References of "Luxen, André"
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See detailCustomizing an adaptive case management software in a GMP production lab as a quality management system for clinical trial PET radiopharmaceuticals development and production
Aerts, Joël ULg; Renard; Léonard, Marc ULg et al

Poster (2013)

The Cyclotron Research Centre (CRC) of the University of Liège develops and produces innovative radiopharmaceuticals for research and clinical diagnostic applications in humans. We report our recent ... [more ▼]

The Cyclotron Research Centre (CRC) of the University of Liège develops and produces innovative radiopharmaceuticals for research and clinical diagnostic applications in humans. We report our recent experience in the implementation of an adaptive case management software as a tool of tractability and quality management in our GMP1 facility. [less ▲]

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See detailEvaluation of a new [18F] labeled tracer targeting synaptic vesicle protein 2C by ex vivo autoradiography and in vivo PET study in rat brain.
Warnock, Geoffrey; Aerts, Joël ULg; Mestdagh, Nathalie et al

Poster (2013)

Introduction The synaptic vesicle protein 2 (SV2) family is a group of integral membrane glycoproteins homologous to the major facilitator superfamily and could be involved in several neuronal diseasesa ... [more ▼]

Introduction The synaptic vesicle protein 2 (SV2) family is a group of integral membrane glycoproteins homologous to the major facilitator superfamily and could be involved in several neuronal diseasesa. The binding of the novel, no-carrier-added, [18F] labeled compound [18F]UCB-F to the SV2C isoform was evaluated in rat brain. Methods Radiochemistry No-carrier added [18F]UCB-F was obtained following the method shown in Fig. 1. The identity and purity of the tracer were evaluated by radioUPLC and chiral radioHPLC. Autoradiography Sprague Dawley rat brain sections were incubated at RT with buffered [18F]UCB-F solutions and exposed on film. Matching sections were stained with cresyl violet for structural identification. PET studies PET studies (Siemens Concorde Focus 120 µPET) were performed under isoflurane anesthesia. The tracer was injected as a bolus via the tail vein. After a 10-min transmission scan to correct for attenuation, dynamic emission data was recorded for a total of 60 min. The impact of P-glycoprotein (P-gp) activity on tracer uptake in the brain was evaluated using cyclosporine (50 mg/kg SC). Metabolite analysis During PET studies, arterial blood samples were taken for the measurement of tracer metabolites. Plasma was separated by centrifugation and proteins were acid-precipitated. Metabolites were detected using HPLC and confirmed by gamma counting. Results The tracer was obtained with a decay corrected yield of ±10%. Specific activity ranged from 10 GBq/µmol to 40 GBq/µmol. Ex vivo autoradiography showed that the binding of [18F]UCB-F to SV2C closely matched the expected distribution b (Fig.2). In vivo PET studies revealed that [18F]UCB-F briefly entered the brain, but exhibited extremely rapid washout. A large accumulation in the liver and intestines was observed. Metabolite analysis in the plasma revealed high protein binding and rapid metabolism. Inhibition of P-gp transport with cyclosporin had no clear effect on the rapid washout from the brain. Conclusions Despite a close match between [18F]UCB-F SV2C binding and the expected brain distribution, the pharmacokinetics in rat brain appear unfavorable for the use of this tracer to quantify SV2C in vivo. Acknowledgement / References a Lynch & al (2004) Proc. Natl. Acad. Sci. USA 101:9861 b Janz & Sudhof (1999) Neuroscience 94:1279 c The authors thank the Walloon Region and the FRNS Belgium for financial support. [less ▲]

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See detailRadiosynthesis and first small animal microPET imaging of [18F]UCB-H, a new fluorine-18 labelled tracer targeting synaptic vesicle protein 2A (SV2A)
Aerts, Joël ULg; Otabashi, Muhamed; Giacomelli, Fabrice ULg et al

Conference (2013)

Aim. We report the radiosynthesis and first rat microPET imaging of a new fluorine-18 tracer targeting the synaptic vesicle protein 2A, SV2A, identified as the binding site of the antiepileptic drug ... [more ▼]

Aim. We report the radiosynthesis and first rat microPET imaging of a new fluorine-18 tracer targeting the synaptic vesicle protein 2A, SV2A, identified as the binding site of the antiepileptic drug levetiracetam. Materials and Method. Two different nucleophilic radiosynthesis pathways were tested to obtain [18F]UCB-H, a no-carrier-added tracer in the 2-[18F]fluoropyridine family. The methods were automated on FastLab™ synthesizers. 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. All animal protocols were reviewed and accepted by animal ethical committees. Results and conclusion. A radiosynthesis yield of 30% was obtained (uncorrected for decay, 150 minutes of synthesis). Analytical methods were developed and validated to demonstrate that the quality of the tracer solution was compatible with in vivo injection. After intravenous injection, the tracer rapidly entered the brain, followed by rapid washout. PET imaging revealed high uptake of the tracer in the brain and spinal cord, matching the expected SV2A homogeneous distribution. Results indicate that [18F]UCB-H is suitable to quantify SV2A proteins in vivo and to estimate target occupancy of drugs targeting SV2A. Acknowledgments. The authors thank UCB Pharma SA Belgium for collaboration and the Walloon Region Belgium and the FRNS Belgium for financial support. [less ▲]

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See detailThe proline-rich motif of the proDer p 3 allergen propeptide is crucial for protease-protease interaction.
Dumez, Marie-Eve ULg; Herman, Julie; Campisi, Vincenzo ULg et al

in PloS one (2013), 8(9), 68014

The majority of proteases are synthesized in an inactive form, termed zymogen, which consists of a propeptide and a protease domain. The propeptide is commonly involved in the correct folding and specific ... [more ▼]

The majority of proteases are synthesized in an inactive form, termed zymogen, which consists of a propeptide and a protease domain. The propeptide is commonly involved in the correct folding and specific inhibition of the enzyme. The propeptide of the house dust mite allergen Der p 3, NPILPASPNAT, contains a proline-rich motif (PRM), which is unusual for a trypsin-like protease. By truncating the propeptide or replacing one or all of the prolines in the non-glycosylated zymogen with alanine(s), we demonstrated that the full-length propeptide is not required for correct folding and thermal stability and that the PRM is important for the resistance of proDer p 3 to undesired proteolysis when the protein is expressed in Pichia pastoris. Additionally, we followed the maturation time course of proDer p 3 by coupling a quenched-flow assay to mass spectrometry analysis. This approach allowed to monitor the evolution of the different species and to determine the steady-state kinetic parameters for activation of the zymogen by the major allergen Der p 1. This experiment demonstrated that prolines 5 and 8 are crucial for proDer p 3-Der p 1 interaction and for activation of the zymogen. [less ▲]

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See detailDifferential effects of aging on the neural correlates of recollection and familiarity
Angel, Lucie; Bastin, Christine ULg; Genon, Sarah ULg et al

in Cortex : A Journal Devoted to the Study of the Nervous System & Behavior (2013), 49

The present experiment aimed to investigate age differences in the neural correlates of familiarity and recollection, while keeping performance similar across age groups by varying task difficulty. Twenty ... [more ▼]

The present experiment aimed to investigate age differences in the neural correlates of familiarity and recollection, while keeping performance similar across age groups by varying task difficulty. Twenty young and twenty older adults performed an episodic memory task in an event-related fMRI design. At encoding, participants were presented with pictures, either once or twice. Then, they performed a recognition task, with a Remember/Know paradigm. A similar performance was observed for the two groups in the Easy condition for recollection and in the Hard condition for familiarity. Imaging data revealed the classic recollection-related and familiarity-related networks, common to young and older groups. In addition, we observed that some activity related to recollection (left frontal, left temporal, left parietal cortices and left parahippocampus) and familiarity (bilateral anterior cingulate, right frontal gyrus and left superior temporal gyrus) was reduced in older compared to young adults. However, for recollection processes only, older adults additionally recruited the right precuneus, possibly to successfully compensate for their difficulties, as suggested by a positive correlation between recollection and precuneus activity. [less ▲]

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See detailMulticlass classification of FDG PET scans for the distinction between Parkinson's disease and atypical parkinsonian syndromes
Garraux, Gaëtan ULg; Phillips, Christophe ULg; Schrouff, Jessica ULg et al

in NeuroImage: Clinical (2013), 2

Most available pattern recognition methods in neuroimaging address binary classification problems. Here, we used relevance vector machine (RVM) in combination with booststrap resampling (‘bagging’) for ... [more ▼]

Most available pattern recognition methods in neuroimaging address binary classification problems. Here, we used relevance vector machine (RVM) in combination with booststrap resampling (‘bagging’) for non-hierarchical multiclass classification. The method was tested on 120 cerebral 18fluorodeoxyglucose (FDG) positron emission tomography (PET) scans performed in patients who exhibited parkinsonian clinical features for 3.5 years on average but that were outside the prevailing perception for Parkinson's disease (PD). A radiological diagnosis of PD was suggested for 30 patients at the time of PET imaging. However, at follow-up several years after PET imaging, 42 of them finally received a clinical diagnosis of PD. The remaining 78 APS patients were diagnosed with multiple system atrophy (MSA, N = 31), progressive supranuclear palsy (PSP, N = 26) and corticobasal syndrome (CBS, N = 21), respectively. With respect to this standard of truth, classification sensitivity, specificity, positive and negative predictive values for PD were 93% 83% 75% and 96%, respectively using binary RVM (PD vs. APS) and 90%, 87%, 79% and 94%, respectively, using multiclass RVM (PD vs. MSA vs. PSP vs. CBS). Multiclass RVM achieved 45%, 55% and 62% classification accuracy for, MSA, PSP and CBS, respectively. Finally, a majority confidence ratio was computed for each scan on the basis of class pairs that were the most frequently assigned by RVM. Altogether, the results suggest that automatic multiclass RVM classification of FDG PET scans achieves adequate performance for the early differentiation between PD and APS on the basis of cerebral FDG uptake patterns when the clinical diagnosis is felt uncertain. This approach cannot be recommended yet as an aid for distinction between the three APS classes under consideration. [less ▲]

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See detailConcurrent Synaptic and Systems Memory Consolidation during Sleep
Mascetti, Laura; Foret, Ariane; Schrouff, Jessica ULg et al

in Journal of Neuroscience (2013), 33(24), 10182-10190

Memories are consolidated during sleep by two apparently antagonistic processes: (1) reinforcement of memory-specific cortical interactions and (2) homeostatic reduction in synaptic efficiency. Using fMRI ... [more ▼]

Memories are consolidated during sleep by two apparently antagonistic processes: (1) reinforcement of memory-specific cortical interactions and (2) homeostatic reduction in synaptic efficiency. Using fMRI, we assessed whether episodic memories are processed during sleep by either or both mechanisms, by comparing recollection before and after sleep. We probed whether LTP influences these processes by contrasting two groups of individuals prospectively recruited based on BDNF rs6265 (Val66Met) polymorphism. Between immediate retrieval and delayed testing scheduled after sleep, responses to recollection increased significantly more in Val/Val individuals than in Met carriers in parietal and occipital areas not previously engaged in retrieval, consistent with “systems-level consolidation.” Responses also increased differentially between allelic groups in regions already activated before sleep but only in proportion to slow oscillation power, in keeping with “synaptic downscaling.” Episodic memories seem processed at both synaptic and systemic levels during sleep by mechanisms involving LTP. [less ▲]

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See detailInteraction between hippocampal and striatal systems predicts subsequent consolidation of motor sequence memory.
Albouy, Geneviève; Sterpenich, Virginie; Vandewalle, Gilles ULg et al

in PLoS ONE (2013), 8(3), 59490

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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 ▲]

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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

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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 ▲]

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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 ▲]

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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)

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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 ▲]

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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 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 ▲]

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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 ▲]

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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 ▲]

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