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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 detailValine-based biphenylsulphonamide matrix metalloproteinase inhibitors as tumor imaging agents
Oltenfreiter, R.; Staelens, L.; Kersemans, V. et al

in Applied Radiation & Isotopes (2006), 64(6), 677-685

Among matrix metalloproteinases (MMPs), the subfamily of gelatinases (MMP-2, MMP-9) is of particular interest due to their ability to degrade type IV collagen and other non-fibrillar collagen domains and ... [more ▼]

Among matrix metalloproteinases (MMPs), the subfamily of gelatinases (MMP-2, MMP-9) is of particular interest due to their ability to degrade type IV collagen and other non-fibrillar collagen domains and proteins such as fibronectin and laminin. Whilst malignant cells often over-express various MMPs, the gelatinases have been most consistently detected in malignant tissues and associated with tumor growth, metastatic potential and angiogenesis. Radiosynthesis of carboxylic (1') and hydroxamic (2') MMPIs resulted in radiochemical yields of 70 +/- 5% (n = 6) and 60 5% (n = 4), respectively. Evaluation in A549-inoculated athymic mice showed a tumor uptake of 2.0 +/- 0.7%ID/g (3 h p.i.), a tumor/blood ratio of 0.5 and a tumor/muscle ratio of 4.6 at 48 h p.i. for 1'. For compound 2' a tumor uptake of 0.7 +/- 0.2%ID/g (3 h p.i.), a tumor/blood ratio of 1.2 and a tumor/muscle ratio of 1.8 at 24 h p.i. were observed. HPLC analysis of the blood (plasma) showed no dehalogenation or other metabolites of 1' 2 h p.i. For compound 2', 65.4% of intact compound was found in the blood (plasma) and one polar metabolite (31%) was detected whereas in the tumor 91.8% of the accumulated activity was caused by intact compound and only 8.1% by the metabolite. Planar imaging, using a Toshiba GCA-9300A/hg SPECT camera, showed that tumor tissue could be visualized and that image quality improved by decreasing specific activity resulting in lower liver uptake, indicating some degree of saturable binding in the liver. In vivo evaluation of these radioiodinated carboxylic and hydroxamic MMP inhibitor tracers revealed that MMP inhibitors could have potential as tumor imaging agents, but that further research is necessary. (c) 2006 Elsevier Ltd. All rights reserved. [less ▲]

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See detailSynthesis, radiosynthesis, in vitro and preliminary in vivo evaluation of biphenyl carboxylic and hydroxamic matrix metalloproteinase (MMP) inhibitors as potential tumor imaging agents.
Oltenfreiter, R.; Staelens, L.; Hillaert, U. et al

in Applied Radiation & Isotopes (2005), 62(6), 903-13

Excess matrix degradation is one of the hallmarks of cancer and is an important factor in the process of tumor progression. It is implicated in invasion, metastasis, growth, angiogenesis and migration ... [more ▼]

Excess matrix degradation is one of the hallmarks of cancer and is an important factor in the process of tumor progression. It is implicated in invasion, metastasis, growth, angiogenesis and migration. Many characteristics of matrix metalloproteinases (MMPs) make them attractive therapeutic and diagnostic targets. MMP expression is upregulated at the tumor site, with localization of activity in the tumor or the surrounding stroma, providing a target for medical imaging techniques. Radioiodinated carboxylic and hydroxamic MMP inhibitors 2-(4′-[123I] iodo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid (9) and 2-(4′-[123I] iodo-biphenyl-4-sulfonylamino)-3-methyl-butyramide (11), their unlabelled standards and precursors were synthesized. Radioiodination was conducted by electrophilic aromatic substitution of the tributylstannyl precursors and resulted in radiochemical yields of 70±5% (n=6) and 60±5% (n=4), respectively. In vitro zymography and enzyme assays showed for both hydroxamic acid and carboxylic acid compounds a good inhibition activity and a high selectivity for MMP-2. In vivo biodistribution in NMRI mice showed no long-term accumulation in organs and the possibility to accumulate in the tumor in a later phase of this study. [less ▲]

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See detailEpimerization study on [18F]FDG produced by an alkaline hydrolysis on solid support under stringent conditions
Mosdzianowski, C.; Lemaire, Christian ULg; Simoens, F. et al

in Applied Radiation & Isotopes (2002), 56(6), 871-875

Since 1998, routine [18F]FDG syntheses are being carried out by alkaline hydrolysis on a solid support, i.e. the labeled intermediate is trapped on a tC18 solid phase extraction cartridge, purified and ... [more ▼]

Since 1998, routine [18F]FDG syntheses are being carried out by alkaline hydrolysis on a solid support, i.e. the labeled intermediate is trapped on a tC18 solid phase extraction cartridge, purified and finally hydrolyzed within the cartridge, at room temperature, using sodium hydroxide. The present study demonstrated that no epimerization of [18F]FDG to [18F]FDM occurs even when 12 N NaOH is used and when the hydrolysis time is extended up to 1 h. The alkaline hydrolysis on solid support appears to be a simple method leading to [18F]FDG with high purity. [less ▲]

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See detailFast Routine Production of L-[11C-methyl]methionine with Al2O3KF
Schmitz, Frédéric; Plenevaux, Alain ULg; Del-Fiore, Guy et al

in Applied Radiation & Isotopes (1995), 46(9), 893-897

No-carrier-added (nca) L-[11C-methyl]methionine was prepared via the very fast S-alkylation of L-homocysteine adsorbed on AI203/KF with [11C]iodomethane at room temperature in ethanol. The alkylation was ... [more ▼]

No-carrier-added (nca) L-[11C-methyl]methionine was prepared via the very fast S-alkylation of L-homocysteine adsorbed on AI203/KF with [11C]iodomethane at room temperature in ethanol. The alkylation was realized with a radiochemical yield of 94 +/- 4% EOB (n = 20). More than 90% (n = 20) of the precursor L-homocysteine remained adsorbed on the solid support and was eliminated by a simple filtration. After reaction, neither racemization nor by-product were detected. The purification process was thus limited to a C18 Sep-Pak followed by an alumina Sep-Pak. The radiochemical purity measured on the final solution was shown to be > 99%. The only chemical contaminant was L-homocysteine (+ 10 µg). With this new technique, L-[11C-methyl]methionine was ready for injection within 10 min from [11C]CO2 with a specific activity ranging around 37 + 5.6 GBq (1 +/- 0.15 Ci)//tmol EOB. Through this procedure L-[11C-methyl]methionine can be prepared without preparative HPLC purification, This is an important simplification for the fast routine production of one of the most widely used radiopharmaceutical compounds for PET. [less ▲]

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See detailENANTIOSELECTIVE SYNTHESIS OF NCA (S)-L-([ALPHA-C-11]METHYL)-TRYPTOPHAN
Plenevaux, Alain ULg; Lemaire, Christian ULg; Delfiore, Guy et al

in Applied Radiation & Isotopes (1994), 45(6), 651-653

N.c.a. (S)-L-([alpha-C-11]methyl)-tryptophan was prepared by treatment at -78-degrees-C of (2S,3aR,8aS)-1,2-bis(-methoxycarbonyl)-1,2,3,3a,8,8a-hexahydropyrrolo[2, 3-b]-indole with lithium ... [more ▼]

N.c.a. (S)-L-([alpha-C-11]methyl)-tryptophan was prepared by treatment at -78-degrees-C of (2S,3aR,8aS)-1,2-bis(-methoxycarbonyl)-1,2,3,3a,8,8a-hexahydropyrrolo[2, 3-b]-indole with lithium diisopropylamide and [C-11]CH3I. After hydrolysis with HI and HPLC purification, the title compound was isolated with a radiochemical yield of 36% (EOB corrected) within 22 min; e.e. was shown > 97% (n = 20); specific activity was ranging between 0.8 and 1.2 Ci (30-45 GBq)/mu mol EOB. [less ▲]

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See detailENANTIOSELECTIVE SYNTHESES OF NCA (S)-L-[BETA-C-11]-4-CHLOROPHENYLALANINE AND (S)-L-(ALPHA-METHYL)-[BETA-C-11]-4-CHLOROPHENYLALANINE
Plenevaux, Alain ULg; Al-Darwich, M. J.; Lemaire, Christian ULg et al

in Applied Radiation & Isotopes (1994), 45(3), 361-369

The radiolabeling of (S)-L-4-chlorophenylalanine and (S)-L-(alpha-methyl)-4-chlorophenylalanine were realized with carbon-11 at position beta through a radiochemical synthesis relying on the highly ... [more ▼]

The radiolabeling of (S)-L-4-chlorophenylalanine and (S)-L-(alpha-methyl)-4-chlorophenylalanine were realized with carbon-11 at position beta through a radiochemical synthesis relying on the highly enantioselective reaction between 4-chloro[alpha-C-11]benzyl bromide and the lithium enolate of (S)-1-(t-butyloxycarbonyl)-2-(t-butyl)-3-methyl-1,3-imidazolidine-4-one for (S)-L-[beta-C-11]-4-chlorophenylalanine and of (2S,5S)-1-(t-butyloxycarbonyl)-2-(t-butyl)-3,5-dimethyl-1,3-imidazolidin e-4-one for (S)-L-(alpha-methyl)-[beta-C-11]-4-chlorophenylalanine. Quantities of about 25-35 mCi were obtained at the end of synthesis, ready for injection, after hydrolysis and HPLC purification with a radiochemical yield of 19% corrected to EOB within 45 min. The enantiomeric excesses were shown to be greater than or equal to 97% for both molecules without chiral separation. The radiochemical and the chemical purities of the final compounds were greater than or equal to 98% and the specific activity at the end of synthesis ranged between 250-800 mCi/mu mol. [less ▲]

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See detailNUCLEOPHILIC ENANTIOSELECTIVE SYNTHESIS OF 6-[F-18]FLUORO-L-DOPA VIA 2 CHIRAL AUXILIARIES
Lemaire, Christian ULg; Plenevaux, Alain ULg; Cantineau, Robert et al

in Applied Radiation & Isotopes (1993), 44(4), 737-744

Asymmetric nucleophilic synthesis of 6-[F-18]fluoro-L-dopa was investigated in order to reach an enantiomeric excess of close to 100% of the L form of this amino acid. The radiochemical synthesis required ... [more ▼]

Asymmetric nucleophilic synthesis of 6-[F-18]fluoro-L-dopa was investigated in order to reach an enantiomeric excess of close to 100% of the L form of this amino acid. The radiochemical synthesis required [F-18]fluoride as fluorinating agent and regioselective nucleophilic substitution of commercially available 6-nitroveratraldehyde. The [F-18]fluorobenzaldehyde thus obtained was easily converted to the corresponding 2-[F-18]fluoro-4,5-dimethoxybenzyl bromide. This alkylating agent was added to the lithium enolates of 1-(S)-(-)camphor imine of t-butyl glycinate (1) and (S)-(-)- 1 -Boc-2-t-butyl-3-methyl-4-imidazolidinone [(S)- Boc-BMI] (2) in order to compare the enantiomeric excess of the L form obtained in each case with these two chiral inductors. The L-isomer of fluorodopa was isolated after H1 hydrolysis and HPLC purification in 5-10% radiochemical yield (decay corrected). The overall synthesis time was of 110 min. Through this synthetic pathway, the L-isomer of fluorodopa was obtained in 83% e.e with 1 and 96% e.e with 2 respectively, as determined by chiral HPLC. A practical three step preparative scale synthesis of 6-[F-19]fluoro-D,L-dopa is also presented. [less ▲]

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See detailSYNTHESIS OF F-18 SUBSTITUTED AROMATIC-ALDEHYDES AND BENZYL BROMIDES, NEW INTERMEDIATES FOR NCA [F-18] FLUORINATION
Lemaire, Christian ULg; Damhaut, Philippe; Plenevaux, Alain ULg et al

in Applied Radiation & Isotopes (1992), 43(4), 485-494

The synthesis of various [F-18]fluoroaromatic aldehydes using activated nitro precursors and aminopolyether supported nucleophilic substitution with F-18(-) is reported. These radiolabelled fluorinated ... [more ▼]

The synthesis of various [F-18]fluoroaromatic aldehydes using activated nitro precursors and aminopolyether supported nucleophilic substitution with F-18(-) is reported. These radiolabelled fluorinated aldehydes (radiochemical yields: 50-75%) are powerful key intermediates leading after treatment with NaBH4 and SOBr2 (SOCl2) to further active intermediates for example substituted [F-18]fluorobenzyl bromides (yields 30-50% EOB). These benzaldehydes and bromides are particularly useful for the preparation of new radiopharmaceuticals (e.g. fluorotroprapride, fluorodexetimide) either by reductive amination or by aromatic N-alkylation. The preparation of various amino acids in D, L (50:50) or enriched L form by asymmetric synthesis is also possible (e.g. L-6-[F-18]fluorodopa, L-4-[F-18]fluoro-m-tyrosine). It can be anticipated that the F-18-labelled fluoroaldehydes will find widespread application in radiopharmaceutical chemistry. [less ▲]

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See detailSYNTHESIS OF NONACTIVATED F-18 FLUORINATED AROMATIC-COMPOUNDS THROUGH NUCLEOPHILIC-SUBSTITUTION AND DECARBOXYLATION REACTIONS
Plenevaux, Alain ULg; Lemaire, Christian ULg; Palmer, Anthtony J. et al

in Applied Radiation & Isotopes (1992), 43(8), 1035-1040

The synthesis of no-carrier-added 3-[F-18]fluoroanisole, 2-[F-18]fluoroanisole, [F-18]fluorobenzene and 4-[F-18]fluoroveratrole are reported. The strategy consists of amino-polyether supported ... [more ▼]

The synthesis of no-carrier-added 3-[F-18]fluoroanisole, 2-[F-18]fluoroanisole, [F-18]fluorobenzene and 4-[F-18]fluoroveratrole are reported. The strategy consists of amino-polyether supported nucleophilic substitution with [F-18]F- on activated nitro aromatic aldehyde precursors followed by decarbonylation using Tris(triphenylphosphine) rhodium (I) chloride. The experimental parameters for this reaction have been studied and optimized with 2-[F-18]fluoro-4-methoxybenzaldehyde and then successfully applied to four other F-18-fluorinated aromatic aldehydes. The decarbonylation yields obtained were 84 +/- 5% (corrected for decay) within 15 min at 150-degrees-C in 1,4-dioxan. [less ▲]

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See detailAN APPROACH TO THE ASYMMETRIC-SYNTHESIS OF L-6-[F-18]FLUORODOPA VIA NCA NUCLEOPHILIC FLUORINATION
Lemaire, Christian ULg; Guillaume, Marcel; Cantineau, Robert et al

in Applied Radiation & Isotopes (1991), 42(7), 629-635

The NCA asymmetric synthesis of L-6-[F-18]fluorodopa starting from (1R,2R,5R)-[(+)-2-hydroxypinanyl-3-idene]glycine t-butyl ester as chiral agent has been developed. After F-18-fluorination of the two ... [more ▼]

The NCA asymmetric synthesis of L-6-[F-18]fluorodopa starting from (1R,2R,5R)-[(+)-2-hydroxypinanyl-3-idene]glycine t-butyl ester as chiral agent has been developed. After F-18-fluorination of the two commercially available aldehydes either 6-nitroveratraldehyde or 6-nitropiperonal, the required alkylating [F-18]fluorobenzyl bromide derivative can be easily prepared by treatment with NaBH4 followed by SOBr2. Alkylation of the Schiff base was carried out with the lithium salt of 2,2,6,6-tetramethylpiperidine as base in anhydrous THF at -78-degrees-C. Following hydrolysis of the protecting groups with hydroxylamine and Hl, the L-amino acid was obtained in 75% L form (ee 50%) with a 10% decay corrected (120 min) radiochemical yield. [less ▲]

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