References of "Luxen, André"
     in
Bookmark and Share    
Full Text
Peer Reviewed
See detailSynthesis and biological evaluation of potential threonine synthase inhibitors: Rhizocticin A and Plumbemycin A.
Gahungu, Mathias; Arguelles-Arias, Anthony; Fickers, Patrick et al

in Bioorganic & Medicinal Chemistry (2013), 21(17), 4958-67

Rhizocticins and Plumbemycins are natural phosphonate antibiotics produced by the bacterial strains Bacillus subtilis ATCC 6633 and Streptomyces plumbeus, respectively. Up to now, these potential ... [more ▼]

Rhizocticins and Plumbemycins are natural phosphonate antibiotics produced by the bacterial strains Bacillus subtilis ATCC 6633 and Streptomyces plumbeus, respectively. Up to now, these potential threonine synthase inhibitors have only been synthesized under enzymatic catalysis. Here we report the chemical stereoselective synthesis of the non-proteinogenic (S,Z)-2-amino-5-phosphonopent-3-enoic acid [(S,Z)-APPA] and its use for the synthesis of Rhizocticin A and Plumbemycin A. In this work, (S,Z)-APPA was synthesized via the Still-Gennari olefination starting from Garner's aldehyde. The Michaelis-Arbuzov reaction was used to form the phosphorus-carbon bond. Oligopeptides were prepared using liquid phase peptide synthesis (LPPS) and were tested against selected bacteria and fungi. [less ▲]

Detailed reference viewed: 20 (6 ULg)
Full Text
Peer Reviewed
See detailSleep stabilizes visuomotor adaptation memory: a functional magnetic resonance imaging study
Albouy, Geneviève ULg; Vandewalle, Gilles ULg; Sterpenich, Virginie et al

in Journal of Sleep Research (2013), 22(2), 144-54

Detailed reference viewed: 38 (12 ULg)
Full Text
Peer Reviewed
See detailBenevolent sexism alters executive brain responses
Dardenne, Benoît ULg; Dumont, Murielle; Sarlet, Marie et al

in Neuroreport (2013), 24(10), 572-577

Benevolence is widespread in our societies. It is defined as considering a subordinate group nicely but condescendingly, that is, with charity. Deleterious consequences for the target have been reported ... [more ▼]

Benevolence is widespread in our societies. It is defined as considering a subordinate group nicely but condescendingly, that is, with charity. Deleterious consequences for the target have been reported in the literature. In this experiment, we used functional MRI (fMRI) to identify whether being the target of (sexist) benevolence induces changes in brain activity associated with a working memory task. Participants were confronted by benevolent, hostile, or neutral comments before and while performing a reading span test in an fMRI environment. fMRI data showed that brain regions associated previously with intrusive thought suppression (bilateral, dorsolateral,prefrontal, and anterior cingulate cortex) reacted specifically to benevolent sexism compared with hostile sexism and neutral conditions during the performance of the task. These findings indicate that, despite being subjectively positive, benevolence modifies task-related brain networks by recruiting supplementary areas likely to impede optimal cognitive performance. [less ▲]

Detailed reference viewed: 31 (3 ULg)
Full Text
Peer Reviewed
See detailExploration of the mechanisms underlying the ISPC effect: Evidence from behavioral and neuroimaging data
Grandjean, Julien; D'Ostilio, Kevin ULg; Fias, Wim et al

in Neuropsychologia (2013), 51

The item-specific proportion congruent (ISPC) effect in a Stroop task – the observation of reduced interference for color words mostly presented in an incongruent color – has attracted growing interest ... [more ▼]

The item-specific proportion congruent (ISPC) effect in a Stroop task – the observation of reduced interference for color words mostly presented in an incongruent color – has attracted growing interest since the original study by Jacoby (2003). Two mechanisms have been proposed to explain the effect: associative learning of contingencies and item-specific control through word reading modulation. Both interpretations have received empirical support from behavioral data. Therefore, the aim of this study was to investigate the responsible mechanisms of the ISPC effect with the classic two-item sets design using fMRI. Results showed that the ISPC effect is associated with increased activity in the anterior cingulate (ACC), dorsolateral prefrontal (DLPFC), and inferior and superior parietal cortex. Importantly, behavioral and fMRI analyses specifically addressing the respective contribution of associative learning and item-specific control mechanisms brought support for the contingency learning account of the ISPC effect. Results are discussed in reference to task and procedure characteristics that may influence the extent to which item-specific control and/or contingency learning contribute to the ISPC effect. [less ▲]

Detailed reference viewed: 27 (5 ULg)
Full Text
Peer Reviewed
See detailThe impact of visual perceptual learning on sleep and local slow wave initiation
Mascetti, Laura ULg; Muto, Vincenzo ULg; Matarazzo, Luca et al

in Journal of Neuroscience (2013)

Detailed reference viewed: 62 (27 ULg)
Full Text
Peer Reviewed
See detailPerformance Evaluation of the GE eXplore CT 120 Micro-CT for Various Scanning Protocols
Bahri, Mohamed Ali ULg; Bretin, Florian ULg; Warnock, Geoffrey ULg et al

Poster (2012, November 03)

The aim of this study was to evaluate the performance of the General Electric (GE) eXplore CT 120 micro-CT using the same methodology and image quality assurance vmCT phantom developed for the GE eXplore ... [more ▼]

The aim of this study was to evaluate the performance of the General Electric (GE) eXplore CT 120 micro-CT using the same methodology and image quality assurance vmCT phantom developed for the GE eXplore Ultra. In addition, Quality assurance in Radiology and Medicine (QRM) low contrast and bar pattern phantoms were used. The phantoms were imaged using the six protocols regularly used in our laboratory (Fast scan 220 (P1) or 360 (P2): 70 kV, 32 mA, 220 or 360 views; Soft tissue fast scan (P3): 70 kV, 50 mA, 220 views, Soft tissue step & shoot (P4): 80 kV, 32 mA, 220 views; Low Noise (P5): 100 kV, 50 mA, 720 views and In Vivo Bone scan (P6): 100 kV, 50 mA, 360 views). Data were reconstructed with an isotropic voxel size of 100 µm (50 µm when protocol detector-binning was reduced to 2x2). The MTF obtained with the slanted edge and coil methods agreed very well. A 10% modulation transfer function (MTF) was observed in the range 3.6-4.8 mm-1 (P1&2 = 4.2; P3&4 = 4.8; P5 = 3.6 and P6 = 3.8), corresponding to 95-138 µm resolutions. The smallest bars visually observed on the QRM pattern phantom image were 100 µm. The geometric accuracy was better than 0.1%. A highly linear (R2 > 0.999) relationship between measured and expected CT numbers for both the CT number accuracy and linearity sections of the phantom was observed with a voltage dependent slope. A cupping effect was observed on the uniform slices. This effect was clearly highlighted by the uniformity-to-noise ratio (P1 = 0.58, P2&3&4 = 0.75, P5 = 1.35 and P6 = 2.74) especially for the low-noise protocols P5 and P6. The best low contrast discrimination was observed for P2 and P5 protocols. In conclusion the eXplore CT 120 achieved a resolution in the range 95-138 µm. It was found to be linear and geometrically accurate. The major difference between the protocols was the noise level which limits the detectability of low contrasts. [less ▲]

Detailed reference viewed: 217 (18 ULg)
Full Text
Peer Reviewed
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 ▲]

Detailed reference viewed: 41 (8 ULg)
Full Text
Peer Reviewed
See detailIn Ovo PET Imaging Of A Human Colorectal Carcinoma Model In Chicken Chorioallantoic Membrane
Warnock, Geoffrey ULg; Turtoi, Andrei ULg; Blomme, Arnaud ULg et al

Poster (2012, October)

Aim. The objective of this study was to use in vivo PET/CT imaging as a validation tool for a novel human colorectal carcinoma model being developed in chicken chorioallantoic membrane (CAM). For this ... [more ▼]

Aim. The objective of this study was to use in vivo PET/CT imaging as a validation tool for a novel human colorectal carcinoma model being developed in chicken chorioallantoic membrane (CAM). For this initial pilot study a cell line modeling colon cancer was selected and imaged using [18F]fluorodeoxyglucose (FDG). <br />Materials and methods. A window was made in the shell of fertilized chicken eggs and 3x106 SW1222 human colorectal carcinoma cells were implanted at day 10 post-fertilization. On day 17 the shell window was enlarged to allow direct injection of FDG (12.2 ± 4.5 MBq/egg) into a CAM blood vessel. During injection the egg was warmed on a heating pad. A mixture of ketamine/medetomidine (50 :1 mg/ml, 0.2 ml/egg) was injected into the albumin in some eggs to assess the effect of anesthesia. After FDG injection the egg was returned to the incubator for a 45 min uptake period before imaging. Imaging was performed on a Siemens Focus 120 microPET with structural CT on a General Electric eXplore CT120. A Minerve cell system allowed reproducible positioning between modalities. PET data was acquired in list mode before histogramming into a single 10 min frame for reconstruction using a 3D maximum a posteriori (MAP) method with all corrections except scatter. A standard 100 µm (theoretical) image resolution protocol (70 kV, 50 mA, 32 ms, 220 views) was used to obtain structural CT data. Image coregistration was performed in PMOD version 3.3. In a separate egg, the influence of added contrast on the CT data was investigated by adding iodinated contrast agent (Iobitridol 35 mgI/ml) to the albumin. <br />Results. FDG uptake was clear in chick and tumor, with notably high uptake at the major joints. Tumors were identified by localization of FDG uptake on the surface of the CAM. A lack of soft tissue contrast between tumor, CAM and albumin made precise structural identification of the tumor difficult. Anesthesia was crucial to image quality in both PET and CT. CT contrast between the soft tissues of the chick and surrounding albumin/structures was improved by addition of contrast agent. <br />Conclusion. For the first time we demonstrate successful imaging of FDG uptake in a human colorectal carcinoma chicken CAM model in ovo. Methods to improve structural data are under investigation and will be used in further studies. With such improvement, this model could be of great value to PET oncology imaging. [less ▲]

Detailed reference viewed: 164 (53 ULg)
Full Text
Peer Reviewed
See detailPerformance Measurements of the microPET FOCUS 120 for Iodine-124 Imaging
Taleb, Dounia ULg; Bahri, Mohamed Ali ULg; Seret, Alain ULg et al

in IEEE Transactions on Nuclear Science (2012), PP

This study aimed to evaluate the performance of the microPET FOCUS 120 for 124I in terms of counting rate capability and image quality using the NEMA NU 4-2008 methodology. Scanner sensitivity was ... [more ▼]

This study aimed to evaluate the performance of the microPET FOCUS 120 for 124I in terms of counting rate capability and image quality using the NEMA NU 4-2008 methodology. Scanner sensitivity was measured for 124I for comparison and reached 75 cps/kBq, respectively, with the usual 350-650 keV energy window (EW) and 6 ns time window (TW). The noise equivalent count rate (NECR) index was defined as: NECR = RT2/(RP+RGP) (T = true, P = prompt, GP = γ-prompt). A rat phantom maximum NECR of 48 kcps was obtained for the 250-590 keV EW with 6 ns TW. An almost identical maximum NECR of 43 kcps was recorded for 350-590 and 350-650 keV EW and 6 ns TW. The 2 ns TW reduced the sensitivity and NECR by 40-50% for all EW. The mouse phantom NECR study was limited because of the maximum available activity concentration of 124I. The 250-590 keV EW showed the largest scatter and γ-prompt plus scatter fractions with 25.7% and 43%, respectively, for the rat phantom and 12.2% and 27% for the mouse phantom. With the 350-590 keV EW, these fractions decreased to 20% and 33.5% for the rat phantom and to 10% and 21% for the mouse phantom. The image quality was investigated with the NEMA NU 4-2008 dedicated phantom for four (two analytic and two iterative) 2D or 3D reconstruction methods. The lowest spillover ratios (SOR) for the phantom non-emitting regions were obtained for the 350-590 and 350-650 keV EWs. Recovery coefficients (RC) of the hot rods were the highest for the 350-590 keV EW except for the 1 mm rod. Scatter correction led to a large decrease in RC. The combination of the 350-590 keV EW with 6 ns TW appeared to be a good compromise between counting rate capability and image quality for the FOCUS 120, especially when maximum a posteriori reconstruction was used without scatter correction. Moreover this combination enabled the best quantification with an error as low as 0.36%. [less ▲]

Detailed reference viewed: 33 (7 ULg)
Full Text
Peer Reviewed
See detailCHARACTERIZATION OF A NOVEL RADIOTRACER TARGETING SYNAPTIC VESICLE PROTEIN 2A (SV2A)
Warnock, Geoffrey ULg; Aerts, Joël ULg; Bahri, Mohamed Ali ULg et al

Poster (2012, September)

Synaptic vesicle protein 2A (SV2A) has been identified as the binding site of the antiepileptic levetiracetam (Keppra) [1]. SV2 proteins are critical for proper nervous system function and have been ... [more ▼]

Synaptic vesicle protein 2A (SV2A) has been identified as the binding site of the antiepileptic levetiracetam (Keppra) [1]. SV2 proteins are critical for proper nervous system function and have been demonstrated to be involved in vesicle trafficking. Their implication in epilepsy makes them an interesting therapeutic target, and the widespread distribution of SV2A in particular may provide an opportunity to develop a PET-based measure of neuronal function in brain diseases. [18F]UCB-H is a fluorine-18 radiolabelled PET imaging agent with a nanomolar affinity for the human SV2A protein. Preclinical PET studies in rodents were carried out using male SD rats, imaged under isoflurane anaesthesia in a Siemens Concorde Focus 120 microPET scanner. Arterial input function was measured using an arteriovenous shunt method and beta microprobe system. [18F]UCB-H was injected IV (3.8 ± 0.54 mCi bolus, specific activity 8.5 ± 0.86 Ci/Emol immediately after synthesis) and dynamic PET data acquired in list mode for 90 min. Images were reconstructed using filtered back projection with correction for all physical effects except scatter. These scans revealed high uptake of [18F]UCB-H in brain and spinal cord, matching the expected homogeneous distribution of SV2A in the rodent brain [2]. Notably, the kinetics of [18F]UCB-H uptake in the brain were fast, peaking at up to 30 % ID/cm3 before a rapid decline. Metabolism of [18F]UCB-H in vivo followed a typical pattern of rapid initial metabolism followed by a reducing rate of metabolism over time, with less than 20% of the activity in plasma attributable to the parent compound after 30 minutes, and was highly reproducible between subjects. One major metabolite was identified. The uptake of [18F]UCB-H in the brain over time was well fitted by a classical 1-tissue compartment model. Mean parameter estimates (mean ± SD, n=7, whole brain VOI) were K1: 3.58 ± 0.65 ml/cm3/min, k2: 0.21 ± 0.03 min-1, Vt: 17.21 ± 2.52 ml/cm3. Uptake of [18F]UCB-H was blocked by pretreatment with brivaracetam (21 mg/kg IV, 10 min prior to [18F]UCB-H), a recently described high affinity SV2A ligand with a 20-fold higher affinity for SV2A than levetiracetam [3]. In contrast, pretreatment with ucb-100230-1, a diastereoisomer of brivaracetam with 3200-fold lower affinity for SV2A [3], had no clear effect of the brain uptake of [18F]UCB-H. Our results indicate that [18F]UCB-H is a suitable radiotracer for the quantification of SV2A proteins in vivo and for estimating target occupancy of drugs targeting SV2A. This is the first PET tracer for in vivo quantification of SV2A. The necessary steps for implementation of [18F]UCB-H production under GMP conditions have been completed and first in human studies are planned. References [1] Lynch, B.A. et al. (2004) PNAS 101(26):9861-6. [2] Janz, R. & Sudhof, T.C. (1999) Neuroscience 94(4):1279-1290.[3] Gillard, M. et al. (2011) Eur J Pharmacol 664:36-44. [less ▲]

Detailed reference viewed: 123 (23 ULg)
Full Text
Peer Reviewed
See detailMicroPET Focus 120 scanner use at high-­‐count rate
Bahri, Mohamed Ali ULg; Warnock, Geoffrey ULg; Taleb, Dounia ULg et al

Poster (2012, September)

Kinetic modeling of physiological processes using imaging techniques requires an accurate measurement of the time-activity curve of the tracer in plasma, known as the arterial input function (IF). The IF ... [more ▼]

Kinetic modeling of physiological processes using imaging techniques requires an accurate measurement of the time-activity curve of the tracer in plasma, known as the arterial input function (IF). The IF can be obtained by manual blood sampling, can be derived from PET images, or continuously measured by the use of small counting systems such as beta microprobes [1]. However, some beta microprobe systems can suffering from high background counts and low sensitivity compared to PET can obligate the use of activities higher than those typical for the imaging system. In the present study, the NEMA NU4-2008 image quality (IQ) phantom [2] was used to evaluate the image quality of the microPET Focus 120 at high activity values. Attenuation correction was obtained from transmission measurement using 57Co point source. Eight emission scans of 20 minutes were performed at decreasing activity starting from 109 MBq to 3.7 MBq (total activity in the field-of-view). To study the effect of normalization in high count rate studies, several normalization scans were performed using activities ranging between 18 and 212 MBq. Images were reconstructed with all corrections using Fourier rebinning and filtered backprojection. The mean activity and the coefficients of variation of the uniform slices were measured. All high activity reconstructed images showed a detector-block-patterned artifact with an overestimation of the counts when normalization activity is higher than that used in the IQ phantom and underestimation of the counts when normalization activity is below the activity used in the IQ phantom. Using the same high activity for acquisition and normalization considerably reduces the patterned-artifact but does not eliminate it entirely. The observed artifact is due to pulse pile-up in the detectors at high count-rates. A dedicated rejection of the pulse pile-up does not appear to have been implemented for the microPET Focus 120. An alternative would be to re-calibrate the detectors with higher activity values to prevent any pile-up effect or to create an attenuation volume into which phantoms or small animals could be inserted thus decreasing the artifact. This latter option is under development. References: [1] G. Warnock et al, European Journal of Nuclear Medicine and Molecular Imaging Research, 1-13 (2011) [2] NEMA Standards Publication NU4-2008. Rosslyn, VA: National Electrical Manufacturers Association; (2008). [less ▲]

Detailed reference viewed: 127 (10 ULg)
Full Text
Peer Reviewed
See detailSmall animal imaging with human PET
Bahri, Mohamed Ali ULg; Tombuloglu, S; Warnock, Geoffrey ULg et al

Poster (2012, September)

PET studies provide valuable information in the assessment of animal models for human diseases. MicroPET systems provide the high resolution needed to explore small organs but suffer from a reduced axial ... [more ▼]

PET studies provide valuable information in the assessment of animal models for human diseases. MicroPET systems provide the high resolution needed to explore small organs but suffer from a reduced axial FOV. Multiple bed positions are then used to obtain whole body scans resulting in increased scan time and incomplete dynamic data. In contrast, human PET systems have larger axial FOV but a lower resolution. In this study, an image-based model of the scanner spatial response function combined with a 3D-OSEM reconstruction algorithm were used to improve spatial resolution of the Siemens ECAT EXACT HR+ PET scanner. A stationary double Gaussian model [1] of the ECAT EXACT HR+ point spread function was derived from 18F point source measurements performed at different radial and axial locations in the scanner FOV. This model was used in a 3D-OSEM reconstruction (3D-OSEM-RM). Sinograms were normalized and attenuation and scatter corrected using the Siemens ECAT tools before reconstruction. Both NEMA NU 2-1994 performance phantoms and NEMA NU4-2008 image quality phantom mimicking small animals were used to evaluate the accuracy of corrections for physical effects and the overall image quality. A 50 min dynamic FDG rat study was conducted on the ECAT HR+ and reconstructed with 3D-OSEM-RM. The images were used to compute the metabolic rate of glucose (MRglu) in multiple brain structures. These images were also visually compared to the static image obtained with a FOCUS 120 microPET immediately after the HR+ dynamic scan. The standard deviations of the two Gaussians used to model the transaxial (axial) resolution in a central FOV of 5 cm radius were σ1 = 1.6 (2.75) mm and σ2 = 3.66 (4.16) mm, and the ratio of the weights between the first and second Gaussians was ρ = 0.2 (0.7). Image uniformity and accuracy of scatter and attenuation corrections, evaluated following NEMA NU 2-1994, were found to be very similar between 3D-OSEM, 3D-OSEM-RM, 2D- and 3D-FBP reconstructed images. When using the NEMA NU4-2008 image quality phantom a significant increase of the hot rod recovery coefficient was observed. This effect was rod size dependent and amounted to 17-35% for the 3D-OSEM-RM compared to the 3D-OSEM and to 35-62% compared to the FBP reconstructions. Nevertheless the values obtained with 3D-OSEM-RM were around 20-35% lower than those obtained with the FOCUS 120 microPET scanner. Most of the small brain structures observed on microPET images were also visible on the images obtained with the HR+ scanner and 3D-OSEM-RM. Rat cerebral MRglu values calculated on 3D-OSEM-RM images were in the range of published values [2] (e.g. whole brain = 25.34 μmol/min/100g). Using an approximate model of the ECAT EXACT HR+ spatial response in 3D-OSEM resulted in sufficient image quality for dynamic whole body scans of small rodents, despite the large FOV, and resulted in improved contrast compared to images generated using the built-in software. This methodology will be applied for future small animal dosimetry and modeling studies in our laboratory. [1] Comtat et al. IEEE Nucl Sci Symp Conf Record. pp. 4120-4123 (2008) [2] Schiffer et al. J Nucl Med 48:277-287 (2007) [less ▲]

Detailed reference viewed: 139 (14 ULg)
Full Text
Peer Reviewed
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 ▲]

Detailed reference viewed: 80 (19 ULg)
Full Text
Peer Reviewed
See detailPET In Conscious Rodents - Quantification of Stress During The Training Process
Warnock, Geoffrey ULg; Bahri, Mohamed Ali ULg; Bretin, Florian ULg et al

Poster (2012, September)

Recently several methods for performing PET studies in conscious rodents have been developed [1-3]. These methods have the potential to greatly improve the translational nature of PET studies in rodents ... [more ▼]

Recently several methods for performing PET studies in conscious rodents have been developed [1-3]. These methods have the potential to greatly improve the translational nature of PET studies in rodents. One of the most easily implemented methods is the training of a rat to tolerate head fixation in a restraining device. Training consists of intervals of restraint over several days. However, the stress induced by this training procedure has not been quantified in detail. Limited changes in plasma corticosterone have been reported, but this data may be confounded by sample timing and baseline levels. An implantable telemetry system (Telemetry Research) was used to remotely measure blood pressure, heart rate and core temperature during training. Transmitters were implanted in the abdominal cavity under isoflurane anesthesia, with the blood pressure sensor fixed in the abdominal aorta. Training was started after a recovery period of at least 1 week. Training consisted of a 5 min period of acclimatization in the cage containing the restraining device, followed by increasing durations of restraint in the device on subsequent training days (15, 30, 45, 60, 90 min). Telemetry data was acquired from 5 min prior to acclimatization to 60 minutes post-training. In this initial pilot study, a single rat was trained, without head fixation, for 4 consecutive days and again on day 7. All reported values are mean ± SEM across the five training days. In the home cage, prior to acclimatization, baseline heart rate (HR) was 294 ± 15 bpm. During the acclimatization period, HR was elevated to 411 ± 7 bpm. Immediately after starting training, HR was 419 ± 16 bpm. During the training period HR showed a tendency to decrease, with raised periods at undefined intervals. After return to the home cage, HR remained elevated for 15-20 min before returning to a value (313 ± 9 bpm) close to baseline. A similar pattern was seen in blood pressure (mean; BP). Baseline BP was 76 ± 7 mmHg, increasing to 94 ± 9 mmHg during acclimatization. After commencing training, a peak in BP was reached at 102 ± 8 mmHg. After the 15-20 min recovery interval, BP returned to a baseline of 77 ± 9 mmHg. The HR and BP responses to acclimatization and to the training protocol persisted throughout all training days, with the main noticeable difference being the number of bouts of increased HR, which increased with training duration. Core body temperature (baseline: 37.45 ± 0.21 °C) increased during restraint training, with a subsequent post-training peak (38.21 ± 0.03 °C). Measurement of core temp is complicated during longer training sessions by the need to charge the transmitter. This early data indicates that stress induced by the training procedure for conscious PET persists after several days of training. In subsequent studies the head will be fixed and the effect of the training on plasma corticosterone and central glucose metabolism (using [18F]FDG) will be examined. [1] Momosaki et al. (2004) Synapse 54:207–213 [2] Wyss et al. (2009) NeuroImage 48:339–347 [3] Itoh et al. (2009) J Nucl Med 50:749–756 [less ▲]

Detailed reference viewed: 47 (17 ULg)
Full Text
Peer Reviewed
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 ▲]

Detailed reference viewed: 37 (7 ULg)
Full Text
Peer Reviewed
See detailAutomatic multiclass classification of 18FDG-PET scans for the distinction between Parkinson’s disease and atypical parkinsonian syndromes
Phillips, Christophe ULg; Schrouff, Jessica ULg; Luxen, André ULg et al

Poster (2012, June 10)

Part of the difficulty in the early diagnosis of Parkinson’s disease (PD) is in differentiating it from atypical parkinsonian disorders (APS) that have a poorer prognosis such as multiple system atrophy ... [more ▼]

Part of the difficulty in the early diagnosis of Parkinson’s disease (PD) is in differentiating it from atypical parkinsonian disorders (APS) that have a poorer prognosis such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). 18flurodeoxyglucose (FDG) positron emission tomography (PET) has been recommended for the early differentiation between PD and APS [1]. Here, 120 FDG PET scans (42, 31, 26 and 21 for the PD, MSA, PSP and CBS resp.) were acquired on average 3.5 years after symptoms onset (because the initial clinical features were outside the prevailing perception for PD) to look, without any a priori assumption, for cerebral FDG uptake patterns that discriminate either between the PD and APS classes, or between the four PD, MSA, PSP and CBS classes. The diagnostic used to label the scans was defined by clinical criteria on average 4.5 years after PET assessment. [less ▲]

Detailed reference viewed: 59 (3 ULg)
Full Text
See detailImaging Guided Proteomics Unveils Heterogeniety in Colorectal Carcinoma Liver Metastases – Implications for Targeted Therapies.
blomme, Arnaud; Turtoi, Andrei ULg; Delvaux, David ULg et al

in Proceedings Giga Day 2012 (2012, May 04)

Detailed reference viewed: 42 (20 ULg)
Peer Reviewed
See detailSynthesis and evaluation of boronic acids as inhibitors of Penicillin Binding Proteins of classes A, B and C
Zervosen, Astrid ULg; Sauvage, Eric ULg; Bouillez, André ULg et al

Poster (2012, April 18)

The widespread use of beta-lactam antibiotics has lead to the worldwide appearance of drug-resistant strains. Bacteria have developed resistance to beta-lactams by three main mechanisms: the production of ... [more ▼]

The widespread use of beta-lactam antibiotics has lead to the worldwide appearance of drug-resistant strains. Bacteria have developed resistance to beta-lactams by three main mechanisms: the production of beta-lactamases that catalyze hydrolysis of beta-lactams, the production of low-affinity, drug resistant Penicillin Binding Proteins (PBPs) and the over expression of resistant PBPs. PBPs are interesting targets because they catalyse the last steps of the biosynthesis of peptidoglycan, which is unique in bacteria and has no mammalian analogs, outside the cytoplasmic membrane. Various non-ß-lactam inhibitors of PBPs have been developed with the objective of attempting to stall the development of ß-lactam resistance. Boronic acids are potent beta-lactamase inhibitors and have been shown to display some specificity for soluble transpeptidases and PBPs, but their potential as inhibitors of the latter enzymes is yet to be widely explored. Recently, a (2, 6-dimethoxybenzamido)methylboronic acid was identified as being a potent inhibitor of Actinomadura sp. R39 transpeptidase (IC50: 1.3 µM). Here, we will discuss the synthesis of a number of acylaminomethylboronic acids, analogs of (2, 6-dimethoxybenzamido)methylboronic acid, and their potential as inhibitors of PBPs. Several boronic acids of this library were able to inhibit PBPs of classes A, B and C from penicillin sensitive strains. Thus (2-nitrobenzamido)methylboronic acid was identified as a good inhibitor of class A PBP (PBP1b from S. pneumoniae, IC50 = 26 µM), class B PBP (PBP2xR6 from S. pneumoniae, IC50 = 138 µM) and class C PBP (R39 from Actinomadura sp., IC50 = 0.6 µM). Crystal structures of complexes of R39 and PBP1b with boronic acid analogs of our library have already been solved and allowed an interpretation of results. We believe that this work opens new avenues towards the development of molecules that will inhibit PBPs, and eventually display bactericidal effect, on distinct bacterial species. [less ▲]

Detailed reference viewed: 43 (13 ULg)