References of "Plenevaux, Alain"
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See detailFeasibility study of repetitive diffusion MRI after Neoadjuvant radiotherapy for following tumor microenvironment.
LALLEMAND, François ULg; Leroi, Natacha ULg; Bahri, Mohamed Ali ULg et al

Conference (2016, March 22)

Purpose/Objective. Neoadjuvant radiotherapy (NeoRT) improves tumor local control and tumor resection in many cancers. The timing between the end of the NeoRT and surgery is mostly driven by the occurrence ... [more ▼]

Purpose/Objective. Neoadjuvant radiotherapy (NeoRT) improves tumor local control and tumor resection in many cancers. The timing between the end of the NeoRT and surgery is mostly driven by the occurrence of side effects or the tumor downsizing. We previously demonstrated in an in vivo model that the timing of surgery and the schedule of NeoRT influenced the tumor dissemination. Here, our aim is to evaluate with functional MRI (fMRI) the impact of the radiation treatment on the tumor microenvironment and subsequently to identify non-invasive markers helping to determine the best timing to perform surgery for avoiding tumor spreading. First, we needed to demonstrate the feasibility of repetitive MRI imaging after NeoRT in mice. Material/methods. We used two models of NeoRT we previously developed in mice: MDA-MB 231 and 4T1 cells implanted in the flank of mice. When tumors reached the planned volume, they are irradiated with 2x5 Gy and then surgically removed at different time points after RT. In the mean time between the end of RT and the surgical procedure, mice were imaged in a 9,4T Agilent® MRI. Diffusion Weighted (DW) -MRI was performed every 2 days between RT and surgery. For each tumors we acquired 8 slices of 1 mm thickness and 0.5 mm gap with an “in plane voxel resolution” of 0.5 mm. For DW-MRI, we performed FSEMS (Fast Spin Echo MultiSlice) sequences, with 9 different B-values (from 40 to 1000) and B0, in the 3 main directions. We also performed IVIM (IntraVoxel Incoherent Motion) analysis, in the aim to obtain information on intravascular diffusion, related to perfusion (F: perfusion factor) and subsequently tumor vessels perfusion. Results. As preliminary results, with the MBA-MB 231 we observed a significant increase of F at day 6 after irradiation than a decrease and stabilization until surgery. No other modifications of the MRI signal, ADC, D or D* were observed. We observed similar results with 4T1 cells, F increased at day 3 than returned to initial signal. The difference in the timing of the peak of F can be related to the difference in tumor growth between MBA-MB 231 and 4T1 (four weeks vs one week). Conclusion. For the first time, we demonstrate the feasibility of repetitive fMRI imaging in mice models after NeoRT. With these models, we show a significant peak of the perfusion factor (F) at day 6 or day 3. This change occurs between the two previous time points of surgery demonstrating a difference in the metastatic spreading. Indeed, after a NeoRT of 2X5Gy we observed more metastases in the lung when MDA-MB 231 tumor bearing mice are operated 4 days after RT compared to 11 days. These preliminary results are very promising for identifying noninvasive markers for determining the best timing for surgery. [less ▲]

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See detailFully automated radiosynthesis of N1-[18F]fluoroethyl-tryptophan and study of its biological activity as a new potential substrate for indoleamine 2,3-dioxygenase PET imaging
Henrottin, Jean ULg; Lemaire, Christian ULg; Egrise, Dominique et al

in Nuclear Medicine & Biology (2016)

Introduction: Indoleamine 2,3-dioxygenase (IDO) catalyzes the initial step in the catabolism of L-tryptophan along the kynurenine pathway and exerts immunosuppressive properties in inflammatory and tumor ... [more ▼]

Introduction: Indoleamine 2,3-dioxygenase (IDO) catalyzes the initial step in the catabolism of L-tryptophan along the kynurenine pathway and exerts immunosuppressive properties in inflammatory and tumor tissues by blocking locally T-lymphocyte proliferation. Recently, 1-(2-[19F]fluoroethyl)-DL-tryptophan (1-[19F]FE-DL-Trp) was reported as a good and specific substrate of this enzyme. Herein, the radiosynthesis of its radioactive isotopomer (1-[18F]FE-DL-Trp, DL-[18F]5) is presented along with in vitro enzymatic and cellular uptake studies. Methods: The one-pot n.c.a. radiosynthesis of this novel potential PET imaging tracer, including HPLC purification and formulation, has been fully automated on a FASTlabTM synthesizer. Chiral separation of both isomers and their formulation were implemented on a second cassette. In vitro enzymatic and cellular uptake studies were then conducted with the D-, L- and DL-radiotracers. Results: The radiolabeling of the tosylate precursor was performed in DMF (in 5 min; RCY: 57% (d.c.), n=3). After hydrolysis, HPLC purification and formulation, DL-[18F]5 was obtained with a global radiochemical yield of 18±3% (not decay corrected, n=7, in 80 min) and a specific activity of 600±180 GBq/µmol (n=5). The subsequent separation of L- and D-enantiomers was performed by chiral HPLC and both were obtained after formulation with a RCY (d.c.) of 6.1% and 5.8%, respectively. In vitro enzymatic assays reveal that L-[18F]5 is a better substrate than D-[18F]5 for human IDO. In vitro cellular assays show an IDO-specific uptake of the racemate varying from 30% to 50% of that of L-[18F]5, and a negligible uptake of D-[18F]5. Conclusion: In vitro studies show that L-[18F]5 is a good and specific substrate of hIDO, while presenting a very low efflux. These results confirm that L-[18F]5 could be a very useful PET radiotracer for IDO expressing cells in cancer imaging. [less ▲]

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See detailMultimodality imaging assessment of the deleterious role of the intraluminal thrombus on the growth of abdominal aortic aneurysm in a rat model
NCHIMI LONGANG, Alain ULg; Courtois, Audrey ULg; EL HACHEMI, Mounia ULg et al

in European Radiology (2015), online

Objectives To evaluate imaging changes occurring in a rat model of elastase-induced abdominal aortic aneurysm (AAA), with emphasis on the intraluminal thrombus (ILT) occurrence. Methods The post-induction ... [more ▼]

Objectives To evaluate imaging changes occurring in a rat model of elastase-induced abdominal aortic aneurysm (AAA), with emphasis on the intraluminal thrombus (ILT) occurrence. Methods The post-induction growth of the AAA diameter was characterized using ultrasound in 22 rats. ILT was reported on 13 rats that underwent 14 magnetic resonance imaging (MRI) 2-18 days post-surgery, and on 10 rats that underwent 18 fluoro-deoxyglucose (FDG) positron emission tomography (PET)/microcomputed tomography examinations 2-27 days post-surgery. Logistic regressions were used to establish the evolution with time of AAA length, diameter, ILT thickness, volume, stratification, MRI and FDG PET signalling properties, and histological assessment of inflammatory infiltrates. Results All of the following significantly increased with time post-induction (p < 0.001): AAA length, AAA diameter, ILT maximal thickness, ILT volume, ILT iron content and related MRI signalling changes, quantitative uptake on FDG PET, and the magnitude of inflammatory infiltrates on histology. However, the aneurysm growth peak followed occurrence of ILT approximately 6 days after elastase infusion. Conclusion Our model emphasizes that occurrence of ILT precedes AAA peak growth. Aneurysm growth is associated with increasing levels of iron, signalling properties changes in both MRI and FDG PET, relating to its biological activities. [less ▲]

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See detailMonte Carlo simulations of the dose from imaging with GE eXplore 120 micro-CT using gate.
Bretin, Florian; Bahri, Mohamed Ali ULg; Luxen, André ULg et al

in Medical Physics (2015), 42(10), 5711-5719

Purpose: Small animals are increasingly used as translational models in preclinical imaging studies, during which the subjects can be exposed to large amounts of radiation. While the radiation levels are ... [more ▼]

Purpose: Small animals are increasingly used as translational models in preclinical imaging studies, during which the subjects can be exposed to large amounts of radiation. While the radiation levels are generally sublethal, studies have shown that low-level radiation can change physiological parameters in mice. In order to rule out any influence of radiation on the outcome of such experiments, or resulting deterministic effects in the subjects, the levels of radiation involved need to be addressed. The aim of this study was to investigate the radiation dose delivered by the GE eXplore 120 microCT non-invasively using Monte Carlo simulations in GATE and to compare results to previously obtained experimental values. Methods: Tungsten X-ray spectra were simulated at 70, 80, and 97 kVp using an analytical tool and their half-value layers were simulated for spectra validation against experimentally measured values of the physical X-ray tube. A Monte Carlo model of the microCT system was set up and four protocols that are regularly applied to live animal scanning were implemented. The computed tomography dose index (CTDI) inside a PMMA phantom was derived and multiple field of view acquisitions were simulated using the PMMA phantom, a representative mouse and rat. Results: Simulated half-value layers agreed with experimentally obtained results within a 7% error window. The CTDI ranged from 20 to 56 mGy and closely matched experimental values. Derived organ doses in mice reached 459 mGy in bones and up to 200 mGy in soft tissue organs using the highest energy protocol. Dose levels in rats were lower due to the increased mass of the animal compared to mice. The uncertainty of all dose simulations was below 14%. Conclusions: Monte Carlo simulations proved a valuable tool to investigate the 3D dose distribution in animals from microCT. Small animals, especially mice (due to their small volume), receive large amounts of radiation from the GE eXplore 120 microCT, which might alter physiological parameters in a longitudinal study setup. [less ▲]

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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 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 detailPreclinical molecular imaging: from the laboratory bench to the patient.
Plenevaux, Alain ULg

Conference (2015, May 14)

Preclinical molecular imaging plays a key role in the study of diseases and the development – evaluation - validation of novel treatments and diagnostic techniques. The actual aim is to facilitate the ... [more ▼]

Preclinical molecular imaging plays a key role in the study of diseases and the development – evaluation - validation of novel treatments and diagnostic techniques. The actual aim is to facilitate the translation of novel therapies and diagnostic agents into patients by providing in vivo proof-of-principle data in animal models of diseases and accordingly match some of the legal requirements before human clinical trials. The real power of preclinical imaging stems in the fact that the in vivo data are collected non-invasively thus making longitudinal studies possible. The evolution of the disease or the actual impact of innovative treatments can be evaluated in the same animal over a long period of time. The major modalities used in preclinical molecular imaging (all present in our laboratory) are the positron emission tomography (microPET), the x-ray tomodensitometry (microCT) and the magnetic resonance imaging (microMRI). The Cyclotron Research Centre (CRC) at ULg is a multidisciplinary laboratory which relies on i.e. a medical cyclotron for radioisotope productions, a radiochemistry unit for the development of new radiopharmaceuticals and process automations, a GMP unit for the radiopharmaceutical productions, a preclinical imaging unit and a clinical imaging unit (with MRI, PET, EEG, TMS…). All expertise and qualified staff are present on site. The CRC has all permissions and approvals for radiopharmaceutical productions and human clinical trials. During this presentation will take the recent development of the first SV2A radioligand [18F]UCB-H to illustrate how the CRC can bring new ideas from the laboratory bench to the patient. [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 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 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 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 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 detailFunctional MRI for predicting metastatic spreading at the time of surgery after neoadjuvant radiotherapy
LALLEMAND, François ULg; Leroi, Natacha ULg; Bahri, Mohamed Ali ULg et al

Poster (2015, April)

Neoadjuvant radiotherapy (NeoRT) improves tumor local control and tumor resection in many cancers. The timing between the end of the NeoRT and surgery is driven by the occurrence of side effects or the ... [more ▼]

Neoadjuvant radiotherapy (NeoRT) improves tumor local control and tumor resection in many cancers. The timing between the end of the NeoRT and surgery is driven by the occurrence of side effects or the tumor downsizing. Some studies demonstrated that the timing of surgery and the RT schedule could influence tumor dissemination and subsequently patient overall survival. Our aim is to evaluate with functional MRI the impact of the radiation treatment on the tumor microenvironment and subsequently to determine the best timing to perform surgery for avoiding tumor spreading. [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 detailIdentification of predictive markers based on functional imaging of metastatic spreading at the time of surgery after neoadjuvant radiotherapy
LALLEMAND, François ULg; Leroi, Natacha ULg; Bahri, Mohamed Ali ULg et al

Poster (2015, January 27)

Neoadjuvant radiotherapy (NeoRT) improves tumor local control and tumor resection in many cancers. The timing between the end of the NeoRT and surgery are driven by the occurrence of side effects or the ... [more ▼]

Neoadjuvant radiotherapy (NeoRT) improves tumor local control and tumor resection in many cancers. The timing between the end of the NeoRT and surgery are driven by the occurrence of side effects or the tumor downsizing. Some studies demonstrated that the timing of surgery and the RT schedule could influence tumor dissemination. Our aim is to evaluate with functional MRI the impact of the radiation treatment on the tumor microenvironment and subsequently to determine the best timing to perform surgery. We used a model of NeoRT, 4T1 cells were implanted in the flank of BalbC mice. Seven days after, tumors were irradiated with 2x5Gy than we surgically removed this lesion 11 days after RT. Diffusion Weighted (DW) and Dynamic Contrast Enhancement (DCE) -MRI was performed every 2 days during 11 days between RT and surgery. We developed a homemade “portacath” specifically dedicated for mice and for repetitive I.V. contrast agent injection. For DW-MRI, we performed sequences with 10 different B-value to achieve IntraVoxel Incoherent Motion analysis. For DCE-MRI, we used FSEMS sequence for keeping the same slices as with DW-MRI. For both images, we performed analysis on the entire tumor volume. We obtained very promising preliminary results showing good uniformity in the ADC (Attenuation Diffusion Coefficient). We succeeded to follow mice with imaging during the 11 days without major troubles. We observed less variability of the ADC signal during the 11 days in the irradiated tumors compared to the control. The signal to noise ratio was relatively poor for the diffusion sequence and need to be improved. For the first time, we demonstrate the feasibility of repetitive MRI functional imaging in a mice model of NeoRT. These results open perspectives for studying modifications of the tumor microenvironment induced by neoadjuvant RT. The techniques need to be improved and correlated to the tumor dissemination in function of the RT schedule and timing of surgery. [less ▲]

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See detailExploration of volumetric cerebral changes, with de micro-MRi, due to psychomotor exercise in mice
Moës, Florian ULg; Plenevaux, Alain ULg; Becker, Guillaume ULg et al

Poster (2015, January 27)

It's well know that exercise is good for health .In addition exercise has postive effects on cognition ,neurodegenerative disease and on mood. Some studies show that exercise has effect on brain so the ... [more ▼]

It's well know that exercise is good for health .In addition exercise has postive effects on cognition ,neurodegenerative disease and on mood. Some studies show that exercise has effect on brain so the aim of this study is to see if there are volumetric changes due to exercise or not. [less ▲]

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