References of "Libert, Lionel"
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See detailIn vivo PET/CT in a human glioblastoma chicken chorioallantoic membrane model: A new tool for oncology and radiotracer development.
Warnock, Geoffrey; Turtoi, Andrei ULg; Blomme, Arnaud ULg et al

in Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine (2013), 54(10), 1782-1788

For many years the laboratory mouse has been used as the standard model for in vivo oncology research, particularly in the development of novel PET tracers, but the growth of tumors on chicken ... [more ▼]

For many years the laboratory mouse has been used as the standard model for in vivo oncology research, particularly in the development of novel PET tracers, but the growth of tumors on chicken chorioallantoic membrane (CAM) provides a more rapid, low cost and ethically sustainable alternative. For the first time, we demonstrate the feasibility of in vivo PET and CT imaging in a U87 glioblastoma tumor model on chicken chorioallantoic membrane (CAM), with the aim of applying this model for screening of novel PET tracers. Methods: U87 glioblastoma cells were implanted on the CAM at day 11 post-fertilization and imaged at day 18. A small animal imaging cell was used to maintain incubation and allow anesthesia using isoflurane. Radiotracers were injected directly into the exposed CAM vasculature. Sodium [18F]fluoride was used to validate the imaging protocol, demonstrating that image-degrading motion can be removed with anesthesia. Tumor glucose metabolism was imaged using [18F]fluorodeoxyglucose and tumor protein synthesis was imaged using 2-[18F]fluoro-L-tyrosine. Anatomical images were obtained by contrast enhanced CT, facilitating clear delineation of the tumor, delineation of tracer uptake in tumor versus embryo and accurate volume measurements. Results: PET imaging of tumor glucose metabolism and protein synthesis was successfully demonstrated in the CAM U87 glioblastoma model. Catheterization of CAM blood vessels facilitated dynamic imaging of glucose metabolism with [18F]fluorodeoxyglucose and demonstrated the ability to study PET tracer uptake over time in individual tumors, while CT imaging improved the accuracy of tumor volume measurements. Conclusion: In summary, we describe the novel application of PET/CT in the CAM tumor model, with optimization of typical imaging protocols. PET imaging in this valuable tumor model could prove particularly useful for rapid, high-throughput screening of novel radiotracers. [less ▲]

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See detailOptimalisation de la radiosynthèse et production au niveau de la curie d'acides aminés aromatiques marqués au fluor-18
Libert, Lionel ULg

Doctoral thesis (2013)

6-[18F]fluoro-L-dopa (FDOPA) and 2-[18F]fluoro-L-tyrosine (FTYR) are useful radiopharmaceuticals for evaluation by positron emission tomography (PET) of the dopaminergic function and oncological studies ... [more ▼]

6-[18F]fluoro-L-dopa (FDOPA) and 2-[18F]fluoro-L-tyrosine (FTYR) are useful radiopharmaceuticals for evaluation by positron emission tomography (PET) of the dopaminergic function and oncological studies, respectively. In comparison to electrophilic synthesis, the no-carrier-added (nca) nucleophilic preparation of these 2 radiopharmaceuticals, described in 2004 by Lemaire et al, has several advantages such a high batch yield and high specific activity. However, this nca enantioselective synthesis using a chiral phase-transfer catalyst requires some chemicals (i.e. corrosive HBr gas) arduous to handle and store and reactions at low and high temperature (0°C, 200°C) difficult to implement into a commercially available synthesizer. Important chemical improvements, realized during this PhD thesis, having resulted in straightforward automation of FDOPA and FTYR synthesis, in a commercially available FASTLab module (GE healthcare) are presented. The first significant improvement to the synthesis has consisted in the development of a fast and reliable method suitable for the preparation of (substituted) [18F]fluorobenzyl halides from several [18F]fluorobenzaldehydes. Aromatic nucleophilic substitution of trimethylammonium benzaldehyde triflate and nitro precursors were realized with nca [18F]fluoride. After labeling, [18F]fluorobenzaldehydes were trapped on a Solid Phase Extraction (SPE) cartridge and the subsequent conversion (reduction and halogenation) into benzyl halides was directly realized, on-line, on the support. Reduction of the aldehydes and the following halogenation step were performed with an aqueous solution of NaBH4 and aqueous solutions of concentrated acid (HI, HBr, HCl), respectively. These two near-quantitative reactions proceed at room temperature within 2 minutes at high yields. The second improvement of the nca synthesis of FDOPA and FTYR has consisted in the enantioselective formation of a new carbon-carbon bond by phase-transfer catalysis in presence of a chiral phase-transfer catalyst (PTC) at RT rather than at 0°C. Seven chiral phase-transfer catalysts with a potential high enantioselectivity, at room temperature, for the asymmetric alkylation of a N-(diphenylmethylene)glycine tert-butyl ester have been prepared. Two of these catalysts affords high enantiomeric excess in FDOPA and FTYR (e.e. ≥ 95%) at room temperature and even at 75°C (e.e. ≥ 90%). One is readily available from a cinchona alkaloid and the other one from a biphenyl substrate. The third improvement concerned the hydrolysis step (200°C, 20 min). Different starting precursors with more labile protective groups than the methoxy were synthesized and evaluated. Among these compounds, the isopropyl ether protective group seems the more advantageous. By exploiting the advantages of the improvements to the chemistry described in this work and the potential of the nca approach, the synthesis of FDOPA and FTYR was automated in a FASTlab module with GMP single use cassettes. After 100 min of bombardment (167 GBq) and 63 min of synthesis, more than 50 GBq (1,35 Ci) of 6-[18F]fluoro-L-dopa (e.e. ≥ 96,3%) with a specific activity in excess of 0.75 TBq/µmol are routinely produced. For FTYR, slightly higher yield was obtained. With such reliable production, 6-[18F]fluoro-L-dopa and 2-[18F]fluoro-L-tyrosine are now available for clinical investigation. [less ▲]

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See detailProduction at the Curie Level of No-Carrier-Added 6-18F-Fluoro-L-Dopa
Libert, Lionel ULg; Franci, Xavier; Plenevaux, Alain ULg et al

in Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine (2013), 54(7), 1154-1161

6-18F-fluoro-L-dopa (18F-FDOPA) has proven to be a useful radiopharmaceutical for the evaluation of presynaptic dopaminergic function using PET. In comparison to electrophilic synthesis, the no-carrier ... [more ▼]

6-18F-fluoro-L-dopa (18F-FDOPA) has proven to be a useful radiopharmaceutical for the evaluation of presynaptic dopaminergic function using PET. In comparison to electrophilic synthesis, the no-carrier-added (NCA) nucleophilic method has several advantages. These include much higher available activity and specific activity. Recently, we have described an NCA enantioselective synthesis using a chiral phase-transfer catalyst. However, some chemicals were difficult to implement into a commercially available synthesizer, restricting access to this radiopharmaceutical to only a few PET centers. Methods: In this paper, 2 important chemical improvements are proposed to simplify production of 18F-FDOPA, resulting in straightforward automation of the synthesis in a commercially available module. Results: First, a fast, simple, and reliable synthesis of 2-18F-fluoro-4,5-dimethoxybenzyl iodide on a solid phase support was developed. Second, a phase-transfer catalyst alkylation of a glycine derivative at room temperature was used to enable enantioselective carbon–carbon bond formation. After hydrolysis and high-performance liquid chromatography purification, a high enantiomeric excess of 18F-FDOPA (~97%) was obtained using a chiral catalyst available from a biphenyl 3 substrate. The total synthesis time was 63 min, and the decay-corrected radiochemical yield was 36% +/- 3% (n = 8). Conclusion: By exploiting the advantages of this NCA approach, using a starting activity of 185 GBq of NCA 18F-fluoride, high activities of 18F-FDOPA (> 45 GBq) with high specific activity (>753 GBq/mmol) are now available at the end of synthesis for use in clinical investigations. [less ▲]

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See detailQuality controls of no-carrier-added aromatic amino acids such as FDOPA and FTYR produced at curie level
Libert, Lionel ULg; Lemaire, Christian ULg; Giacomelli, Fabrice ULg et al

Poster (2013, May)

Aromatic fluoro amino acids such as 2-[18F]fluoro-L-tyrosine (FTYR) and 6-[18F]fluoro-L-DOPA (FDOPA) are useful radiopharmaceuticals for oncologic studies and evaluation of the presynaptic dopaminergic ... [more ▼]

Aromatic fluoro amino acids such as 2-[18F]fluoro-L-tyrosine (FTYR) and 6-[18F]fluoro-L-DOPA (FDOPA) are useful radiopharmaceuticals for oncologic studies and evaluation of the presynaptic dopaminergic function using positron emission tomography. Recently, a no-carrier-added (nca) enantioselective synthesis of these compounds, based on an multistep PTC approach was automated in a FASTlabTM module from GE . From 185 GBq of [18F]fluoride and after 1 hour of synthesis, more than 37 GBq of FTYR or FDOPA are available . This automated production yields enough doses for many PET studies. A monograph for FDOPA prepared by electrophilic substitution exists , but it is not adapted to the nca nucleophilic synthesis of FDOPA and FTYR, as in this case specific activity, by products and possible impurities are different. A complete quality control (QC) has then be developed in accordance with the guidelines of the European Pharmacopeia (Eur. Ph.). [less ▲]

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See detailDosimetry for 6-[18F]Fluoro-L-DOPA in Humans Based on Biodistribution in Mice
Bretin, Florian ULg; Warnock, Geoffrey ULg; Bahri, Mohamed Ali ULg et al

Poster (2012, October)

Aim. The objective of this work was to estimate human dosimetry for 6-[18F]Fluoro-L-DOPA (F-DOPA) from biodistribution in mice, obtained from organ harvesting at different time points and from a hybrid ... [more ▼]

Aim. The objective of this work was to estimate human dosimetry for 6-[18F]Fluoro-L-DOPA (F-DOPA) from biodistribution in mice, obtained from organ harvesting at different time points and from a hybrid method combining dynamic PET followed by organ harvesting. Materials and methods. The tissue distribution of F-DOPA over time was determined in isoflurane-anaesthetized mice. Radioassay was performed on harvested organs at 2, 5, 10, 30, 60 and 120 minutes post administration (n = 5 at each time point). Dynamic PET images were acquired in list-mode with a Siemens FOCUS 120 microPET for 120 minutes after injection and followed by radioassay of harvested organs (n = 4). List-mode data were histogrammed in 6*5s, 6*10s, 3*20s, 5*30s, 5*60s, 8*150s, 6*300s, 6*600s 3D sinograms. Final images were obtained using filtered backprojection with correction for all physical effects except for scatter. Attenuation correction resulted from a pre-injection transmission scan with a cobalt-57 point source. Organs were manually delineated. The organ time-activity-curves (TACs) from both methods were extrapolated from a simulated 35 g standard mouse to a 70 kg standard male human using a technique based on organ to bodyweight ratios. A bladder voiding scenario was used to simulate excretion every 2 h. The absorbed doses in major human organs were calculated using the extrapolated TACs with the commercially available software OLINDA/EXM (Version 1.1). Results. The extrapolated organ activity curves obtained using the harvesting and imaging methods showed a high correlation (r = 0.94 ± 0.05, p < 0.001). However, TACs from PET alone under- or overestimated the activity in individual organs in contrast to TACs obtained using the cross-calibration of the PET data with the activity in post-scan dissected organs. Those organs in the excretion pathways, comprising bladder wall, kidneys and liver, received the highest organ doses. The total body absorbed dose was 0.0118 mGy/MBq for both the imaging based and harvesting based methods. The effective dose was 0.0193 mSv/MBq for the hybrid imaging-harvesting technique and 0.0189 mSv/MBq for the pure harvesting technique. Conclusion. The doses obtained agreed well with the few results available in the literature. The hybrid technique combining dynamic PET scanning followed by organ harvesting appeared to be a good alternative to the gold standard ex vivo radioassay method. It is much faster and minimizes the effect of some weakness of the pure imaging technique, such as partial volume effect. [less ▲]

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See detailDosimetry for 6-[18F]Fluoro-L-DOPA in humans based on in vivo microPET scans and ex vivo tissue distribution in mice
Bretin, Florian ULg; Warnock, Geoffrey ULg; Bahri, Mohamed Ali ULg et al

Poster (2012, September)

Radiation dosimetry of new radiopharmaceuticals generally starts with studies in small animals such as mice and rats. The traditional technique has long been ex vivo measurement of the biodistribution ... [more ▼]

Radiation dosimetry of new radiopharmaceuticals generally starts with studies in small animals such as mice and rats. The traditional technique has long been ex vivo measurement of the biodistribution over time using harvested organs at different times post administration of the radiopharmaceutical. Since this approach requires a significant amount of animals, dynamic microPET studies, where the biodistribution of the tracer over time can be determined in vivo in a single scan, are an invaluable alternative. Due to known imaging artifacts and limitations, such as partial volume effect, a hybrid technique combining harvesting organs (post-scan) and dynamic imaging was introduced to achieve a cross-calibration to account for these limitations. Since 6-[18F]Fluoro-L-DOPA is a widely used PET tracer to study the dopaminergic system in neurology and oncology and there is no sound published dosimetry data, absorbed doses for major organs in humans were estimated using the traditional ex vivo technique and by dynamic microPET imaging in mice, allowing direct comparison of the results from the two techniques. The tissue distribution over time of 6-[18F]Fluoro-L-DOPA was determined by radioassay of harvested organs at 2, 5, 10, 30, 60, 120 minutes post administration (n=5 at each time point) in isoflurane-anaesthetized mice. Dynamic PET images were acquired with a FOCUS 120 microPET for 120 minutes after injection of 6-[18F]Fluoro-L-DOPA followed by radioassay of harvested organs (n=4). A bladder voiding scenario was used to simulate excretion every 2 h. The organ time-activity-curves (TACs) from both methods were extrapolated from a simulated 35 g standard mouse to a 70 kg standard male human using a technique based on organ to bodyweight ratios. The absorbed doses in major human organs were calculated with the commercially available human dosimetry software OLINDA/EXM (Version 1.1) using the extrapolated TACs. The extrapolated organ TACs obtained using the two methods showed a high correlation (average r = 0.94 ± 0.05, p < 0.001). However, TACs from PET alone under- or overestimated the activity in individual organs in contrast to TACs obtained using the cross-calibration of the PET data with the activity in post-scan dissected organs. Those organs in the excretion pathways, comprising bladder wall, kidneys and liver, received the highest organ doses. The total body absorbed dose was 0.0118 mGy/MBq for both the imaging based and harvesting based methods. The effective dose was 0.0193 mSv/MBq for the hybrid imaging-harvesting technique and 0.0189 mSv/MBq for the pure harvesting technique. Scaling errors in the PET TACs are likely caused by quantification errors such as partial volume effects and image artifacts. The use of a hybrid imaging technique to cross-calibrate the TACs improved the accuracy of the imaging-based dosimetry estimates. Therefore the hybrid technique combining dynamic imaging and harvesting organs (post-scan) is a suitable alternative to the gold standard ex vivo radioassay method. It yields comparable results yet reduces significantly the amount of animals needed in the study and can accelerate data acquisition. [less ▲]

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See detailFast Production of Highly Reactive No-Carrier-Added [18F]Fluoride for the Labeling of Radiopharmaceuticals
Lemaire, Christian ULg; Aerts, Joël ULg; Voccia, Samuel et al

in Angewandte Chemie (International ed. in English) (2010), 49

The 18F labeling of radiopharmaceuticals requires nearly anhydrous solutions of [18F]fluoride. Aqueous K2CO3 is generally used to elute [18F]fluoride from an anion-exchange resin. Replacing aqueous K2CO3 ... [more ▼]

The 18F labeling of radiopharmaceuticals requires nearly anhydrous solutions of [18F]fluoride. Aqueous K2CO3 is generally used to elute [18F]fluoride from an anion-exchange resin. Replacing aqueous K2CO3 with strong organic bases, such as the phosphazene base P2Et enabled the recovery of highly reactive [18F]fluoride and avoided the azeotropic evaporation of water, which is very difficult on a microchip device. [less ▲]

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See detailNew Improvements in the Enantioselective Synthesis of 2-[18F]Fluoro-L-Tyrosine and 6-[18F]Fluoro-L-Dopa
Libert, Lionel ULg; Lemaire, Christian ULg; Denoël, Thibaut ULg et al

in Journal of Labelled Compounds & Radiopharmaceuticals (2009, July), 52(S1), 196

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See detailLarge Scale Preparation of [18]Fluoromethoxybenzyl Bromides, Key Precursors for 2-[18F]Fluoro-L-Tyrosine and 6-[18F]Fluoro-L-Dopa
Libert, Lionel ULg; Lemaire, Christian ULg; Wouters, Ludovic ULg et al

in Journal of Labelled Compounds & Radiopharmaceuticals (2009, July), 52(S1), 292

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See detailFast and Reliable Method for the Preparation of Various [18F]Fluorobenzyl Halides
Lemaire, Christian ULg; Libert, Lionel ULg; Plenevaux, Alain ULg et al

in Journal of Labelled Compounds & Radiopharmaceuticals (2009, July), 52(S1), 178

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See detailMicrowave-Assisted Synthesis of Vinyl Esters through Ruthenium-Catalyzed Addition of Carboxylic Acids to Alkynes
Nicks, Francois ULg; Libert, Lionel ULg; Delaude, Lionel ULg et al

in Australian Journal of Chemistry (2009), 62(3), 227-231

A rapid and efficient method is described for the selective synthesis of enol esters via the microwave-accelerated addition of carboxylic acids to terminal alkynes. The method employs the readily ... [more ▼]

A rapid and efficient method is described for the selective synthesis of enol esters via the microwave-accelerated addition of carboxylic acids to terminal alkynes. The method employs the readily available [RuCl2(p-cymene)(PPh3)] complex as catalyst without the need of bases, and reactions are complete in 20 min. [less ▲]

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See detailMicrowave-assisted synthesis of vinyl esters through ruthenium-catalyzed addition of carboxylic acids to alkynes
Nicks, Francois ULg; Libert, Lionel ULg; Delaude, Lionel ULg et al

in Polymer Preprints (2008), 49(2), 944-945

1-Hexen-2-yl 4-acetoxybenzoate was regioselectively prepd. via microwave-assisted ruthenium-catalyzed addn. of 4-acetoxybenzoic acid to 1-hexyne. Species of catalysts, reaction time and temp. play roles ... [more ▼]

1-Hexen-2-yl 4-acetoxybenzoate was regioselectively prepd. via microwave-assisted ruthenium-catalyzed addn. of 4-acetoxybenzoic acid to 1-hexyne. Species of catalysts, reaction time and temp. play roles in the reaction respect to yields and selectivity, therefore were examd. Microwave effect was obsd. and preferred to the generation of the Markovnikov-type product compared to traditional heating. [less ▲]

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