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See detailBiodistribution and radiation dosimetry for the novel SV2A radiotracer [18F]UCB-H: Firstin- human study.
Bretin, Florian ULg; Bahri, Mohamed Ali ULg; BERNARD, Claire ULg et al

in Molecular Imaging & Biology (in press)

Abstract- [18F]UCB-H is a novel radiotracer with a high affinity for SV2A, a protein expressed in synaptic vesicles. SV2A is the binding site of levetiracetam, a “first in class” antiepileptic drug with a ... [more ▼]

Abstract- [18F]UCB-H is a novel radiotracer with a high affinity for SV2A, a protein expressed in synaptic vesicles. SV2A is the binding site of levetiracetam, a “first in class” antiepileptic drug with a distinct but still poorly understood mechanism of action. The objective of this study was to determine the biodistribution and radiation dosimetry of [18F]UCB-H in a human clinical trial and to establish injection limits according to biomedical research guidelines. Additionally, the clinical radiation dosimetry results were compared to estimations in previously published preclinical data. Dynamic whole body PET/CT imaging was performed over approximately 110 minutes on five healthy male volunteers after injection of 144.5 ± 7.1 MBq (range, 139.1 – 156.5 MBq) of [18F]UCB-H. Major organs were delineated on CT images and time-activity curves were obtained from co-registered dynamic PET emission scans. Time-integrated activity coefficients were calculated as area under the curve using trapezoidal numerical integration. Urinary excretion data based on PET-activities including voiding was simulated using the dynamic bladder module of OLINDA/EXM. The radiation dosimetry was calculated using OLINDA/EXM. The effective dose to the OLINDA/EXM 70 kg standard male was 1.54E-02 ± 6.84E-04 mSv/MBq, with urinary bladder wall, gallbladder wall and the liver receiving the highest absorbed dose. The brain, the tracer’s main organ of interest, received an absorbed dose of 1.89E-02 ± 2.32E-03 mGy/MBq. This first human dosimetry study of [18F]UCB-H indicated that the tracer shows similar radiation burdens to widely used common clinical tracers. Single injections of at maximum 672 MBq for USA practice and 649 MBq for European practice keep radiation exposure below recommended limits. Recently published preclinical dosimetry data extrapolated from mice provided satisfactory prediction of total body and effective dose, but showed significant differences in organ absorbed doses compared to human data. [less ▲]

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See detailDesign and synthesis of PET-probes targeting AMPA-subtype receptors
Deverdenne, François ULg; Claes, Giselle ULg; Goffin, Eric ULg et al

Poster (2015, June 05)

The AMPA subtype of glutamatergic receptors is the main actor in the excitatory neurotransmission in the mammalian central nervous system. These receptors are involved in the expression and the ... [more ▼]

The AMPA subtype of glutamatergic receptors is the main actor in the excitatory neurotransmission in the mammalian central nervous system. These receptors are involved in the expression and the maintenance of the long-term potentiation, a phenomenon closely linked to cognitive and memorization processes. Based on experimental data collected in recent years, the use of AMPA potentiators seems to be an interesting approach in the treatment of cognitive deficits (e.g. Alzheimer disease), schizophrenia or depression. Such AMPA signal potentiation could be mediated by positive allosteric modulators (PAMs) of the AMPA receptors, a class of compounds able to produce a fine signal tuning in the presence of the endogenous ligand in the synapse, providing less toxicity than direct agonists. With this approach, the laboratory of Medicinal Chemistry of Liège university developed many series of AMPA potentiators , among which 1,2,4-benzothiadiazine 1,1-dioxides (BTDs). In order to better understand the in vivo mapping of AMPA receptors and its evolution in neurological diseases, the present work aims at developing the design and the synthesis of BTDs positive allosteric modulators radiolabeled with a fluorine-18 atom. Based on previously synthesized series in this field, we investigate the synthesis of a new class of high-affinity AMPA potentiators characterized by the presence of a fluorine atom at selected positions on the structure of the AMPA potentiators. Thanks to in vitro pharmacological evaluations, we will further determine the best candidates for their fluorine-18 radiolabeling. [less ▲]

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See detailAutomated production at the curie level of no-carrier-added 6-[18F]fluoro-L-dopa and 2-[18F]fluoro-L-tyrosine on a FASTlab synthesizer
Lemaire, Christian ULg; Libert, Lionel; Franci, Xavier et al

in Journal of Labelled Compounds (2015), 58

An efficient, fully automated, enantioselective multi-step synthesis of no-carrier-added (nca) 6-[18F]fluoro-L-dopa ([18F]FDOPA) and 2-[18F]fluoro-L-tyrosine ([18F]FTYR) on a GE FASTlab synthesizer in ... [more ▼]

An efficient, fully automated, enantioselective multi-step synthesis of no-carrier-added (nca) 6-[18F]fluoro-L-dopa ([18F]FDOPA) and 2-[18F]fluoro-L-tyrosine ([18F]FTYR) on a GE FASTlab synthesizer in conjunction with an additional high-performance liquid chromatography (HPLC) purification has been developed. A PTC (phase-transfer catalyst) strategy wasused to synthesize these two important radiopharmaceuticals. According to recent chemistry improvements, automationof the whole process was implemented in a commercially available GE FASTlab module, with slight hardware modificationusing single use cassettes and stand-alone HPLC. [18F]FDOPA and [18F]FTYR were produced in 36.3 ± 3.0 % (n = 8) and50.5 ± 2.7 % (n = 10) FASTlab radiochemical yield (decay corrected). The automated radiosynthesis on the FASTlab modulerequires about 52 min. Total synthesis time including HPLC purification and formulation was about 62 min. Enantiomericexcesses for these two aromatic amino acids were always >95 %, and the specific activity of was >740 GBq/μmol. Thisautomated synthesis provides high amount of [18F]FDOPA and [18F]FTYR (>37 GBq end of synthesis (EOS)). The process, fullyadaptable for reliable production across multiple PET sites, could be readily implemented into a clinical good manufacturingprocess (GMP) environment. [less ▲]

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See detailDesign and synthesis of PET-probes targeting AMPA subtype receptors
Deverdenne, François ULg; Claes, Giselle ULg; Goffin, Eric ULg et al

Poster (2015, May 13)

The AMPA subtype of glutamatergic receptors is the main actor in the fast excitatory neurotransmission in the mammalian central nervous system. These receptors are involved in the expression and the ... [more ▼]

The AMPA subtype of glutamatergic receptors is the main actor in the fast excitatory neurotransmission in the mammalian central nervous system. These receptors are involved in the expression and the maintenance of the long-term potentiation, a phenomenon closely linked to cognitive and memorization processes. Based on experimental data, it also appears that glutamatergic systems are involved in several pathological diseases. For instance, a lack of glutamatergic neurotransmission is observed in cognitive disorders or schizophrenia and an excessive activity is observed in Parkinson or Huntington diseases. The in vivo study of glutamate receptors mapping and its evolution appears to be an essential step for a better understanding of its implications. However, according to the literature, design of such a probe remains difficult due to the lack of specificity of the probes. Taking into account the potential in vitro and in vivo activity and specificity of benzothiadizine dioxides (BTDs) acting as AMPA positive allosteric modulators, we are investing the development of new compounds of this class radiolabeled with a fluorine-18 atom. Hence, we are currently developing new series of BTDs characterized by the presence of a fluorine atom and a 7-phenoxy-substituent that are expected to be more active and more specific. Finally, pharmacological tests to evaluate the best candidates for the radiochemical synthesis and in vivo evaluations are currently in progress. [less ▲]

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See detailPartial volume effect impact on PET preclinical dosimetry: a simulation study
Seret, Alain ULg; Bahri, Mohamed Ali ULg; Bretin, Florian et al

Conference (2015, May 09)

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See detailRegiospecific radiolabeling of Nanofitin on Ni Magnetic Beads with 18F-FBEM and in vivo PET studies
Dammicco, Sylvestre ULg; Lemaire, Christian ULg; Cinier, Mathieu et al

Poster (2015, May)

Nanofitins(NFs) are a small, single chain and cysteine-free protein able to selectively bind a defined biological target. They derive from Sac7d bacterial protein family and are highly stable over a wide ... [more ▼]

Nanofitins(NFs) are a small, single chain and cysteine-free protein able to selectively bind a defined biological target. They derive from Sac7d bacterial protein family and are highly stable over a wide range of pH (0-13) and temperature (Tm ~80°C). Their extreme stability, low cost and high tolerability for chemical coupling make NFs an interesting alternative to antibodies. The aim of this study was to develop the first synthesis of a radiolabeled NF since no in vivo biodistribution kinetic studies have been published. [less ▲]

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See detailStrategies of regioselective radiolabeling of Nanofitin binder for imaging
Goux, Marine ULg; Dammicco, Sylvestre ULg; Becker, Guillaume ULg et al

Poster (2015, May)

Recently, new strategies emerged in the field of monoclonal antibodies radiolabeling for PET imaging with the use of positron emitter such as fluorine-18, zirconium-89 or gallium-68. Despite their ... [more ▼]

Recently, new strategies emerged in the field of monoclonal antibodies radiolabeling for PET imaging with the use of positron emitter such as fluorine-18, zirconium-89 or gallium-68. Despite their important role in the therapeutic world, antibodies have many disadvantages related to their structure. Moreover, conjugation of chelating agent often occurs on lysines, which is non-regioselective and leads to a heterogeneous mixture of products. In addition, the slow clearance of antibodies can be a problem to obtain a good contrast when they are used in imaging. To address these different limitations, we developed a chemistry-free chelating system consisting of a highly phosphorylatable peptide tag fused genetically to a Nanofitin. A specific phosphorylation step, with the alpha subunit of the casein kinase II, generates a nanocluster of 4 phosphates that can interact strongly with metal ion like zirconium or gallium. This strategy has already demonstrated its powerfulness for the stable and specific anchoring of protein on zirconium phosphonate-based microarray [1]. Considering this tag has been created to specifically anchoring protein on zirconium phosphonate-based microarray, we are currently working on a sequence derived from calcium-binding proteins to chelate specifically lanthanides[2]. As described by Pardoux et al.[3], our strategy is to functionalize this sequence with a phosphate nanocluster able to chelate zirconium or gallium. Our first results shown that a mono-phosphorylatable tag phosphorylated in vitro is able to chelate terbium(III) with a lower affinity than the wild type. Considering that terbium(III) is bigger than gallium(III) or zirconium(IV), we can suppose that the cage obtained is too small but suitable for other ions. In order to validate our hypothesis, we have planned to radiolabel those tags and determine their affinity for gallium(III). In order to validate the use of Nanofitin as a potent alternative tool for in vivo imaging, we have made biokinetic studies in mice with PET and MRI imaging. In these studies, we have radiolabelled with fluorine-18 a Nanofitin and we are currently making use of its specific binding to a cell-surface receptor to target a very precise cell population by using an animal model. Once the phosphorylatable tag optimized for regioselective radiolabelling and the Nanofitin targeting validated in an animal model, the next steps will be to combine these two approaches: we will fuse genetically the tag to the specific Nanofitin, radiolabel it with gallium-68 and perform the biokinetic study of this new radiopharmaceutical product. [1] M. Cinier, M. Petit, F. Pecorari, D. R. Talham, B. Bujoli, and C. Tellier, “Engineering of a phosphorylatable tag for specific protein binding on zirconium phosphonate based microarrays.,” J. Biol. Inorg. Chem., vol. 17, no. 3, pp. 399–407, Mar. 2012. [2] L. J. Martin, “Development of Lanthanide-Binding Tags (LBTs) as powerful and versatile peptides for use in studies of proteins and protein interactions,” 2008. [3] R. Pardoux, S. Sauge-merle, D. Lemaire, P. Delangle, L. Guilloreau, J. Adriano, and C. Berthomieu, “Modulating Uranium Binding Affinity in Engineered Calmodulin EF-Hand Peptides : Effect of Phosphorylation,” PLoS One, vol. 7, no. 8, 2012. [less ▲]

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See detail[18F]UCB-H as a new PET radiotracer for Synaptic vesicle protein 2A: A first clinical trial
Bahri, Mohamed Ali ULg; Stifkens, Mathieu; Bastin, Christine ULg et al

Poster (2015, January 27)

SV2A is widely distributed in the brain and has been demonstrated to be involved in vesicle trafficking. The critical role of SV2A in proper nervous system function is shown, e.g., by the fact that it is ... [more ▼]

SV2A is widely distributed in the brain and has been demonstrated to be involved in vesicle trafficking. The critical role of SV2A in proper nervous system function is shown, e.g., by the fact that it is a binding site and the primary mechanism of levetiracetam. Levetiracetam is an antiepileptic drug which has recently been suggested to reduce synaptic deficits in a mouse model for Alzheimer’s disease. We here aimed to investigate the cerebral distribution of [18F]UCB-H, which has a high affinity with the SV2A. Dynamic PET data of the head of 4 healthy volunteers were acquired over 100 minutes after injection of 170.4 ± 24.9 MBq of GMP produced [18F]UCB-H. The arterial input function (IF) was obtained by blood sampling. The IF was also derived from the dynamic data using the correlation coefficient method. Blood data revealed a consistent amount of [18F]UCB-H in whole blood and plasma indicating a very low degree of binding of the tracer to the red blood cells. The image-derived arterial IFs were showed to be very similar to the measured ones with a peak-ratio around 0.91 and an area-under-curve ratio about 0.98. The [18F]UCB-H PET data showed a high and rapid uptake in the grey matter structures, matching the known ubiquitous distribution of the SV2A in the brain. The kinetics of the tracer in the brain was characterized by an initial high uptake phase followed by rapid washout allowing the standard compartmental modeling (1-tissue, 2-tissue, and Logan Plot). The three models gave similar results with both the measured and image-derived IFs. The total distribution volume of the tracer in the brain was greater than 7 mL/cm3. Our results suggest that [18F]UCB-H is a good candidate as radiotracer for brain SV2A proteins and could be used for human studies. Image-derived IF showed to be useful for quantitative studies without the need to the arterial blood sampling. SV2A modifications may consequently be assessed in neurological pathologies such as Alzheimer’s disease. [less ▲]

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See detailN1-Fluoroalkyltryptophan analogues: synthesis and in vitro study as potential substrates for indoleamine 2,3-dioxygenase
Henrottin, Jean ULg; Zervosen, Astrid ULg; Lemaire, Christian ULg et al

in ACS Medicinal Chemistry Letters (2015)

ABSTRACT: Indoleamine 2,3-dioxygenase (hIDO) is an enzyme that catalyzes the oxidative cleavage of the indole ring of L-tryptophan through the kynurenine pathway, thereby exerting immunosuppressive ... [more ▼]

ABSTRACT: Indoleamine 2,3-dioxygenase (hIDO) is an enzyme that catalyzes the oxidative cleavage of the indole ring of L-tryptophan through the kynurenine pathway, thereby exerting immunosuppressive properties in inflammatory and tumoral tissues. The syntheses of 1-(2-fluoroethyl)-tryptophan (1-FETrp) and 1-((1-(2-fluoroethyl)-1H-1,2,3-triazol-4-yl)methyl)-tryptophan, two N1-fluoroalkylated tryptophan derivatives, are described here. In vitro enzymatic assays with these two new potential substrates of hIDO show that 1-FETrp is a good and specific substrate of hIDO. Therefore, its radioactive isotopomer, 1-[18F]FETrp, should be a molecule of choice to visualize tumoral and inflammatory tissues and/or to validate new potential inhibitors. [less ▲]

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See detailEvaluation of [18F]UCB-H as a novel PET tracer for synaptic vesicle protein 2A in the brain.
Warnock, Geoffrey; Aerts, Joël ULg; Bahri, Mohamed Ali ULg et al

in Journal of Nuclear Medicine (The) (2014), 55(8), 1336-1341

Synaptic vesicle 2 (SV2) proteins are critical to proper nervous system function and are involved in vesicle trafficking. The SV2A isoform has been identified as the binding site of the antiepileptic ... [more ▼]

Synaptic vesicle 2 (SV2) proteins are critical to proper nervous system function and are involved in vesicle trafficking. The SV2A isoform has been identified as the binding site of the antiepileptic levetiracetam (LEV), making it an interesting therapeutic target for epilepsy. [18F]UCB-H is a novel PET imaging agent with a nanomolar affinity for human SV2A. Methods: preclinical PET studies were carried out in isoflurane anesthetized rats. Arterial input function was measured using an arteriovenous shunt and beta microprobe system. [18F]UCB-H was injected IV (140 ± 20 MBq bolus). Results: brain uptake of [18F]UCB-H was high, matching the expected homogeneous distribution of SV2A. The distribution volume (Vt) for [18F]UCB-H was calculated using Logan’s graphical analysis and the effect of LEV pretreatment on Vt measured. In control animals the mean whole-brain Vt was 9.76 ± 0.52 ml/cm3 (mean ± SD, n=4, test-retest), and the mean reproducibility in test-retest studies was 10.4 ± 6.5 %. Uptake of [18F]UCB-H was dose-dependently blocked by pretreatment with LEV (0.1 - 100 mg/kg IV). Conclusion: our results indicate that [18F]UCB-H is a suitable radiotracer for the imaging of SV2A in vivo. 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 and first in human studies are planned. [less ▲]

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See detailPrior light history impacts on higher order cognitive brain function
Chellappa, Sarah Laxhmi ULg; Ly, Julien; Meyer, Christelle ULg et al

Conference (2014, June 17)

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See detail[18F]UCB-H AS A NEW PET RADIOTRACER FOR SYNAPTIC VESICLE PROTEIN 2A
Bahri, Mohamed Ali ULg; Bastin, Christine ULg; Aerts, Joël ULg et al

Poster (2014, June 06)

Synaptic vesicle protein 2A (SV2A) is widely distributed in the brain and has been demonstrated to be involved in vesicle trafficking. The critical role of SV2A in proper nervous system function is shown ... [more ▼]

Synaptic vesicle protein 2A (SV2A) is widely distributed in the brain and has been demonstrated to be involved in vesicle trafficking. The critical role of SV2A in proper nervous system function is shown, for example, by the fact that it is a binding site and the primary mechanism of levetiracetam. Levetiracetam is an antiepileptic drug which has recently been suggested to reduce synaptic deficits in a mouse model for Alzheimer’s disease and to improve cognition in patients with amnestic mild cognitive impairment. We here aimed to investigate the cerebral distribution of [18F]UCB-H, a fluorine-18 radiolabelled PET imaging tracer, which has a high affinity with the SV2A. [18F]UCB-H was radiosynthesized under GMP conditions. Dynamic PET data of the head of four healthy volunteers were acquired over 100 minutes after injection of 170.4 ± 24.9 MBq of [18F]UCB-H. The arterial input function was obtained by blood sampling during the dynamic PET acquisition. The analysis of the blood data reveled a consistent amount of [18F]UCB-H in whole blood and plasma which indicates a very low degree of binding of the tracer to the red blood cells. The unchanged fraction of [18F]UCB-H in plasma showed a bi-exponential behavioral decrease with a starting fraction of 92% of the injected amount of the tracer, measured at 3 min post injection. This fraction decreased to about 50% at 10 min post injection. The [18F]UCB-H PET data showed a high and rapid uptake in the grey matter structures, matching the known ubiquitous distribution of the SV2A in the brain. The kinetics of the tracer in the brain was characterized by an initial high uptake phase followed by rapid washout allowing the standard compartmental modeling (1-tissue compartment, 2-tissue compartment, and Logan graphical analysis). The three models gave consistent results. The two-tissue compartment model fitted the experimental data best and provided a total distribution volume of the [18F]UCB-H in the brain greater than 7 mL/cm3 and a specific distribution volume around 3 mL/cm3. Our results suggest that [18F]UCB-H is a good candidate as radiotracer for brain SV2A proteins and could be used for human studies. In the future, SV2A modifications might be assessed in neurological pathologies such as Alzheimer’s disease. [less ▲]

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See detailDesign and synthesis of high-affinity ligands of AMPA receptors and study of their Fluorine-18 radiolabeling
Deverdenne, François ULg; Goffin, Eric ULg; Plenevaux, Alain ULg et al

Poster (2014, June 05)

The AMPA subtype of glutamatergic receptors is the main actor in the excitatory neurotransmission in the mammalian central nervous system. These receptors are involved in the expression and the ... [more ▼]

The AMPA subtype of glutamatergic receptors is the main actor in the excitatory neurotransmission in the mammalian central nervous system. These receptors are involved in the expression and the maintenance of the long-term potentiation, a phenomenon closely linked to cognitive and memorization processes. Based on experimental data collected in recent years, the use of AMPA potentiators seems to be an interesting approach in the treatment of cognitive deficits (e.g. Alzheimer disease), schizophrenia or depression. Such AMPA signal potentiation could be mediated by positive allosteric modulators (PAMs) of the AMPA receptors, a class of compounds able to produce a fine signal tuning in the presence of the endogenous ligand in the synapse, providing less toxicity than direct agonists. With this approach, the laboratory of Medicinal Chemistry of Liège university developed many series of AMPA potentiators , among which 1,2,4-benzothiadiazine 1,1-dioxides (BTDs). In order to better understand the in vivo mapping of AMPA receptors and its evolution in neurological diseases, the present work aims at developing the design and the synthesis of BTDs positive allosteric modulators radiolabeled with a fluorine-18 atom. Based on previously synthesized series in this field, we investigate the synthesis of a new class of high-affinity AMPA potentiators characterized by the presence of a fluorine atom at selected positions on the structure of the AMPA potentiators. Thanks to in vitro pharmacological evaluations, we will further determine the best candidates for their fluorine-18 radiolabeling. [less ▲]

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See detailSynthesis of N-fluoroalkyl-tryptophan and study of their biological activity as potential substrates for indoleamine 2,3-dioxygenase
Henrottin, Jean ULg; Zervosen, Astrid ULg; Lemaire, Christian ULg et al

Poster (2014, June)

Indoleamine 2,3-dioxygenase (rhIDO) is an enzyme mainly expressed in brain and tumor cells and catalyzing the oxidative cleavage of the indole ring of L-tryptophan through the kynurenine pathway ... [more ▼]

Indoleamine 2,3-dioxygenase (rhIDO) is an enzyme mainly expressed in brain and tumor cells and catalyzing the oxidative cleavage of the indole ring of L-tryptophan through the kynurenine pathway. Furthermore this enzyme could be responsible for the eventual suppression of immune responses by blocking locally T-lymphocyte proliferation. The syntheses of 1-(2-fluoroethyl)-tryptophan (1-[19F]FETrp) and 1-((1-(2-fluoroethyl)-1H-1,2,3-triazol-4-yl)methyl)-tryptophan, two N-fluoroalkylated tryptophan derivatives, are described here. In vitro enzymatic assays with these two new potential substrates of rhIDO show that 1-[19F]FETrp is a good and specific substrate of hIDO. [less ▲]

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See detailStereoselective synthesis of peptidoglycan fragments on solid support
Simon, Justine ULg; Lamborelle, Nicolas ULg; Joris, Bernard ULg et al

Poster (2014, June)

The mammalian proteins, Nod1 and Nod2, are able to recognize peptidoglycan motifs during bacterial infection. Interestingly, Nod1 is a detector of peptides and muropeptides containing the meso-2,6 ... [more ▼]

The mammalian proteins, Nod1 and Nod2, are able to recognize peptidoglycan motifs during bacterial infection. Interestingly, Nod1 is a detector of peptides and muropeptides containing the meso-2,6-diaminopimelic acid (m-A2pm), a non-proteinogenic amino acid found in Gram- bacteria. In this work, we describe a synthesis of peptidoglycan motifs entirely on solid support. Solid-Phase Peptide Synthesis (SPPS), Cross Metathesis (CM) and sugar chemistry are three methods to anchor respectively amino acids, m-A2pm and sugars derivatives on a resin as solid support. [less ▲]

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See detail[18F]UCB-H AS A BRAIN SV2A RADIOTRACER: A FIRST CLINICAL TRIAL
Bahri, Mohamed Ali ULg; Bastin, Christine ULg; Aerts, Joël ULg et al

Poster (2014, May 27)

[18F]UCB-H is a fluorine-18 radiolabelled PET imaging tracer with a high affinity for the synaptic vesicle protein 2A (SV2A). This protein, involved in vesicle trafficking and widely distributed in the ... [more ▼]

[18F]UCB-H is a fluorine-18 radiolabelled PET imaging tracer with a high affinity for the synaptic vesicle protein 2A (SV2A). This protein, involved in vesicle trafficking and widely distributed in the brain, represents the binding site and the primary mechanism of the antiepileptic drug levetiracetam. Levetiracetam has recently been suggested to reduce synaptic deficits in a mouse Alzheimer’s disease model and to improve cognition in patients with amnestic mild cognitive impairment, suggesting a possible role for this protein in synaptic integrity. The objective of this study was to investigate the cerebral distribution of [18F]UCB-H in healthy human volunteers. Dynamic PET imaging of the head of four healthy volunteers was performed over 100 minutes after injection of 170.4 ± 24.9 MBq of GMP produced [18F]UCB-H. The input function was acquired by arterial blood sampling during the dynamic PET acquisition. Blood data analysis showed a consistent tracer amount in whole blood and plasma indicating a very low degree of binding of the tracer to the red blood cells. Unchanged [18F]UCB-H fraction in plasma follows a bi-exponential behavioral decrease with a starting fraction of 92% of the injected amount of the tracer, measured at 3 min post injection. This fraction decreases to about 50% at 10 min post injection. The [18F]UCB-H PET data revealed a high and rapid uptake in the grey matter structures, matching the known ubiquitous distribution of SV2A in the brain. The kinetics of the tracer in the brain was characterized by an initial high uptake phase followed by rapid washout allowing the standard compartmental modeling (1-tissue compartment, 2-tissue compartment, and Logan graphical analysis). The three models gave consistent results. The two-tissue compartment model fitted the experimental data best and provided a total distribution volume of [18F]UCB-H in the brain greater than 7 mL/cm3 and a specific distribution volume around 3 mL/cm3. Our results indicate that [18F]UCB-H is a new radiotracer for brain SV2A proteins suitable for human studies. Further studies are warranted to assess SV2A modifications in neurological pathologies such as Alzheimer’s disease. [less ▲]

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See detailHybrid MicroPET Imaging for Dosimetric Applications in Mice: Improvement of Activity Quantification in Dynamic MicroPET Imaging for Accelerated Dosimetry Applied to 6-[ 18 F] Fluoro- L -DOPA and 2-[ 18 F]Fluoro- L -Tyrosine
Bretin, Florian ULg; Mauxion, T; Warnock, G et al

in Molecular Imaging and Biology (2014), 16(3), 383-394

Purpose: Dynamic microPET imaging has advantages over traditional organ harvesting, but is pronetoquantificationerrorsinsmallvolumes.Hybridimaging,wheremicroPETactivitiesarecross- calibrated using post ... [more ▼]

Purpose: Dynamic microPET imaging has advantages over traditional organ harvesting, but is pronetoquantificationerrorsinsmallvolumes.Hybridimaging,wheremicroPETactivitiesarecross- calibrated using post scan harvested organs, can improve quantification. Organ harvesting, dynamic imaging and hybrid imaging were applied to determine the human and mouse radiation dosimetry of 6-[18 F]fluoro-L-DOPA and 2-[18 F]fluoro-L-tyrosine and compared. Procedures: Two-hour dynamic microPET imaging was performed with both tracers in four separate mice for 18 F-FDOPA and three mice for 18 F-FTYR. Organ harvesting was performed at 2, 5, 10, 30, 60 and 120 min post tracer injection with n=5 at each time point for 18 F-FDOPA and n=3 at each time point for 18 F-FTYR. Human radiation dosimetry projected from animal data was calculated for the three different approaches for each tracer using OLINDA/EXM. S- factors for the MOBY phantom were used to calculate the animal dosimetry. Results: Correlations between dose estimates based on organ harvesting and imaging was improved from r=0.997 to r=0.999 for 18 F-FDOPA and from r=0.985 to r=0.996 (p<0.0001 for all) for 18 F-FTYR by using hybrid imaging. Conclusion: Hybrid imaging yields comparable results to traditional organ harvesting while partially overcoming the limitations of pure imaging. It is an advantageous technique in terms of number of animals needed and labour involved. [less ▲]

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