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See detailEVALUATION OF SV2Alox/Cre TRANSGENIC MOUSE USING [18F]UCB-H IN IN VITRO AUTORADIOGRAPHY
Serrano Navacerrada, Maria Elisa ULg; Becker, Guillaume ULg; MENTEN, Catherine ULg et al

Poster (2015, September 04)

Background: SV2A is the most studied isoform of the Synaptic Vesicle 2 proteins, which are involved in the synaptic vesicle trafficking. Interestingly, the SV2A has been identify as the binding site for ... [more ▼]

Background: SV2A is the most studied isoform of the Synaptic Vesicle 2 proteins, which are involved in the synaptic vesicle trafficking. Interestingly, the SV2A has been identify as the binding site for the antiepileptic drug levetiracetam, showing a close relation between the epilepsy, the dysregulation of the SV2A levels and the response to antiepileptic medications. SV2A floxed-mice were developed using a cre-lox technique, leading to a strong decrease of SV2A expression in the CA3 field of the hippocampus. We aim here to validate this model using [18F]UCB-H, a novel PET imaging radiotracer with a nanomolar affinity for human SV2A. Methods: In vitro autoradiography were performed on SV2Alox/Cre+ transgenic mouse brain slices. SV2Alox/Cre- mouse was used as control. To obtain a structural reference, brain slices underwent eosin-haematoxylin staining. Images of both procedures were coregistered using π-PMOD software. Regions of interest (Dentate Gyrus, CA1, CA2 and CA3) were drawn according to a stereotaxic atlas of the mouse brain. Results: Analyses showed significant differences in radiotracer binding (p<0.001) between SV2Alox/Cre+ mouse and SV2Alox/Cre- mouse highlighting an important reduction for the labelling density in Ammon's horn, particularly in CA1, compared to Dentate Gyrus where the diminution was less marked. Conclusions: Here, we used the radiotracer [18F]UCB-H to probe the decreased expression of SV2A protein in the hippocampus of SV2Alox/Cre+ mouse versus SV2Alox/Cre- control mouse. Our results contribute to the validation of the model, and encourage us to proceed with further longitudinal and behavioural studies. [less ▲]

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See detailIn vivo quantification of dopaminergic terminals loss in Parkinson’s Disease rat model: comparison between [18F]FMT and [18F]FDOPA.
Becker, Guillaume ULg; Bahri, Mohamed Ali ULg; Michel, Anne et al

Poster (2015, September 02)

Objectives: Rat models of Parkinson’s disease (PD), such as unilaterally lesioned rats with 6-hydroxydopamine (6-OHDA), are useful to evaluate novel antiparkinsonian therapies. MicroPET imaging, using L-3 ... [more ▼]

Objectives: Rat models of Parkinson’s disease (PD), such as unilaterally lesioned rats with 6-hydroxydopamine (6-OHDA), are useful to evaluate novel antiparkinsonian therapies. MicroPET imaging, using L-3,4-dihydroxy-6-[18F]-fluoro-phenylalanine ([18F]FDOPA) allows longitudinal evaluations of DA terminals loss. However, chemical structure of [18F]FDOPA leads to suboptimal PET imaging. 18F-fluoro-m-tyrosine ([18F]FMT) is an effective PET tracer to evaluate DA terminals integrity and L-aromatic amino acid decarboxylase (AAAD) metabolic pathway. So far, there are no available quantitative PET studies comparing the two methods in hemiparkinsonian rats. In this study, we compare imaging data provided by [18F]FMT PET and [18F]FDOPA PET in 6-OHDA-lesioned rats. Methods: 10 µg of 6-OHDA were injected into the right medial forebrain bundle (MFB) of male Sprague-Dawley rats (n=8). As control, sham-treated rats (n=8) were injected with vehicle only but otherwise treated identically. Striatal DA presynaptic activity was assessed by dynamic PET with both [18F]FMT and [18F]FDOPA. Structural T2-weighted brain images were acquired on a 9.4T MRI and were used for co-registration. After normalization on a MRI template, kinetic analysis was performed by “Patlak Reference” model, using PMOD software. Six days after the last PET scan, rats were sacrificed, and striatum were rapidly removed for striatal DA and metabolites quantification. Results: Striatal accumulation was observed for both tracers. However, while the administration of [18F]FDOPA required two peripheral inhibitors (benserazide and entacapone), only benserazide is needed with [18F]FMT. As consequence of the 6-OHDA-lesion, significant decrease of both [18F]FMT and [18F]DOPA accumulation was recorded in the striatum ipsilateral to the lesion. Lesioned rats had dramatically reduced uptake constant Ki in the ipsilateral striatum compared to the contralateral striatum (p<0.001 for [18F]FMT and p<0.05 for [18F]DOPA) and to the ipsilateral striatum of sham-treated rats (p<0.001 for both tracers). The DA content in the ipsilateral striatum was significantly lower (p<0.001) than in the contralateral striatum in the 6-OHDA-injected group, whereas such difference was not measured with the sham group. This indicate that [18F]FMT PET is as effective as [18F]DOPA PET to quantify loss of DA presynaptic function in unilaterally 6-OHDA lesioned rats. Conclusions: Our results are in agreement with data reporting correlation between these two tracers in a Non-human primate model of PD. The sensitivity of the data quantification obtained in this study, confirms the interest to pursue longitudinal investigations with [18F]FMT to monitor dopaminergic dysfunction in a more progressive preclinical model of PD. [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 detail[18F]UCB-H as a new PET radiotracer for Synaptic vesicle protein 2A: A first clinical trial.
Bahri, Mohamed Ali ULg; Stifkens, M; Bastin, Christine ULg et al

in Tijdschrift voor Nucleaire Geneeskunde (2015, May 09), 37(3), 1457-1458

The 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 ... [more ▼]

The 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, e.g., by the fact that it is a binding site and the primary mechanism of the antiepileptic drug levetiracetam. This drug 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 but 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 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 image-derived arterial IFs 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 PET images showed a high and rapid uptake of [18F]UCB-H 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. For the three standard compartmental models (1-tissue, 2-tissue, and Logan Plot), similar results were obtained with both the measured and image-derived IFs. Nevertheless 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 (dosimetry has already been reported elsewhere). Image-derived IF showed to be useful for quantitative studies without the need to the arterial blood sampling. This new tracer could help to assess SV2A modifications in neurological pathologies such as Alzheimer’s disease. [less ▲]

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See detail[18F]FMT: a reliable PET tracer for in vivo evaluation of dopaminergic dysfunction in Parkinson’s Disease rat model.
Seret, Alain ULg; Becker, Guillaume ULg; Bahri, Mohamed Ali ULg et al

Poster (2015, May 09)

Background: Rat models of Parkinson’s disease (PD), such as lesioned rats with 6-hydroxydopamine (6-OHDA), are useful for studying dopamine (DA)-related functions. 6-[18F]fluoro-m-tyrosine (6-[18F]FMT) is ... [more ▼]

Background: Rat models of Parkinson’s disease (PD), such as lesioned rats with 6-hydroxydopamine (6-OHDA), are useful for studying dopamine (DA)-related functions. 6-[18F]fluoro-m-tyrosine (6-[18F]FMT) is an effective PET tracer to evaluate of DA terminals integrity and L-aromatic amino acid decarboxylase (AAAD) metabolic pathway. However, there are currently no available quantitative PET studies using [18F]FMT in 6-OHDA lesioned rats. In this context, we investigated the feasibility of in vivo PET study using [18F]FMT on 6-OHDA PD’s model. Methods: 10 µg of 6-OHDA were injected into the right medial forebrain bundle (MFB) of male Sprague-Dawley rats (n=8). As control, sham-treated rats (n=8) were injected with vehicle only but otherwise treated identically. Striatal DA presynaptic activity was assessed by dynamic [18F]FMT PET, 30 min after benserazide pretreatment. Structural T2-weighted brain images were acquired on a 9.4T MRI and were used for co-registration. After normalization on a MRI template, kinetic analysis was performed by “Patlak Reference” model, using PMOD software. Results: Striatal accumulation of [18F]FMT was observed in rats pretreated with benserazide, a peripheral AAAD inhibitor. As consequence of the 6-OHDA-lesion, significant decrease of [18F]FMT accumulation was recorded in the striatum ipsilateral to the lesion. Lesioned rats had dramatically reduced uptake constant Ki in the ipsilateral striatum compared to the contralateral striatum (p<0.001) and to the ipsilateral striatum of sham-treated rats (p<0.005). The Ki ratio (Ipsi./Contra.) was equivalent to 94% in the sham group and dropped to 41% in the lesioned group. Conclusions: [18F]FMT PET enables us to quantify loss of DA presynaptic function in unilaterally 6-OHDA lesioned rats. These results encourage us to pursue further investigations in a longitudinal way and to monitor the progression of the dopaminergic dysfunction in more moderate and gradual preclinical PD models. [less ▲]

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See detailHigh output [18F]FDOPA on AllInOne (Trasis) at commercial scale
Otabashi, Muhammad; Cascione, Christian; Lemaire, Christian ULg et al

in Journal of Labelled Compounds & Radiopharmaceuticals (2015, May), 58

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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 detail18F-FMT: a reliable PET tracer for in vivo evaluation of dopaminergic dysfunction in Parkinson’s Disease rat model.
Becker, Guillaume ULg; Bahri, Mohamed Ali ULg; Michel, Anne et al

Poster (2015, March 18)

Objectives: Rat models of Parkinson’s disease (PD), such as lesioned rats with 6-hydroxydopamine (6-OHDA), are useful for studying dopamine (DA)-related functions. 6-18F-fluoro-m-tyrosine (6-18F-FMT) is ... [more ▼]

Objectives: Rat models of Parkinson’s disease (PD), such as lesioned rats with 6-hydroxydopamine (6-OHDA), are useful for studying dopamine (DA)-related functions. 6-18F-fluoro-m-tyrosine (6-18F-FMT) is an effective PET tracer to evaluate of DA terminals integrity and L-aromatic amino acid decarboxylase (AAAD) metabolic pathway. However, there are currently no available quantitative PET studies using 18F-FMT in 6-OHDA lesioned rats. In this context, we investigated the feasibility of in vivo PET study using 18F-FMT on 6-OHDA PD’s model. Methods: 10 µg of 6-OHDA were injected into the right medial forebrain bundle (MFB) of male Sprague-Dawley rats (n=8). As control, sham-treated rats (n=8) were injected with vehicle only but otherwise treated identically. Striatal DA presynaptic activity was assessed by dynamic 18F-FMT-PET. Structural T2-weighted brain images were acquired on a 9.4T MRI and were used for co-registration. After normalization on a MRI template, kinetic analysis was performed by “Patlak Reference” model, using PMOD software. Results: Striatal accumulation of 18F-FMT was observed in rats pretreated with benserazide, a peripheral AAAD inhibitor. As consequence of the 6-OHDA-lesion, significant decrease of 18F-FMT accumulation was recorded in the striatum ipsilateral to the lesion. Lesioned rats had dramatically reduced uptake constant Ki in the ipsilateral striatum compared to the contralateral striatum (p<0.001) and to the ipsilateral striatum of sham-treated rats (p<0.005). The Ki ratio (Ipsi./Contra.) was equivalent to 94% in the sham group and dropped to 41% in the lesioned group. Conclusions: 18F-FMT PET enables us to quantify loss of DA presynaptic function in unilaterally 6-OHDA lesioned rats. These results encourage us to pursue further investigations in a longitudinal way and to monitor the progression of the dopaminergic dysfunction in more moderate and gradual preclinical PD models. [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 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 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 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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See detailEnantioselective synthesis of [small alpha]-benzylated lanthionines and related tripeptides for biological incorporation into E. coli peptidoglycan
Denoel, Thibaut; Zervosen, Astrid ULg; Lemaire, Christian ULg et al

in Organic & Biomolecular Chemistry (2014)

The synthesis of modified tripeptides (S)-Ala-[gamma]-(R)-Glu-X, where X = (R,S) or (R,R) diastereomers of [small alpha]-benzyl or [small alpha]-(4-azidobenzyl)lanthionine, was carried out. The chemical ... [more ▼]

The synthesis of modified tripeptides (S)-Ala-[gamma]-(R)-Glu-X, where X = (R,S) or (R,R) diastereomers of [small alpha]-benzyl or [small alpha]-(4-azidobenzyl)lanthionine, was carried out. The chemical strategy involved the enantioselective alkylation of a 4-MeO-phenyloxazoline. The reductive opening of the alkylated oxazolines, followed by cyclization and oxidation, led to four PMB-protected sulfamidates. Subsequent PMB removal, Boc protection and regioselective opening with cysteine methyl ester led to protected lanthionines. These compounds were further converted in a one pot process to the corresponding protected tripeptides. After ester and Boc deprotection, the four tripeptides were evaluated as potential analogues of the natural tripeptide (S)-Ala-[gamma]-(R)-Glu-meso-A2pm. These compounds were evaluated for introduction, by means of the biosynthetic recycling pathway, into the peptidoglycan of Escherichia coli. A successful in vitro biosynthesis of UDP-MurNAc-tripeptides from the tripeptides containing [small alpha]-benzyl lanthionine was achieved using purified murein peptide ligase (Mpl). Bioincorporation into E. coli W7 did not occur under different tested conditions probably due to the bulky benzyl group at the C[small alpha] carbon of the C-terminal amino acid. [less ▲]

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