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See detailNeuro-functional correlates of the protective effects of exercise against cocaine sensitization and dopamine D2 receptors density: a [18F]Fallypride microPET study.
Becker, Guillaume ULiege; Lespine, Louis-Ferdinand ULiege; Serrano Navacerrada, Maria Elisa ULiege et al

in Molecular Imaging and Biology (in press)

Preclinical studies suggest that free access to a running wheel can attenuate behavioural effects of addictive drugs such as psychomotor sensitization to cocaine in rodents. This phenomenon has an ... [more ▼]

Preclinical studies suggest that free access to a running wheel can attenuate behavioural effects of addictive drugs such as psychomotor sensitization to cocaine in rodents. This phenomenon has an integral role in the process of drug addiction in craving and relapse (Steketee and Kalivas, 2011). Free wheel-running was recently shown to be efficacious at preventing the initiation or the long-term expression of psychomotor sensitization to cocaine in mice or rats (Diaz et al., 2013; Geuzaine and Tirelli, 2014). In the present study, we investigated the neuro-functional correlates of the protection against psychomotor sensitization to cocaine afforded by free wheel-running on dopaminergic neurotransmission, using microPET imaging with [18F]Fallypride, a Dopamine 2 receptor (D2R) antagonist. Sixty-four 28-day-old female C57BL/6J mice were randomly assigned to one of the two housing conditions, defined by the presence or the absence of a running wheel in the cage over a 6-week pre-testing period. Since mice from the two types of housing received either saline (controls) or cocaine (8 mg/kg, i.p.) during testing (9 once-daily sessions to establish sensitization plus 1 single session to test its expression), a basic 2x2 randomized blocks design was generated (2-way ANOVA and planned comparisons; n=10). Experimentation lasted 85 days, with a 42-day period of pre-testing and a 3-week interval preceding the test for long-term expression of sensitization (LTES). All mice underwent a microPET (Focus 120, Siemens) the day after the LTES. The microPET protocol consisted of a 60 min. dynamic acquisition after the injection of 10 MBq of [18F]Fallypride in the tail vein. Wheel-running strongly and significantly attenuated LTES (interaction) to cocaine (Cohen’s d=1.63; t(21)=3.75, p<.001) and cocaine-treated mice exhibited a clear-cut and significant increase (main effect) of the [18F]Fallypride BP (d=0.88, t(31)=2.45, p =.02). Wheel-running induced an overall moderate-sized decrease (main effect) of the [18F]Fallypride BP, but without achieving statistical significance (d=0.64, t(31)=1.79, p =.08). These findings suggest that LTES is associated with an increase of the [18F]Fallypride BP in the mouse striatum, probably reflecting an increase in postsynaptic D2R density in this region. Also, the protecting effect of free running on psychomotor sensitization goes together with a decrease in D2R density in the striatum of exercised mice. We intend to complement the present study with an identical experiment to reach a total number of 80 mice (n=20). This will confer to our study a sufficient power (80%) for the main effect of wheel-running exercise on [18F]Fallypride BP to be detected at an alpha-level of 5%. Finally, autoradiography studies, performed on the same mice with [18F]Fallypride, will strengthen our in vivo results. [less ▲]

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See detailEvaluating the In Vivo Specificity of [18F]UCB-H for the SV2A Protein, Compared with SV2B and SV2C in Rats Using microPET.
Serrano Navacerrada, Maria Elisa ULiege; Becker, Guillaume ULiege; Bahri, Mohamed Ali ULiege et al

in Molecules (2019), 24(9), 1705

The synaptic vesicle protein 2 (SV2) is involved in synaptic vesicle trafficking. The SV2A isoform is the most studied and its implication in epilepsy therapy led to the development of the first SV2A PET ... [more ▼]

The synaptic vesicle protein 2 (SV2) is involved in synaptic vesicle trafficking. The SV2A isoform is the most studied and its implication in epilepsy therapy led to the development of the first SV2A PET radiotracer [18F]UCB-H. The objective of this study was to evaluate in vivo, using microPET in rats, the specificity of [18F]UCB-H for SV2 isoform A in comparison with the other two isoforms (B and C) through a blocking assay. Twenty Sprague Dawley rats were pre-treated either with the vehicle, or with specific competitors against SV2A (levetiracetam), SV2B (UCB5203) and SV2C (UCB0949). The distribution volume (Vt, Logan plot, t* 15 min) was obtained with a population-based input function. The Vt analysis for the entire brain showed statistically significant differences between the levetiracetam group and the other groups (p < 0.001), but also between the vehicle and the SV2B group (p < 0.05). An in-depth Vt analysis conducted for eight relevant brain structures confirmed the statistically significant differences between the levetiracetam group and the other groups (p < 0.001) and highlighted the superior and the inferior colliculi along with the cortex as regions also displaying statistically significant differences between the vehicle and SV2B groups (p < 0.05). These results emphasize the in vivo specificity of [18F]UCB-H for SV2A against SV2B and SV2C, confirming that [18F]UCB-H is a suitable radiotracer for in vivo imaging of the SV2A proteins with PET. [less ▲]

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See detailWheel-running exercise before and during gestation against acute and sensitized cocaine psychomotor-activation in offspring.
Lespine, Louis-Ferdinand ULiege; Plenevaux, Alain ULiege; Tirelli, Ezio ULiege

in Behavioural Brain Research (2019), 363

While animal research has consistently reported preventive effects of exercise against drug abuse vulnerability, little is known about the influence of the developmental stage during which exercise is ... [more ▼]

While animal research has consistently reported preventive effects of exercise against drug abuse vulnerability, little is known about the influence of the developmental stage during which exercise is displayed on addictive drugs responsiveness. This study aimed to determine whether prenatal exercise could attenuate acute cocaine reactivity and psychomotor sensitization in youth offspring. We used a split-plot factorial design where C57BL/6 J females were randomly assigned into sedentary or exercised (wheel-running) conditions before and during gestation, the wheels being removed on gestational day 18. Offspring were weaned, gendered and individually housed on 24–28 days old. At 38–42 days old, they were tested for their acute psychomotor responsiveness to 8 mg/kg cocaine and their initiation of sensitization over 8 additional once-daily administrations, the long-term expression of sensitization occurring 30 days later. Adolescent females born from exercised mothers were much less responsive to the acute psychomotor-stimulating effect of cocaine than those born from sedentary mothers (d=0.75, p=0.02), whereas there was no evidence for such a difference in males (d=0.34, p=0.17). However, we did not find sizeable attenuating effects of prenatal exercise on the initiation and the long-term expression of the psychomotor-activating effect of cocaine, in either sex (Cohen’s ds varying from −0.13 to 0.39). These results suggest that prenatal exercise may induce initial protection against cocaine responsiveness in youth females, a finding that warrants further research. [less ▲]

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See detailQuantification of [18F]UCB-H Binding in the Rat Brain: From Kinetic Modelling to Standardised Uptake Value
Serrano Navacerrada, Maria Elisa ULiege; Bahri, Mohamed Ali ULiege; Becker, Guillaume ULiege et al

in Molecular Imaging and Biology (2018)

Purpose: [18F]UCB-H is a specific positron emission tomography (PET) biomarker for the Synaptic Vesicle protein 2A (SV2A), the binding site of the antiepileptic drug levetiracetam. With a view to ... [more ▼]

Purpose: [18F]UCB-H is a specific positron emission tomography (PET) biomarker for the Synaptic Vesicle protein 2A (SV2A), the binding site of the antiepileptic drug levetiracetam. With a view to optimising acquisition time and simplifying data analysis with this radiotracer, we compared two parameters: the distribution volume (Vt) obtained from Logan graphical analysis using a Population-Based Input Function, and the Standardised Uptake Value (SUV). Procedures: Twelve Sprague Dawley male rats, pre-treated with three different doses of levetiracetam were employed to develop the methodology. Three additional kainic acid (KA) treated rats (temporal lobe epilepsy model) were also used to test the procedure. Image analyses focused on: (i) length of the dynamic acquisition (90 versus 60 min); (ii) correlations between Vt and SUV over 20-min consecutive time-frames; (iii) and (iv) evaluation of differences between groups using the Vt and the SUV; and (v) preliminary evaluation of the methodology in the KA epilepsy model. Results: A large correlation between the Vt issued from 60 to 90-min acquisitions was observed. Further analyses highlighted a large correlation (r 9 0.8) between the Vt and the SUV. Equivalent differences between groups were detected for both parameters, especially in the 20–40 and 40– 60-min time-frames. The same results were also obtained with the epilepsy model. Conclusions: Our results enable the acquisition setting to be changed from a 90-min dynamic to a 20-min static PET acquisition. According to a better image quality, the 20–40-min time-frame appears optimal. Due to its equivalence to the Vt, the SUV parameter can be considered in order to quantify [18F]UCB-H uptake in the rat brain. This work, therefore, establishes a starting point for the simplification of SV2A in vivo quantification with [18F]UCB-H, and represents a step forward to the clinical application of this PET radiotracer. [less ▲]

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See detailTHE SV2A PROTEIN: IMAGING SYNAPTIC DENSITY DURING THE PROGRESSION OF THE TEMPORAL LOBE EPILEPSY IN THE KASE RAT MODEL
Serrano Navacerrada, Maria Elisa ULiege; Bahri, Mohamed Ali ULiege; Becker, Guillaume ULiege et al

Poster (2018, October 18)

Introduction The temporal lobe epilepsy (TLE) is the most common epileptic disorder. New antiepileptic drugs target the Synaptic Vesicle protein 2A (SV2A) (1). Nevertheless, the prevailing literature ... [more ▼]

Introduction The temporal lobe epilepsy (TLE) is the most common epileptic disorder. New antiepileptic drugs target the Synaptic Vesicle protein 2A (SV2A) (1). Nevertheless, the prevailing literature addressing the relation between this protein and the epilepsy is limited (2, 3). This study provides insights on the role of the SV2A protein during the four stages of TLE (4, 5), throughout its in vivo study with the [18F]UCB-H radiotracer (6). Methods Twenty-four male Sprague-Dawley were subjected to multiple injections (7) of i) Saline (Sham), or ii) 5mg/kg of Kainic Acid (KA). The rats not reacting to KA (NKA) were also scanned. In each TLE stages, a [18F]UCB-H dynamic scan was performed, followed by a T2-structural MRI. EEG recordings were performed to determine the number of crises. Data processing was done with PMOD 3.6. Results were expressed as SUV and statistically analyzed with the SPSS and the SPM. Results During the acute phase, statistically significant differences were found between Sham and KA in striatum, cerebellum, and medulla. In the latent phase, these SUV differences were detected between the NKA and KA in the same regions along with hippocampus and thalamus. When the spontaneous crises started, these group differences became statistically significant in all the regions but the cortex. During the chronic phase, all the regions showed statistically significant differences between groups. Furthermore, the voxel-wise analysis highlighted statistically significant differences in voxels at the level of amygdala and hippocampus. Conclusions These results show that [18F]UCB-H is able to detect early modifications in SV2A expression (3 days after the TLE model creation), in particular in regions implicated in the epileptic process. This radiotracer can potentially be used as a suitable biomarker for the early detection of the epileptic disease, being able to distinguish between stages in this neurodegenerative disease. [less ▲]

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See detailSound production and sonic apparatus in deep-living cusk-eels (Genypterus chilensis and Genypterus maculatus)
Parmentier, Eric ULiege; Bahri, Mohamed Ali ULiege; Plenevaux, Alain ULiege et al

in Deep-Sea Research. Part I, Oceanographic Research Papers (2018)

Cusk-eels (Ophidiidae) are known sound producers, but many species live in deep water where sounds are difficult to record. For these species sonic ability has been inferred from inner anatomy. Genypterus ... [more ▼]

Cusk-eels (Ophidiidae) are known sound producers, but many species live in deep water where sounds are difficult to record. For these species sonic ability has been inferred from inner anatomy. Genypterus (subfamily Ophidiinae) are demersal fishes inhabiting the continental shelf and slope at depths between 50 and 800 m. Males and females G. maculatus have been maintained together in a tank and 9 unsexed specimens of G. chilensis in a second tank, providing a valuable opportunity to record the sounds of living species usually found at great depths. Genypterus chilensis and G. maculatus respectively produced one and two sound types mainly between 7 and 10 pm. Sound 1 in Genypterus maculatus consists of trains of pulses that vary in amplitude and pulse period; call 2 sounded like a growl that results from the rapid emission of pulses that define sound 1. Genypterus chilensis produced a growl having an unusual feature since the first peak of the second pulse has always greater amplitude than all other peaks. These sounds are probably related to courtship behavior since floating eggs are found after night calls. The anatomical structures of the sound-producing organ in both species present an important panel of highly derived characters including three pairs of sonic muscles, a neural arch that pivots on the first vertebral body and a thick swimbladder with unusual features. Sonic structures are similar between species and between sexes. Therefore both biological sexes are capable of sound production although precedent from shallow ophidiids and sonic fishes in general suggests that males are more likely to produce courtship calls. This study reports two main types of information. It demonstrates that two deep-living species are capable of sound production, which is a pioneer step in the acoustic study of deep-sea fauna. Recorded sounds should also help to locate fish in open sea. As these species are currently used to diversify the aquaculture industry in Chile, deeper studies on their acoustic behavior should also help to target spawning period and to identify mature specimens. [less ▲]

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See detailEPILEPSY AND THE SV2A PROTEIN: new insights about the disease.
Serrano Navacerrada, Maria Elisa ULiege; Raedt, Robrecht; Becker, Guillaume ULiege et al

Conference (2018, September 13)

Around two million of people worldwide are affected by neurodegenerative diseases, such as Alzheimer, Parkinson or Epilepsy. Despite the social and the economic impact of these diseases, their causes ... [more ▼]

Around two million of people worldwide are affected by neurodegenerative diseases, such as Alzheimer, Parkinson or Epilepsy. Despite the social and the economic impact of these diseases, their causes still remain unclear. In the case of the epilepsy, for example, around 25% of the patients suffer drug-resistant epilepsy, for which there is no medicament able to mitigate the epileptic crises or the associated symptomatology, such as cognitive problems and mood disorders. In 1974, UCB Pharma synthetized a new antiepileptic drug with a high therapeutic index: the Levetiracetam. The target of this medicament is the Synaptic Vesicle Protein 2A (SV2A) whose specific role in the pathology is still unknown. The main goal of my thesis is to better understand the relationship between this protein and the epilepsy. On the one hand, the production and phenotyping of conditional knockout mice for the SV2A protein allowed us to discover a possible implication of this protein in the spatial memory and anxiety process, an important part of the epileptic symptomatology. On the other hand, the synthesis of the radiotracer [18F]UCB-H, with a high affinity for the SV2A protein, enabled the in vivo evaluation (with the mPET technique) of a rat model of the temporal lobe epilepsy through the disease process. Results showed a strong correlation between the severity of the epilepsy (EEG technique) and the SV2A levels in different brain regions, highlighting the importance of this protein in the development of the disease. In summary, although further studies in humans are necessary, this protein emerges as an important key in clinical diagnosis and medical research, being implicated in all the aspects of the epileptic disease. [less ▲]

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See detailEPILEPSY AND THE SV2A PROTEIN: new insights about the disease.
Serrano Navacerrada, Maria Elisa ULiege; Raedt, Robrecht; Becker, Guillaume ULiege et al

Conference (2018, September 13)

Around two million of people worldwide are affected by neurodegenerative diseases, such as Alzheimer, Parkinson or Epilepsy. Despite the social and the economic impact of these diseases, their causes ... [more ▼]

Around two million of people worldwide are affected by neurodegenerative diseases, such as Alzheimer, Parkinson or Epilepsy. Despite the social and the economic impact of these diseases, their causes still remain unclear. In the case of the epilepsy, for example, around 25% of the patients suffer drug-resistant epilepsy, for which there is no medicament able to mitigate the epileptic crises or the associated symptomatology, such as cognitive problems and mood disorders. In 1974, UCB Pharma synthetized a new antiepileptic drug with a high therapeutic index: the Levetiracetam. The target of this medicament is the Synaptic Vesicle Protein 2A (SV2A) whose specific role in the pathology is still unknown. The main goal of my thesis is to better understand the relationship between this protein and the epilepsy. On the one hand, the production and phenotyping of conditional knockout mice for the SV2A protein allowed us to discover a possible implication of this protein in the spatial memory and anxiety process, an important part of the epileptic symptomatology. On the other hand, the synthesis of the radiotracer [18F]UCB-H, with a high affinity for the SV2A protein, enabled the in vivo evaluation (with the mPET technique) of a rat model of the temporal lobe epilepsy through the disease process. Results showed a strong correlation between the severity of the epilepsy (EEG technique) and the SV2A levels in different brain regions, highlighting the importance of this protein in the development of the disease. In summary, although further studies in humans are necessary, this protein emerges as an important key in clinical diagnosis and medical research, being implicated in all the aspects of the epileptic disease. [less ▲]

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See detailDecrease in SV2A expression in the hippocampus involves changes in cognition and anxiety-like features.
Serrano Navacerrada, Maria Elisa ULiege; Bartholomé, Odile ULiege; Van Den Ackerveken, Priscilla ULiege et al

Poster (2018, July)

The Synaptic Vesicle Protein 2A (SV2A) is a transmembrane protein whose link with the epilepsy has been reported in multiples articles. However, the behavioral consequences of the decrease in its ... [more ▼]

The Synaptic Vesicle Protein 2A (SV2A) is a transmembrane protein whose link with the epilepsy has been reported in multiples articles. However, the behavioral consequences of the decrease in its expression remain still unclear. The purpose of our research is to better understand the role of this protein through the evaluation of cKO (Grik4 +/-, SV2A lox/lox) mice of both sexes, which present a specific decrease in the hippocampus. After a first evaluation of the SV2A levels in the hippocampus with the in vitro [18F]UCB-H autoradiography, differences in brain metabolism were assessed with [18F]FDG in mPET and ex vivo autoradiography. Finally, the phenotype of cKO mice was analyzed with a behavioral test battery. Our results showed a strong reduction of SV2A expression in the whole hippocampus of cKO mice, with regard to the WT mice, not accompanied by statistically significant differences in brain metabolism between groups, either in vivo or ex vivo. No statistically significant differences were found in spontaneous locomotor activity or fear-linked memory. However, cKO males showed significant more anxiety than WT (less percent of entries in open arms) and females presented spatial memory deficits measured in the Barnes Maze (less time spend in quadrant during the test). These results could explain the comorbidity between anxiety, memory impairment and epilepsy present both in animal models and in humans, suggesting an important role of SV2A in the symptomatology of other neurodegenerative diseases, such as the Alzheimer disease, or in anxiety-related pathologies. [less ▲]

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See detailThe severe deficiency of the somatotrope GHRH/GH/IGF1 axis of Ghrh-/- mice is associated with an important splenic atrophy and relative B lymphopenia
Bodart, Gwennaëlle ULiege; Farhat, Khalil ULiege; Charlet-Renard, Jeanne de Chantal ULiege et al

in Frontiers in Endocrinology (2018), 9(Art. 296),

A debate is still open about the precise control exerted by the somatotrope GH-releasing hormone (GHRH)/growth hormone (GH)/insulin-like growth factor 1 axis on the immune system. The objective of this ... [more ▼]

A debate is still open about the precise control exerted by the somatotrope GH-releasing hormone (GHRH)/growth hormone (GH)/insulin-like growth factor 1 axis on the immune system. The objective of this study was to directly address this question through the use of Ghrh−/− mice that exhibit a severe deficiency of their somatotrope axis. After control backcross studies and normalization for the reduced global weight of transgenic mice, no difference in weight and cellularity of the thymus was observed in Ghrh−/− mice when compared with C57BL/6 wild-type (WT) control mice. Similarly, no significant change was observed in frequency and number of thymic T cell subsets. In the periphery, Ghrh−/− mice exhibited an increase in T cell proportion associated with a higher frequency of sjTREC and naïve T cells. However, all Ghrh−/− mice displayed an absolute and relative splenic atrophy, in parallel with a decrease in B cell percentage. GH supplementation of transgenic mice for 6 weeks induced a significant increase in their global as well as absolute and relative splenic weight. Interestingly, the classical thymus involution following dexamethasone administration was shown to recover in WT mice more quickly than in mutant mice. Altogether, these data show that the severe somatotrope deficiency of Ghrh−/− mice essentially impacts the spleen and B compart- ment of the adaptive immune system, while it only marginally affects thymic function and T cell development. [less ▲]

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See detail[18F]UCB-H BINDING QUANTIFICATION IN RAT BRAIN: FROM MODELLING TO SUV
Serrano Navacerrada, Maria Elisa ULiege; Bahri, Mohamed Ali ULiege; Becker, Guillaume ULiege et al

Poster (2018, March 22)

Introduction Image quantification in Positron Emission Tomography (PET) is usually achieved through the invasive and sometimes infeasible arterial blood sampling [1, 2]. Alternative methods have been ... [more ▼]

Introduction Image quantification in Positron Emission Tomography (PET) is usually achieved through the invasive and sometimes infeasible arterial blood sampling [1, 2]. Alternative methods have been proposed, but a validation of their results is necessary [3, 4]. In the scope of improving the use of [18F]UCB-H, a specific biomarker for the Synaptic Vesicle protein 2A (SV2A) [5, 6, 7, 8], we have compared the distribution volume (VT) obtained through full kinetic modelling using a Population Based Input Function (PBIF) [9], and the Standardized Uptake Value (SUV). Methods Twelve Sprague Dawley male rats were pre-treated with vehicle (saline), 1 or 10 mg/kg of SV2A ligand (Keppra®, IP). Thirty minutes later, [18F]UCB-H was injected (IV) and a 90 min microPET dynamic acquisition was started followed by a T2 structural MRI. Primary image analysis was focused in examining tracer measurement stability through 10 min time windows. Subsequently, we calculated the correlation between VT (90 minutes) and SUV values over consecutive 20-minute time frames searching for the optimal frame to perform a static acquisition [10]. Finally, we did a supplementary test-retest static acquisition, from 60 to 80 minutes, in order to test group differences in SUV. Results/Discussion Evaluation of ten minutes time windows showed more stability in VT than in SUV measures, for all the groups. This change in signal seems to decrease in late time frames. We found also a strong correlation (R2>0.6) between dynamic VT and twenty minutes frame SUV, especially between 20 min and 60 min. From this, we can infer that an optimal frame to perform a static acquisition with [18F]UCB-H would be between 50 and 80 minutes. Using a static acquisition from 60 to 80 minutes, the SUV highlighted statistically significant differences between the group injected with vehicle and the other groups (p<0.01), but not between groups pre-treated with 1mg/kg and 10mg/kg of Keppra®. Conclusions Our work shows that a strong correlation between the SUV and the VT parameter based on a PBIF does exist. This opens the way to a possible simplification for SV2A in vivo imaging with [18F]UCB-H. Despite the fact that SUV is affected by many factors [11] and that it can overestimate results relative to VT [10], it is able to detect important differences in SV2A expression. Based on these results, SUV could become an interesting and easy to obtain parameter to study group differences in the context of several diseases. References 1. Acton PD et al. Radiologic Clinics of North America. 2004; 42(6):1055. 2. Kinahan PE & Fletcher JW. Seminars in Ultrasound, CT and MRI 2010; 31(6): 496. 3. Heurling K et al. Brain Res. 2017; 1670:220. 4. Tomasi G et al. Molecular Imaging and Biology. 2012; 14(2):131. 5. Bretin F et al. EJNMMI res. 2013; 3(1):35. 6. Warnock GI et al. J Nucl Med. 2014; 55(8):1336. 7. Bretin F et al. Molecular Imaging and Biology. 2015; 17(4):557. 8. Salmon E et al. Alzheimer's & Dementia. 2017; 13(7):781. 9. Becker G et al. Molecular Pharmaceutics. 2017; 14(8):2719. 10. Lockhart SN et al. PLoS One. 2016; 11(6):e0158460. 11. Boellaard R. J Nucl Med. 2009; 50(Suppl 1):11S-20S. Acknowledgement This work was funded by University of Liège, F.R.S.-FNRS, Walloon Region and UCB Pharma. Alain Plenevaux is research director from F.R.S.-FNRS. [less ▲]

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See detailSexual dimorphism in the sonic system and otolith morphology of Neobythites gilli (Ophidiiformes)
Parmentier, Eric ULiege; Boistel, Renaud; Bahri, Mohamed Ali ULiege et al

in Journal of Zoology (2018), 305

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See detailIncreased hippocampal volume in exercising mice: comparison of control conditions with in vivo voxel based morphometry
Becker, Guillaume ULiege; Lespine, Louis-Ferdinand ULiege; Bahri, Mohamed Ali ULiege et al

Poster (2018, March)

Introduction Both human and animal studies have shown that physical exercise (primarily aerobic exercise) may have facilitating effects on brain plasticity and cognition. In rodents, improvements of ... [more ▼]

Introduction Both human and animal studies have shown that physical exercise (primarily aerobic exercise) may have facilitating effects on brain plasticity and cognition. In rodents, improvements of various forms of learning and memory induced by wheel-running have been associated with numerous neuroplastic changes such as increased hippocampal neurogenesis. A few studies, using magnetic resonance imaging (MRI), consistently reported hippocampal volumetric increase relative to non-exercising mice. However, the control group is commonly limited either to a locked wheel or no wheel. Methods In the present study, we intended to test whether 6 weeks of voluntary wheel-running exercise during adulthood induced a detectable volumetric change in mice brain in comparison to non-exercised control mice housed either with a locked wheel or without such wheel. 54 C57Bl6 males were randomly assigned to one of the three groups and individually housed for 6 weeks before imaging session. MRI (Agilent 9.4T) acquisition consisted in 3D T2 volume sequence (voxel size: 0.21 mm isotropic) using a dedicated surface coil receiver. We used Dartel soware for the preprocessing of the data, and the Voxel Based Morphometry was done with SPM mouse toolbox (F test, threshold p < .001 uncor). A small volume correction was applied to limit the analysis to the hippocampus. Results/Discussion VBM analysis shows significant clusters with increased grey matter volume in the hippocampus (cluster sizes 1531 and 3460, p < .001) when we compare the wheel vs locked wheel groups. Regarding the wheel vs no wheel comparison, significant clusters were observed in the hippocampus (cluster sizes 955 and 238, p < .001). Interestingly, no dierences were found when we compare the two control groups (locked wheel vs no wheel). Conclusions In this study, we replicate previous studies depicting an increased hippocampal volume under physical exercise in mice using VBM. Moreover, we certified here that attempting to study the impact of physical exercise on brain volume, control groups with a locked wheel or no wheel are equivalent. [less ▲]

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See detailNanofitin as a New Molecular-Imaging Agent for the Diagnosis of Epidermal Growth Factor Receptor Over-Expressing Tumors
Goux, Marine; Becker, Guillaume ULiege; Gorre, Harmony et al

Scientific conference (2018, January 19)

In this study, we provide the first report of the use of the Nanofitin scaffold for generating targeted PET radiotracers, using the anti-EGFR B10 Nanofitin as proof-of-concept. 18F-FBEM-Cys-B10 shows a ... [more ▼]

In this study, we provide the first report of the use of the Nanofitin scaffold for generating targeted PET radiotracers, using the anti-EGFR B10 Nanofitin as proof-of-concept. 18F-FBEM-Cys-B10 shows a favorable in vivo profile. The posibility to drive Nanofitin molecular recognition capability, over a fast and tunable in vitro selection system could facilitate the development of valuable PET-based companion diagnostics. [less ▲]

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See detailSv2a protein levels in the kainic acid epilepsy rat model during the acute phase
Serrano Navacerrada, Maria Elisa ULiege; Becker, Guillaume ULiege; Bahri, Mohamed Ali ULiege et al

in Epilepsia (2017, December), 58(Supplement S5), 1225

Introduction The Kaïnic Acid model (KA) is one of the most validated models of temporal lobe epilepsy (TLE) (Lévesque et al.,2016). Its administration induces status epilepticus (SE), characterized by an ... [more ▼]

Introduction The Kaïnic Acid model (KA) is one of the most validated models of temporal lobe epilepsy (TLE) (Lévesque et al.,2016). Its administration induces status epilepticus (SE), characterized by an extensive neuronal damage in limbic structures (Sperk et al.,1983). Post-mortem studies, such as the epilepsy model presented in (Wang et al., 2014), show a reduction of SV2A protein levels during the chronic phase, however, no data have been reported during the acute phase (0-48h after KA injection).. The present pilot study is undertaken to evaluate in vivo, with the specific radiotracer [18F]UCB-H (Bretin et al., 2015; Warnock et al., 2014), the SV2A expression 24h after a SE produced by KA administration. Methods Two Sprague-Dawley rats were scanned at two different times: baseline, and 24h after three systemic injections of 5mg/kg KA. The scanning process consisted of a first scan with microPET (Focus 120), during 1 hour, using [18F]UCB-H (41 ± 5 MBq IV tail vein). This is followed by MRI (9.4T Agilent, anatomical T2). A coregistration was performed with PMOD 3.6 software. Data were expressed as SUV and AUC were calculated for the different brain regions. Results [18F]UCB-H microPET images exhibited a small reduction (around 10%) in SV2A brain levels after KA injections compared to the baseline, marked in thalamus, hippocampus and amygdale. MRI images obtained 24h after KA injections are in accordance with previous histological studies, revealing inflammatory edema, tissue necrosis and increased ventricle volume (Sperk et al.,1983). Conclusions These preliminary results obtained in KA treated rats show that [18F]UCB-H is able to detect alterations in SV2A levels in relevant regions for epilepsy. This radiotracer emerges as a valuable tool to follow in vivo SV2A through longitudinal studies. KA model in rats deserves as a tool for the study of epilepsy, exhibiting the same features than the human disease. References [1] Lévesque et al., J Neurosci Methods, 2016 [2] Sperk et al., Neuroscience, 1983 [3] Wang et al., J Mol Neurosci., 2014 [4] Bretin et al., Molecular Imaging and Biology, 2015 [5] Warnock et al., J Nucl Med., 2014 [5] Van Nieuwenhuyse et al., Brain Research, 2015 [6] Hellier et al., Epilepsy Res., 1998 [less ▲]

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See detailMeasuring brain synaptic vesicle protein 2A with positron emission tomography and [18F]UCB-H.
Bahri, Mohamed Ali ULiege; Plenevaux, Alain ULiege; Aerts, Joël ULiege et al

in Alzheimer's and Dementia: Translational Research and Clinical Interventions (2017), 4(4), 481-486

Introduction: Brain distribution of synaptic vesicle protein 2Awas measured with fluorine-18 UCBH ([18F]UCB-H) and positron emission tomography (PET). Methods: Images of synaptic density were acquired in ... [more ▼]

Introduction: Brain distribution of synaptic vesicle protein 2Awas measured with fluorine-18 UCBH ([18F]UCB-H) and positron emission tomography (PET). Methods: Images of synaptic density were acquired in healthy volunteers (two young participants and two seniors). Input function was measured by arterial blood sampling (arterial input function) and derived from PET images using carotid activity (image-derived input function). Logan graphical analysis was used to estimate regional synaptic vesicle protein 2A distribution volume. Results: [18F]UCB-H uptake was ubiquitous in cortical and subcortical gray matter. Arterial input function and image-derived input function provided regional distribution volume with a high linear relationship. Discussion: The cerebral distribution of [18F]UCB-H is similar to that recently observed with carbon-11 UCB-J ([11C]UCB-J). An accurate [18F]UCB-H quantification can be performed without invasive arterial blood sampling when no suitable reference region is available, using dynamic PET carotid activity. Brain synaptic density can be studied in vivo in normal and pathological aging. [less ▲]

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See detailNanofitin as a New Molecular-Imaging Agent for the Diagnosis of 2 Epidermal Growth Factor Receptor Over-Expressing Tumors.
Goux, Marine; Becker, Guillaume ULiege; Gorré, Harmony et al

in Bioconjugate Chemistry (2017), 28(9), 2361-2371

Epidermal growth-factor receptor (EGFR) is involved in cell growth and proliferation and is over-expressed in malignant tissues. Although anti-EGFR-based immunotherapy became a standard of care for ... [more ▼]

Epidermal growth-factor receptor (EGFR) is involved in cell growth and proliferation and is over-expressed in malignant tissues. Although anti-EGFR-based immunotherapy became a standard of care for patients with EGFR-positive tumors, this strategy of addressing cancer tumors by targeting EGFR with monoclonal antibodies is less-developed for patient diagnostic and monitoring. Indeed, antibodies exhibit a slow blood clearance, which is detrimental for positron emission tomography (PET) imaging. New molecular probes are proposed to overcome such limitations for patient monitoring, making use of low-molecular-weight protein scaffolds as alternatives to antibodies, such as Nanofitins with better pharmacokinetic profiles. Anti-EGFR Nanofitin B10 was reformatted by genetic engineering to exhibit a unique cysteine moiety at its C-terminus, which allows the development of a fast and site-specific radiolabeling procedure with 18F−4-fluorobenzamido-N-ethylamino-maleimide (18F−FBEM). The in vivo tumor targeting and imaging profile of the anti-EGFR Cys−B10 Nanofitin was investigated in a double-tumor xenograft model by static small-animal PET at 2 h after tail-vein injection of the radiolabeled Nanofitin 18F−FBEM−Cys−B10. The image showed that the EGFR- positive tumor (A431) is clearly delineated in comparison to the EGFR-negative tumor (H520) with a significant tumor-to-background contrast. 18F−FBEM−Cys−B10 demonstrated a significantly higher retention in A431 tumors than in H520 tumors at 2.5 h post-injection with a A431-to-H520 uptake ratio of 2.53 ± 0.18 and a tumor-to-blood ratio of 4.55 ± 0.63. This study provides the first report of Nanofitin scaffold used as a targeted PET radiotracer for in vivo imaging of EGFR-positive tumor, with the anti-EGFR B10 Nanofitin used as proof-of-concept. The fast generation of specific Nanofitins via a fully in vitro selection process, together with the excellent imaging features of the Nanofitin scaffold, could facilitate the development of valuable PET-based companion diagnostics. [less ▲]

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See detailDesign and Synthesis of [18F]BPAM121, a PET-Probe Targeting AMPA-subtype Glutamatergic Receptors.
Manos-Turvey, Alexandra ULiege; Lemaire, Christian ULiege; Becker, Guillaume ULiege et al

Poster (2017, August)

AMPA receptors (AMPARs), one of three sub-groups of ionotropic glutamate receptors present in the central nervous system, are recognised for their involvement in long-term potentiation (LTP), and learning ... [more ▼]

AMPA receptors (AMPARs), one of three sub-groups of ionotropic glutamate receptors present in the central nervous system, are recognised for their involvement in long-term potentiation (LTP), and learning and memory processes. [1] They represent a valid cognitive enhancer target, particularly in the fight against Alzheimer’s disease (AD). [2,3] Benzothiadiazine 1,1-dioxides, such as BPAM121, have emerged as important allosteric modulators of AMPARs, working solely in the presence of the endogenous transmitter. [4] Synthesis of BPAM121 labelled with fluorine-18 was proposed, to investigate the utility of this molecule as a PET probe in vivo, and evaluate its potential as an AD diagnostic tool (Figure 1). [Figure 1. a) Structure of BPAM121, b) Established radiochemical synthesis of [18F]BPAM121.] This work documents the successful optimization of synthesis, purification and formulation of [18F]BPAM121 using an automated FASTlab (GE Healthcare) synthesizer. In particular, the influence of higher-level [18F]fluoride ion starting concentrations on final product formulation requirements is discussed. Initial results revealed [18F]BPAM121 successfully passes the blood brain barrier, and further biological studies are currently underway. References [1] S. F. Traynelis et al. Pharmacol. Rev. 2010, 62, 405-496. 
 [2] J. Keifer, Z. Zheng, Eur. J. Neurosci. 2010, 32, 269-277. 
 [3] L. Gao et al. J. Neurochem. 2016, 136, 620-636. 
 [4] P. Francotte et al. J. Med. Chem. 2010, 53, 1700-1711. 
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See detailRegiospecific radiolabelling of Nanofitin on Ni Magnetic Beads with [18F]FBEM and in vivo PET studies
Dammicco, Sylvestre ULiege; Goux, Marine; Lemaire, Christian ULiege et al

in Nuclear Medicine and Biology (2017)

Introduction: Nanofitins are low molecular weight, single chain and cysteine-free protein scaffolds able to selectively bind a defined biological target. They derive from Sac7d bacterial protein family ... [more ▼]

Introduction: Nanofitins are low molecular weight, single chain and cysteine-free protein scaffolds 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 of production and high tolerability for chemical coupling make Nanofitins a very interesting alternative to antibodies and their fragments. Here, a hexahistidine tagged model Nanofitin (H4) directed against hen egg white lysozyme was radiolabelled and injected in mice to provide a baseline biodistribution and pharmacokinetic profiles to support future Nanofitin development programs. Method: A single cysteine residue has been genetically inserted in a model Nanofitin and its regioselective radiolabelling has been performed with 4-[18F]fluorobenzamido-N-ethylamino-maleimide ([18F]FBEM). The synthesis of [18F]FBEM has been completely implemented on a radiosynthesis unit (FastLab) including HPLC purification and formulation. Coupling with the [18F]FBEM has been achieved on a solid support (Ni magnetic beads) allowing rapid purification at room temperature without organic solvent. PET-MRI studies on C57BL/6 mice were conducted after injection of [18F]FBEM-Cys-H4 in order to access the biodistribution of this Nanofitin model. Results: Radiochemical yield (decay corrected) of 54±7% (n=4) was obtained after optimization for coupling the [18F]FBEM to Nanofitin. Pharmacokinetics results of [18F]FBEM-Cys-H4 revealed a fast clearance through the liver and the kidneys. Conclusion: An efficient new method on Ni magnetic beads was developed to radiolabelled his-tagged biomolecules with [18F]FBEM. This procedure was applied on a Nanofitin model Cys-H4 and biodistribution kinetic studies were achieved to evaluate the potential use of Nanofitin for diagnostic imaging. Fast clearance indicates that Nanofitins represent very interesting tools for diagnostic imaging. [less ▲]

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