroethyl)-tryptophan (1-FETrp) and 1-((1-(2-fluoroethyl)-1H-1,2,3-triazol-4-yl)methyl)-tryptophan, two N1-fluoroalkylated tryptophan derivatives, are described here. In vitro enzymatic assays with these two new potential substrates of hIDO show that 1-FETrp is a good and specific substrate of hIDO. Therefore, its radioactive isotopomer, 1-[18F]FETrp, should be a molecule of choice to visualize tumoral and inflammatory tissues and/or to validate new potential inhibitors. [less ▲]

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See detailSynthesis of N-fluoroalkyl-tryptophan and study of their biological activity as potential substrates for indoleamine 2,3-dioxygenase
Henrottin, Jean ULg; Zervosen, Astrid ULg; Lemaire, Christian ULg et al

Poster (2014, June)

Indoleamine 2,3-dioxygenase (rhIDO) is an enzyme mainly expressed in brain and tumor cells and catalyzing the oxidative cleavage of the indole ring of L-tryptophan through the kynurenine pathway ... [more ▼]

Indoleamine 2,3-dioxygenase (rhIDO) is an enzyme mainly expressed in brain and tumor cells and catalyzing the oxidative cleavage of the indole ring of L-tryptophan through the kynurenine pathway. Furthermore this enzyme could be responsible for the eventual suppression of immune responses by blocking locally T-lymphocyte proliferation. The syntheses of 1-(2-fluoroethyl)-tryptophan (1-[19F]FETrp) and 1-((1-(2-fluoroethyl)-1H-1,2,3-triazol-4-yl)methyl)-tryptophan, two N-fluoroalkylated tryptophan derivatives, are described here. In vitro enzymatic assays with these two new potential substrates of rhIDO show that 1-[19F]FETrp is a good and specific substrate of hIDO. [less ▲]

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See detailIndol-2-yl ethanones as novel indoleamine 2,3-dioxygenase (IDO) inhibitors.
Dolusic, Eduard; Larrieu, Pierre; Blanc, Sébastien et al

in Bioorganic & Medicinal Chemistry (2011), 19(4), 1550-61

Indoleamine 2,3-dioxygenase (IDO) is a heme dioxygenase which has been shown to be involved in the pathological immune escape of diseases such as cancer. The synthesis and structure-activity relationships ... [more ▼]

Indoleamine 2,3-dioxygenase (IDO) is a heme dioxygenase which has been shown to be involved in the pathological immune escape of diseases such as cancer. The synthesis and structure-activity relationships (SAR) of a novel series of IDO inhibitors based on the indol-2-yl ethanone scaffold is described. In vitro and in vivo biological activities have been evaluated, leading to compounds with IC(50) values in the micromolar range in both tests. Introduction of small substituents in the 5- and 6-positions of the indole ring, indole N-methylation and variations of the aromatic side chain are all well tolerated. An iron coordinating group on the linker is a prerequisite for biological activity, thus corroborating the virtual screening results. [less ▲]

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See detailDiscovery and preliminary SARs of keto-indoles as novel indoleamine 2,3-dioxygenase (IDO) inhibitors.
Dolusic, Eduard; Larrieu, Pierre; Blanc, Sebastien et al

in European journal of medicinal chemistry (2011), 46(7), 3058-65

Indoleamine 2,3-dioxygenase (IDO) is an important new therapeutic target for the treatment of cancer. With the aim of discovering novel IDO inhibitors, a virtual screen was undertaken and led to the ... [more ▼]

Indoleamine 2,3-dioxygenase (IDO) is an important new therapeutic target for the treatment of cancer. With the aim of discovering novel IDO inhibitors, a virtual screen was undertaken and led to the discovery of the keto-indole derivative 1a endowed with an inhibitory potency in the micromolar range. Detailed kinetics were performed and revealed an uncompetitive inhibition profile. Preliminary SARs were drawn in this series and corroborated the putative binding orientation as suggested by docking. [less ▲]

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