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See detailSynthesis of [18F]4-(4-fluorophenyl)-1,2,4-triazole-3,5-dione: an agent for specific radiolabelling of tyrosine
Flagothier, Jessica ULg; Warnier, Corentin ULg; Dammicco, Sylvestre ULg et al

in RSC Advances (2013), 3

We developed a new [18F] prosthetic group, the [18F]4-(4-fluorophenyl)-1,2,4-triazole-3,5-dione ([18F]FPTAD), used for its specific ligation with tyrosine-containing peptides or protein in order to ... [more ▼]

We developed a new [18F] prosthetic group, the [18F]4-(4-fluorophenyl)-1,2,4-triazole-3,5-dione ([18F]FPTAD), used for its specific ligation with tyrosine-containing peptides or protein in order to develop a new and versatile radiolabelling technique that could provide a useful tool for new developments in PET imaging. [less ▲]

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See detailLight-induced Hetero-Diels Alder cycloaddition as a new coupling method to biomolecule radiolabeling
Dammicco, Sylvestre ULg; Luxen, André ULg; Thonon, David et al

Poster (2013, May 16)

The formation of a C-18F bond requires hard conditions which is problematic for the biomolecule radiolabelling. The alternative method which has been developed since a few decades consists in ... [more ▼]

The formation of a C-18F bond requires hard conditions which is problematic for the biomolecule radiolabelling. The alternative method which has been developed since a few decades consists in incorporating the 18F on a prosthetic group and coupling it to the biomolecule. The copper (I)-catalysed 1,2,3-triazole formation involving azides and terminal alkynes is a powerful and rapid method of coupling but present the inconvenient of the employment of cytotoxic reagents. The photoclick conjugation is a promising alternative with no need of catalyst[1]. Recently, a light-induced hetero-Diels Alder cycloaddition involving a 3-(hydroxymethyl)-2-naphthol derivative and an electron-rich olefin has been developed[2]. This reaction seems well adapted for the fast conjugation of radionuclides to biomolecules. Herein we report the synthesis of a [18F]fluoronaphtoquinone derivative as prosthetic group and its reaction with vinyl ethers. [less ▲]

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See detailSynthesis of [18F]4-(4-fluorophenyl)-1,2,4-triazole-3,5-dione: an agent for specific radiolabelling of tyrosine.
Flagothier, Jessica ULg; Warnier, Corentin ULg; Lemaire, Christian ULg et al

in Flagothier, Jessica (Ed.) Journal of Labelled Compounds and Radiopharmaceuticals (2013, May 14)

Objectives: Metal-free and mild tyrosine modification reactions are an attractive alternative to the commonly used lysine and cysteine modification protocols for peptide and proteins labelling. Recently ... [more ▼]

Objectives: Metal-free and mild tyrosine modification reactions are an attractive alternative to the commonly used lysine and cysteine modification protocols for peptide and proteins labelling. Recently, Ban and co-workers have reported a tyrosine bioconjugation through ene-type reactions. Cyclic diazodicarboxamides, which are electrophilic compounds, react selectively in o-position on the phenol side chain of tyrosine in mild aqueous conditions and the 1,2,4-triazolidine-3,5-dione linkage is hydrolytically and thermally stable. We herein present the synthesis of [18F]4-(4-fluorophenyl)-1,2,4-triazole-3,5-dione and the coupling with N-acyl tyrosine methylamide. Methods: The N,N,N-trimethyl-4-nitrobenzeneammonium trifluoromethanesulfonate 1 was prepared following a procedure previously reported [2]. The [18F]prosthetic group 6, [18F]4-(4-fluorophenyl)-1,2,4-triazole-3,5-dione, was synthesized in five steps. Results: The synthesis of the [18F]prosthetic group has been realized with a decay-corrected radiochemical yield of 20% in 90 minutes. The radiochemical yield of the coupling with N-acyl tyrosine methylamide is 40% (DC). This presented synthetic pathway should be easily automated: particulary because the purifications between the different steps are exclusively done on SPE cartridges. Conclusions: We successfully developed an efficient bioconjugation method for fluorine-18 labelling of tyrosine without prior modifications of the peptide in very mild conditions. [less ▲]

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See detailSynthesis of two new alkyne-bearing liners used for the preparation of siRNA for labeling by click chemistry with fluorine-18
Flagothier, Jessica ULg; Kaisin, Geoffroy ULg; Mercier, Frederic et al

in Applied Radiation & Isotopes (2012), 70(8), 1549-1557

Oligonucleotides (ONs) and more particularly siRNAs are promising drugs but their pharmacokinetics and biodistribution are widely unknown. Positron Emission Tomography (PET) using fluorine-18 is a ... [more ▼]

Oligonucleotides (ONs) and more particularly siRNAs are promising drugs but their pharmacokinetics and biodistribution are widely unknown. Positron Emission Tomography (PET) using fluorine-18 is a suitable technique to quantify these biological processes. Click chemistry (Huisgen cycloaddition) is the current method for labeling siRNA. In order to study the influence of a linker bearing by [18F]labeled ONs, on the in vivo pharmacokinetic and metabolism, we have developed two modified ONs by two news linkers. Here we report the synthesis of two alkyne-bearing linkers, the incorporation onto a ONs and the conjugation by click chemistry with a [18F]prosthetic group. [less ▲]

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See detailRadiolabeling of modified siRNA by click chemistry with fluorine-18 for PET studies
Flagothier, Jessica ULg; Mercier, Frédéric; Kaisin, Geoffroy ULg et al

in Journal of Labelled Compounds and Radiopharmaceuticals (2011)

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See detailPhotoclick chemistry: Applications to 18F radiotracers preparation
Thonon, David ULg; Goukens, Eve ULg; Kaisin, Geoffroy ULg et al

in Journal of Labelled Compounds and Radiopharmaceuticals (2011)

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See detailGeneral Method for Labeling siRNA by Click Chemistry with Fluorine-18 for the Purpose of PET Imaging
Mercier, Frédéric; Paris, Jérôme ULg; Kaisin, Geoffroy ULg et al

in Bioconjugate Chemistry (2011), 22(1), 108-114

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See detailClick chemistry : radiolabelling of oligonucleotides with fluorine- 18 for PET
Kaisin, Geoffroy ULg; Flagothier, Jessica ULg; Mercier, Frédéric ULg et al

Poster (2010, June)

Oligonucleotides (ONs), especially small interfering RNA (siRNA), are promising therapeutic agents, but their pharmacokinetics and biodistributions are widely unknown. Positron Emission Tomography (PET ... [more ▼]

Oligonucleotides (ONs), especially small interfering RNA (siRNA), are promising therapeutic agents, but their pharmacokinetics and biodistributions are widely unknown. Positron Emission Tomography (PET) using fluorine-18 is a suitable technique to image and quantify such biological processes. The challenge for the radiochemist is to introduce this short half-life isotope (t1/2(18F)=109.7 min) onto oligonucleotides or, more generally, biomolecules. The most common technique requires the coupling of a prosthetic group bearing the radiotracer with the biomolecule. Current methods for labeling ONs with fluorine-18 have sub-optimal yields and require a long synthesis time.1 Click chemistry, e.g. 1,3-dipolar Huisgen cycloaddition of azides to alkynes, could be an efficient way to increase yields and reduce synthesis time. Conjugations with ONs are usually performed at 3’-ends using a well-chosen linker in order to limit degradation by exonucleases and to avoid alteration of hybridization properties and siRNA gene silencing efficiency. This also allows the development of universal solid supports used for the solidphase synthesis of ONs. Here we report the synthesis of three alkyne-bearing linkers , the synthesis and radiosynthesis of the complementary azido-bearing prosthetic groups (1-(azidomethyl)-4-[18F]- fluorobenzene) and coupling with functionalized ONs. [less ▲]

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See detailUniversal solid support synthesis of modified oligonucleotides labeled by click chemistry for PET studies
Flagothier, Jessica ULg; Mercier, Frederic; Kaisin, Geoffroy ULg et al

Poster (2009, May 29)

Introduction: Positron emission tomography (PET) is a high-resolution, sensitive, molecular and functional imaging technique that permits repeated, non invasive assessment and quantification of specific ... [more ▼]

Introduction: Positron emission tomography (PET) is a high-resolution, sensitive, molecular and functional imaging technique that permits repeated, non invasive assessment and quantification of specific biological and pharmacological processes in humans[1]. In regard to its physical and nuclear characteristics, fluorine-18 appears often as the radionuclide of choice for the preparation of short-lived positron-emitter radiotracers[2]. F-18 labelling reaction of biomolecules such as peptides[3], oligosaccharides, and oligonucleotides[4] (ONs) requires very mild reaction conditions. The method of choice for a highly efficient fluorine-18-labelling of ONs is today the conjugation of a prosthetic group, carrying the radioisotope, with a reactive function of the ONs. Methods: For the ligation reaction of the prosthetic group with the ONs, we selected click reaction and more particularly the CuI catalyzed formation of 1,2,3-triazole using Huisgen 1,3-dipolar cycloaddition of terminal alkynes with azides. This reaction is highly regioselective leading to 1,4-disubstituted 1,2,3-triazoles and can be performed in different solvents with very high yield[5-7]. Conjugations with ONs are usually performed at 3’-ends using a well chosen linker in order to limit degradation by exonucleases[8]. Here we report the synthesis of an alkyne-bearing linker which can be attached at 3’-ends to any sequence of ONs. Results: The linker was prepared in two steps by reaction of commercially available (R)-(+)--hydroxy--butyrolactone with propargylamine followed by protection of the primary hydroxyl with the 4,4’-dimethoxytrityl group[9]. The second step is the reaction with succinic anhydride to obtain a carboxylic function which can be attached to the Amino-SynBase CPG. The resin load was 80 µmol/g. Conclusions: We have prepared a new universal linker which allows introducing an alkyne function at the 3’-end of ONs. This alkyne modified ONs can then react under click conditions with an azide function of a prosthetic group carrying the fluorine radioisotope. As prosthetic group, we selected the 1-azido-4-(3-[18F]fluoropropoxy)benzene which is fully automated produce in our lab[10]. The further results of radiosynthesis of this prosthetic group and the results of click reactions will be presented. Acknowledgement: The authors wish to thank Teller N. from Eurogentec (Seraing, Belgium) for oligonucleotide synthesis. The authors wish to acknowledge the financial support from the Oligopet Projet of the Walloon Region. [less ▲]

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See detailClick chemistry : radiolabelling of oligonucleotides with fluorine-18 for PET imaging
Kaisin, Geoffroy ULg; Flagothier, Jessica ULg; Mercier, Frédéric et al

Poster (2009, March 18)

Click chemistry : radiolabelling of oligonucleotides with fluorine-18 for PET imaging Oligonucleotides (ONs), especially small interfering RNA (siRNA), are promising therapeutic agents, but their ... [more ▼]

Click chemistry : radiolabelling of oligonucleotides with fluorine-18 for PET imaging Oligonucleotides (ONs), especially small interfering RNA (siRNA), are promising therapeutic agents, but their pharmacokinetics and biodistributions are widely unknown. Positron Emission Tomography (PET) using fluorine-18 is a suitable technique to image and quantify such biological processes. The challenge for the radiochemist is to introduce this short half-life isotope (t1/2(18F)=109.7 min) onto oligonucleotides or, more generally, biomolecules. The most common technique requires the coupling of a prosthetic group bearing the radiotracer with the biomolecule. Current methods for labeling ONs with fluorine-18 have sub-optimal yields and require a long synthesis time.{Vries2003} Click chemistry, e.g. 1,3-dipolar Huisgen cycloaddition of azides to alkynes, could be an efficient way to increase yields and reduce synthesis time (see Figure 1). This family of reactions are well suited to the radiolabelling of ONs as they are tolerant to a wide range of solvent and require mild reaction conditions and simple purifications.{Glaser2007} The major strength of this approach is its versatility: it can be easily transposed to any other kind of biomolecules (e.g. peptides, lipids) as long as they can bear an azido or alkyne moiety. Conjugations with ONs are usually performed at 3’-ends using a well-chosen linker in order to limit degradation by exonucleases and to avoid alteration of hybridization properties and siRNA gene silencing efficiency.{Kurreck2009} This also allows the development of universal solid support because synthesis occurs from the 3’ to 5’-end. The linker must fulfil a number of requirements:{Gait2001} - Bearing one alkyne, one primary and one secondary alcohol moiety; - Having a well-defined and known stereochemistry. According to these terms, we propose three different potential linkers (see Figure 2) that can be incorporated into the solid-phase synthesis of ONs. Starting materials are commercially available as pure enantiomers at an affordable price. Here we report the synthesis and characterisation of an alkyne-bearing linker and the synthesis and radiosynthesis of the complementary azido-bearing prosthetic groups (1-(azidomethyl)-4-[18F]-fluorobenzene). [less ▲]

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See detailSynthesis of an universal linker to label oligonucleotides via Click Chemistry
Flagothier, Jessica ULg; Mercier, Frederic; Kaisin, Geoffroy ULg et al

Poster (2009, January 21)

For more than 3 decades, oligonucleotides have been used for therapies, imaging and diagnostics. They are known to hybridize specifically with RNA of a complementary sequence on tissue sections and more ... [more ▼]

For more than 3 decades, oligonucleotides have been used for therapies, imaging and diagnostics. They are known to hybridize specifically with RNA of a complementary sequence on tissue sections and more recently to block the expression of target mRNA when administered in vivo (1). Positron emission Tomography (PET) is a sensitive and non invasive imaging technique, and is the most advanced technology currently available for studying in vivo molecular interactions and therapeutic agents. It is a method of choice to assess the pharmacokinetics of new therapeutics agents such as modified oligonucleotides. Among positron-emitting nuclides, fluorine-18 (t1/2 = 109.8 min) appears to be the best candidate due to its favourable physical and nuclear properties. Several of the methods described in the literature to label oligonucleotides present a number of disadvantages (time of synthesis, low overall radiolabelling yield, non-universal). Due to the speed, selectiveness and the relatively mild experimentals conditions, “Click” chemistry seems a powerful technique. The most explored Click reaction is Huisgen 1,3 dipolar cycloaddition. In our case, this reaction occurs between an alkyne group presents on the oligonucleotide and an azide group on the 18F labelled prosthetic group. The originality of our strategy is the use of a universal linker diverted from the trans-4-hydroxy-proline directly connected to the oligonucleotide. This linker mimics a sugar of the oligonucleotide sequence and should improve their resistance to exonucleases. Synthesis of this compound will be presented. [less ▲]

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See detail18F LABELING OF BIOMOLECULES USING CLICK CHEMISTRY FOR PET APPLICATIONS : SYNTHETIC DEVELOPMENTS
Thonon, David ULg; Flagothier, Jessica ULg; Paris, Jérôme ULg et al

in Drugs of the Future (2008, August), 33(A), 235

Detailed reference viewed: 74 (15 ULg)