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See detailMemantine-induced brain activation as a model for the rapid screening of potential novel antipsychotic compounds: Exemplified by an mGlu2/3 receptor agonist
Dedeurwaerdere, S.; Wintmolders, C.; Straetemans, R. et al

in Society-for-Neuroscience Abstracts/Annual Meeting Publications (2010, November 17), 40

Schizophrenia is a severe, disabling chronic disorder affecting approximately 1% of the population. Unfortunately, patients afflicted by this difficult to treat psychiatric illness remain stigmatized and ... [more ▼]

Schizophrenia is a severe, disabling chronic disorder affecting approximately 1% of the population. Unfortunately, patients afflicted by this difficult to treat psychiatric illness remain stigmatized and are likely to suffer permanent cognitive and social deficits. Improvements and development of more robust and hopefully predictive screening assays for this disease should enhance the identification and development of novel treatments. The present study describes a rapid and robust method for the testing of potential novel antipsychotics by utilising a simplified [14C]2-deoxyglucose (2-DG) uptake autoradiography technique following memantine-induced brain activation. Male C57BL/6JCRL mice were treated with either vehicle, ketamine (30 mg/kg, s.c.) or memantine (20 mg/kg, s.c.). Both NMDA antagonists induced significant increases in 2-DG uptake in specific brain region such as lateral orbital cortex, olfactory tubercle, piriform cortex, cingulate cortex, retrosplenial cortex, lacunosum molecular layer of the hippocampus and the lateral posterior thalamic nucleus. Interestingly, memantine elicited a more robust brain activation signature with a larger dynamic window than ketamine. For further characterisation of the assay, we also tested the effect of diet (fasting versus non-fasting) and different vehicles. In addition, dedicated software, developed particularly for this assay, was evaluated for automated quantification of the brain sections. In subsequent reversal studies, we found that in accordance to the ketamine challenge model (Duncan et al. 1998), the “atypical” anti-psychotic clozapine (2.5 and 10 mg/kg, s.c.) significantly reversed memantine-induced 2-DG uptake whilst the “typical” anti-psychotic haloperidol (0.32 mg/kg, s.c.) was inactive thus further validating our choice of memantine for the challenge agent. An additional study then determined the effects of a mGlu2/3 receptor agonist on both ketamine and memantine-induced brain activation. Pre-treatment with LY404039 (10 mg/kg, s.c.) fully reversed both the ketamine and memantine-induced increase in 2-DG uptake without effects on basal 2-DG uptake. Finally, a small animal PET study was performed with [18F]-FDG in mice and rats investigating the effect of memantine (20 mg/kg) administration in vivo. This study confirmed the memantine-induced brain activation previously demonstrated by autoradiography. In conclusion, this novel pre-clinical method shows potential for the screening of compounds targeting the NMDA receptor hypofunction hypothesis of schizophrenia and may assist in translating these findings from the bench to clinic. [less ▲]

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See detailIN VIVO PET IMAGING OF THE EFFECT OF THE NMDA ANTAGONIST MEMANTINE ON GLUCOSE METABOLISM IN THE RODENT BRAIN
Warnock, Geoffrey ULg; Dedeurwaerdere, Stefanie; Bahri, Mohamed Ali ULg et al

Poster (2010, September)

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See detailTHE EFFECT OF BETA MICROPROBE IMPLANTATION ON THE BLOOD BRAIN BARRIER
Warnock, Geoffrey ULg; Dedeurwaardere, Stefanie; Bahri, Mohamed Ali ULg et al

Poster (2010, September)

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See detailFast production of highly concentrated reactive [18F] fluoride for aliphatic and aromatic nucleophilic radiolabelling
Aerts, Joël ULg; Voccia, Samuel; Lemaire, Christian ULg et al

in Tetrahedron Letters (2010), 51

The use of a polymeric solid support loaded with a long alkyl chain quaternary ammonium allows the rapid and efficient recovery of cyclotron produced [18F]F- from [18O]water to a low water content organic ... [more ▼]

The use of a polymeric solid support loaded with a long alkyl chain quaternary ammonium allows the rapid and efficient recovery of cyclotron produced [18F]F- from [18O]water to a low water content organic solution compatible with fast nucleophilic labelling of most precursors for PET radiopharmaceuticals in high yield. [less ▲]

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See detailDISPLACEMENT OF 18F-FALLYPRIDE BINDING WITH HALOPERIDOL IN A WITHIN-SUBJECT DESIGN USING A BETA MICROPROBE
Warnock, Geoffrey ULg; Goblet, David ULg; Lemaire, Christian ULg et al

in Journal of Cerebral Blood Flow & Metabolism (2009, October), 29(S1), 352-353

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See detailNEMA NU4-2008 Image Quality Performance Report for the microPET Focus 120 and for Various Transmission and Reconstruction Methods
Bahri, Mohamed Ali ULg; Plenevaux, Alain ULg; Warnock, Geoffrey ULg et al

in Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine (2009), 50

This work aimed to evaluate the image quality and accuracy of attenuation and scatter corrections provided with the microPET Focus 120 scanner using the National Electrical Manufacturers Association NU4 ... [more ▼]

This work aimed to evaluate the image quality and accuracy of attenuation and scatter corrections provided with the microPET Focus 120 scanner using the National Electrical Manufacturers Association NU4-2008 image quality phantom. Methods: Attenuation correction was obtained from transmission measurements using either a 68Ge or a 57Copoint source. Fully correctedemission images were reconstructed using Fourier rebinning (FORE) and filtered backprojection (FBP). For attenuation data obtained with the 57Co source, fully corrected emission images were also reconstructed using FORE and 2-dimensional (2D) ordered-subset expectation maximization (OSEM), 3-dimensional (3D) filtered backprojection (3DRP), 3D OSEM, and 3D maximum a posteriori methods. The mean activity, the coefficients of variation (COVs) of the uniform slices, the recovery coefficients (RCs) for hot rods, and the spillover ratio (SOR) for nonemittingwater and air compartments were measured. Results: For 57Co-based attenuation correction, the mean activity value differed by less than 3% from the true activity.Measuring the attenuation with 68Ge resulted in lower reconstructed activity and higher COV. On the basis of 57Co measurements, the SORs for air and water nonemitting compartments were the closest to zero for attenuation correction. The RC measured on emission images corrected for attenuation but not for scatter did not show any significant difference linked to the transmissionmethod. However, higherRCswere noted for transmission measurement with 68Ge in coincidence with windowing when emission data were corrected for attenuation and scatter. This resulted from a lower mean value in the uniform area. 2D and 3DRP reconstructionmethods showed little effect on themean activity value, whereas iterative 3D methods gave 7%higher values. Higher RCs were found with iterative reconstruction than with FBP and 3DRP. However, the SOR seemed to be optimal with FBP. SORs were higher with iterative methods and decreased with the number of iterations. Conclusion: For studies of small rodents with the Focus 120, 57Co transmission seems to be the most suitable method for attenuation correction. FORE and 2D reconstruction methods appear to be a good compromise between overall image quality and reconstruction time: OSEM provides the largest contrasts, but FBP provides superior attenuation and scatter correction. [less ▲]

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See detailAccurate measurement of arterial input function during FDG PET using a beta microprobe
Warnock, Geoffrey ULg; Lemaire, Christian ULg; Langlois, Xavier et al

in Journal of Cerebral Blood Flow & Metabolism (2009, October), 29(S1), 339-339

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See detailTIME-DEPENDENT PREFERENTIAL IN VIVO D2 OCCUPANCY BY AMISULPRIDE IN THE MEDIAL STRIATUM – CONTINUOUS MEASUREMENT USING A BETA MICROPROBE SYSTEM
Warnock, Geoffrey ULg; Goblet, David ULg; Lemaire, Christian ULg et al

in Journal of Labelled Compounds & Radiopharmaceuticals (2009, July), 52(S1), 105

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See detailUSE OF A BETA MICROPROBE SYSTEM AS AN AFFORDABLE TRANSLATIONAL TOOL COMPARED TO PET – EXAMPLES USING FDG AND 18F-FALLYPRIDE BINDING
Warnock, Geoffrey ULg; Goblet, David ULg; Lemaire, Christian ULg et al

in Journal of Labelled Compounds & Radiopharmaceuticals (2009, July), 52(S1), 55

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See detailTHE USEFULNESS OF AN ARTERIOVENOUS SHUNT COMBINED WITH A BETA MICROPROBE FOR THE MEASUREMENT OF INPUT FUNCTION IN RATS
Warnock, Geoffrey ULg; Goblet, David ULg; Lemaire, Christian ULg et al

in Journal of Labelled Compounds & Radiopharmaceuticals (2009, July), 52(S1), 106

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See detailIn vivo evidence for ligand-specific receptor activation in the central CRF system, as measured by local cerebral glucose utilization.
Warnock, Geoffrey ULg; Moechars, Dieder; Langlois, Xavier et al

in Peptides (2009), 30(5), 947-54

Corticotropin-releasing factor (CRF) is well known for its role in the hypothalamic-pituitary-adrenocortical (HPA) axis and its involvement in stress and anxiety. CRF acts via two main receptor subtypes ... [more ▼]

Corticotropin-releasing factor (CRF) is well known for its role in the hypothalamic-pituitary-adrenocortical (HPA) axis and its involvement in stress and anxiety. CRF acts via two main receptor subtypes, CRF(1) and CRF(2). Other endogenous CRF-related peptide ligands are the Urocortins 1 and 2 and Stresscopin. While CRF is thought to mediate its anxiogenic-like properties through CRF(1), the role of CRF(2) and its endogenous ligands Urocortin 2 and Stresscopin are less clear, with a suggested role in mediating the delayed effects of stress. Measurement of local cerebral glucose utilization (LCGU) provides an estimate of neuronal activity, and is of potential use as a translational tool in comparison to FDG PET. We hypothesized that comparison of the patterns of metabolic changes induced by CRF-related peptides could provide further information on their role in the brain. The present studies examined the effects of CRF-related peptides on LCGU, and the role of CRF(1) and CRF(2) in the CRF-induced LCGU response. CRF induced increases in LCGU in hypothalamic, thalamic, cerebellar and hippocampal regions, and further studies using antagonists or mutant mice lacking a functional CRF(1) receptor clearly suggested a role for CRF(2) in this effect. Urocortin 1 increased LCGU in a dissected hindbrain region. However, central administration of the CRF(2)-selective agonists Urocortin 2 and Stresscopin failed to affect LCGU, which may suggest ligand-dependent receptor activation within the CRF system. The present data supports a role for CRF(2) in the regulation of neuronal glucose metabolism. [less ▲]

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See detailMetabolism of no-carrier-added 2-[18F]fluoro-L-tyrosine in rats
Aerts, Joël ULg; Plenevaux, Alain ULg; Lemaire, Christian ULg et al

in BMC Medical Physics (2008), 8

Background: Several fluorine-18 labelled fluoroamino acids have been evaluated as tracers for the quantitative assessment of cerebral protein synthesis in vivo by positron emission tomography (PET). Among ... [more ▼]

Background: Several fluorine-18 labelled fluoroamino acids have been evaluated as tracers for the quantitative assessment of cerebral protein synthesis in vivo by positron emission tomography (PET). Among these, 2-[18F]fluoro-L-tyrosine (2-[18F]Tyr) has been studied in mice at a low specific activity. Its incorporation into proteins is fast and metabolism via other pathways is limited. The present in vivo study was carried out in normal awake rats using no-carrier-added 2-[18F]Tyr. Under normal physiological conditions, we have studied the incorporation into proteins and the metabolism of the tracer in different brain areas. Methods: No-carrier-added 2-[18F]Tyr was administered to awake rats equipped with chronic arterial and venous catheters. The time course of the plasma activity was studied by arterial blood sampling. The biodistribution of the activity in the main organs was studied at the end of the experiment. The distribution of radioactive species in plasma and brain regions was studied by acidic precipitation of the proteins and HPLC analysis of the supernatant. Results: The absolute uptake of radioactivity in brain regions was homogenous. In awake rats, nocarrier-added 2-[18F]Tyr exhibits a fast and almost quantitative incorporation into the proteins fractions of cerebellum and cortex. In striatum, this incorporation into proteins and the unchanged fraction of the tracer detected by HPLC could be lower than in other brain regions. Conclusion: This study confirms the potential of 2-[18F]fluoro-L-tyrosine as a tracer for the assessment of the rate of protein synthesis by positron emission tomography. The observed metabolism suggests a need for a correction for the appearance of metabolites, at least in plasma. [less ▲]

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See detailInteractions between CRF and acetylcholine in the modulation of cognitive behaviour.
Warnock, Geoffrey ULg; Prickaerts, Jos; Steckler, Thomas

in Levin, E. D. (Ed.) Neurotransmitter Interactions and Cognitive Function (2006)

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