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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 & 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 detailPharmacokinetic characterization of [18F]UCB-H PET radiopharmaceutical in the rat brain.
Becker, Guillaume ULiege; Warnier, Corentin; Serrano Navacerrada, Maria Elisa ULiege et al

in Molecular Pharmaceutics (2017), 14(8), 2719-2725

The synaptic vesicle glycoprotein 2A (SV2A), a protein essential to the proper nervous system function, is found in presynaptic vesicles. Thus, SV2A targeting, using dedicated radiotracers combined with ... [more ▼]

The synaptic vesicle glycoprotein 2A (SV2A), a protein essential to the proper nervous system function, is found in presynaptic vesicles. Thus, SV2A targeting, using dedicated radiotracers combined with positron emission tomography (PET), allows the assessment of synaptic density in the living brain. The first-in-class fluorinated SV2A specific radioligand, [18F]UCB-H, is now available at high-activity through an efficient radiosynthesis compliant with the current good manufacturing practices (cGMP). We report here a non-invasive method to quantify [18F]UCB-H binding in rat brain with microPET. Validation study in rats confirmed the need of high enantiomeric purity to target SV2A in vivo. We demonstrated the reliability of a population-based input function to quantify SV2A in preclinical microPET setting. Finally, we investigated the in vivo metabolism of [18F]UCB-H and confirmed the negligible amount of radiometabolites in the rat brain. Hence, the in vivo quantification of SV2A using [18F]UCB-H microPET seems a promising tool for the assessment of the synaptic density in the rat brain, and opens the way for longitudinal follow-up in neurodegenerative diseases rodents’ models. [less ▲]

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See detailNoninvasive quantification of [18F]UCB-H binding using microPET and population-based input function.
Becker, Guillaume ULiege; Warnier, C; Serrano Navacerrada, Maria Elisa ULiege et al

Poster (2017, February 19)

Introduction: [18F]UCB-H is a validated radiotracer with a high affinity for the synaptic vesicle glycoprotein 2A (SV2A), known as the binding site of the antiepileptic drug levetiracetam [1, 2]. Due to ... [more ▼]

Introduction: [18F]UCB-H is a validated radiotracer with a high affinity for the synaptic vesicle glycoprotein 2A (SV2A), known as the binding site of the antiepileptic drug levetiracetam [1, 2]. Due to the absence of reference region, the major drawback of SV2A microPET imaging in the living rat brain is the invasiveness and the complexity of the arterial input function measurement needed for a full quantification. We provide here evaluation of a population-based input function (PBIF) to estimate input function of [18F]UCB-H. Methods: Standard arterial input functions were measured with an arteriovenous shunt and a β-microprobe system from eight anesthetized Sprague-Dawley (SD) rats, as previously described [2]. The distribution volume (Vt) for [18F]UCB-H was calculated with Logan graphic analysis. After normalization, all individual AIFs were averaged to provide the PBIF, and the Logan graphical analysis was computed on each individual rat using the PBIF instead of individual AIF. Correlations analyses were computed between Vt obtained with each methods (individual AIF vs PBIF). Finally, another cohort of five SD rats was scanned with [18F]UCB-H, and Vt were computed using the PBIF and Logan analysis. Single blood samples were harvested at 15 min after radiotracer injection, just to ensure the consistency of the metabolic parent fraction. Results: The Vt computed with individual AIFs were higly consistent with previously reported values, so are the Vt computed with the PBIF [2]. Individual AIFs Vt and PBIF Vt are highly correlated through all brain areas for the height subjects (r2 =0.9). Coefficients of variance are slightly higher with the PBIF method compare to the individual AIF method (14 % and 9 % respectively for the whole brain). Finally, Vt measurement in the second cohort were consistent with previously reported values, and the metabolization profile matched the parent fraction described by Warnock and coll. [2]. Conclusions: The present study described a method for the noninvasive estimation of the AIF using a PBIF, carrying a potential that might substitute for conventional invasive, indivi- dual AIF measurement. We propose that this method can provide a reasonable solution for longitudinal quantitative [18F]UCB-H microPET studies. [less ▲]

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See detailEvaluating the specificity of [18F] UCB-H for the isoform SV2A, compared with isoforms SV2B and SV2C
Serrano Navacerrada, Maria Elisa ULiege; Becker, Guillaume ULiege; Bahri, Mohamed Ali ULiege et al

Poster (2017, February 01)

Background: SV2A is the most studied isoform of the Synaptic Vesicle 2 proteins, which are involved in the synaptic vesicle trafficking, being important in normal and pathological process, like the ... [more ▼]

Background: SV2A is the most studied isoform of the Synaptic Vesicle 2 proteins, which are involved in the synaptic vesicle trafficking, being important in normal and pathological process, like the epilepsy (1, 2). [18F]UCB-H was developed like a tool to study the role of this isoform with neuroimaging techniques (3, 4). The objective of this study was to evaluate its specificity to this isoform comparing with the others, through a competition assay in rats with ex-vivo autoradiography and mPET imaging. Methods: Forty male Sprague-Dawley were used in ex-vivo autoradiography experiments (N=20) and in microPET imaging (N=20). Animals were pre-treated 30 minutes before the injection of [18F]UCB-H with a dose IP either of vehicle, Keppra (SV2A ligand), UCB068 (SV2B ligand) or UCB054 (SV2C ligand). Ex-vivo autoradiography was carried out 5 minutes after radiotracer injection while mPET images were acquiring with a dynamic scanner of 1 hour. Data were expressed in Standard Uptake Value and then, the area under the curve was calculated for the total process. Results: In ex-vivo autoradiography, ANOVA of two-ways showed statistical significant differences in brain uptake of [18F]UCB-H among the groups pretreated with Keppra or the ligand for SV2B and the control group. Regarding mPET data, statistical significant differences were found between the group injected with keppra and the rest of groups. Conclusion: Even if a considerable affinity between the ligands UCB068 and UCB054, and the receptor for the isoform SV2A exists, it is only detected during the first 5 minutes (ex-vivo technique), being certainly due to a nonspecific binding. This binding is not strong enough to show a direct competition with the radiotracer during a mPET acquisition. These results allow us to conclude that [18F]UCB-H is a suitable radiotracer for the imaging of the isoform SV2A in vivo, allowing us the clinical study about the molecular base of a disease with a high population impact, like the epilepsy. [less ▲]

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See detailBehavioural phenotyping of SV2A lox/lox mice: Motor and anxiety-like features
Serrano Navacerrada, Maria Elisa ULiege; Bartholomé, Odile ULiege; Van Den Ackerveken, Priscilla ULiege et al

Poster (2017)

Background: Epilepsy is one of the most common neurological disorders (Alexopoulos, 2004). Current anti-epileptic drugs, such as Levetiracetam (Keppra®) or Brivaracetam, mainly target the trans-membrane ... [more ▼]

Background: Epilepsy is one of the most common neurological disorders (Alexopoulos, 2004). Current anti-epileptic drugs, such as Levetiracetam (Keppra®) or Brivaracetam, mainly target the trans-membrane Synaptic Vesicle Protein 2A (Hamann et al., 2008). Studies on homozygous SV2A KO mice phenotype, prove the mice to suffer severe seizures and die within 3 weeks (Crowder et al., 1999), establishing a link between this protein and the epilepsy. In 2009, the availability of heterozygous SV2A (+/-) mice as research tool enabled shedding light on the role of protein SV2A, revealing no motor differences but anxiety-like features in these mice compared with the WT (Lamberty et al., 2009), and a pro-epileptic phenotype (Crowder et al., 1999; Kaminski et al., 2008). Recently, a floxed SV2A mouse model has been produced with the Cre/loxP recombination system, this model allows invalidating the protein in CA3 hippocampal region, not followed by epileptic seizures (Menten-Dedoyart et al., 2016). Objectives: Perform a first behavioural phenotyping of SV2A lox/lox mice. Methodology: Two experiments were conducted in parallel to evaluate the effect of 3 different genotypes in the phenotype: WT (Grik4-/-, SV2A lox/lox), HZ (Grik4 +/-, SV2A lox/+) and cKO (Grik4 +/-, SV2A lox/lox) in male (n = 42) and female (n = 33) separately . Mice were housed individually along the experiment, with standard food and water ad libitum. After an acclimatization period of 2 weeks, anxiety-like features as well as exploration abilities were evaluated in an elevated plus-maze (EPM) single session of 5 minutes). 3 days later, spontaneous locomotor activity and habituation to the environment were measured during 1 hour, 3 consecutive days, in the activity chambers (ACT). Results: One-way ANOVA in EPM data presented no significant differences between groups, either in males or in females. A significant difference was found, between time spent in close arms vs open arms (p<0.01; η2p = 0.738 males; η2p = 0.805 females). Mixed between-within subjects ANOVA in ACT reflected no significant differences between groups in both sexes, regarding spontaneous locomotor activity and acclimatization to the activity chamber (p>0.05). Statistical significant differences were found between the 3 days (p<0.01; η2p = 0.716 males; η2p = 0.663 females). Conclusion: Results indicate that a decrease in the hippocampal expresion of SV2A protein does not lead to major behavioral changes. Regarding locomotor activity, the results found in heterozygous SV2A (+/-) mice are in line with (Lamberty et al., 2009), however, our mice did not present anxiety-like features, being necessary a global decrease in brain SV2A levels and not only a partial loss in a restricted region of the brain. Further analyses increasing the number of mice per group, will allow us to intensify our power value from 50-60% (females-males) up to 80%, with large effect size and a signification of p<0.05. An additional test to evaluate the spatial memory may help us better understand the effect a specific reduction in SV2A hippocampal expression has on the phenotype of mice. [less ▲]

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See detailIN VIVO STUDY OF THE SV2A PROTEIN IN THE KAINIC ACID EPILEPSY RAT MODEL
Serrano Navacerrada, Maria Elisa ULiege; Becker, Guillaume ULiege; Bahri, Mohamed Ali ULiege et al

Poster (2017)

Introduction Epilepsy is one of the commonest neurological disorders [1]. Antiepileptic drugs mainly target the SV2A protein [2] but its actual role is still largely unknown. [18F]UCB-H was developed to ... [more ▼]

Introduction Epilepsy is one of the commonest neurological disorders [1]. Antiepileptic drugs mainly target the SV2A protein [2] but its actual role is still largely unknown. [18F]UCB-H was developed to study in vivo SV2A brain proteins [3, 4]. The present pilot study was undertaken to evaluate for the first time in vivo in rats SV2A expression in the Kaïnic Acid (KA) epilepsy model [5]. Although this model is well studied in mice, few reports were devoted to rats. Imaging-wise, rats are very interesting thanks to a bigger brain size (reduction of the partial volume effect). Methods Three male Sprague-Dawley were used, one injected with saline and two with multiple KA injections (3 x 5mg/kg) [6]. 75 days later, when spontaneous seizures started to appear, microPET (Focus 120 ) was performed under isoflurane anesthesia (2.5-3 % in air) for 1 hour with [18F]UCB-H (41 ± 5 MBq IV tail vein) followed by MRI (9.4T Agilent, anatomical T2). Coregistration was done with PMOD 3.6 software. Data were expressed as SUV and areas under the curve were calculated for the different regions. Results [18F]UCB-H microPET images showed an important reduction (20-30%) for SV2A after KA injections mainly localized in amygdala, hippocampus, lateral parietal association cortex and cingulate cortex. The rest of the brain was globally unchanged. MRI revealed atrophy and inflammation in amygdala and hippocampus. Conclusions These preliminary results obtained in KA treated rats showed that [18F]UCB-H was able to detect important modifications for SV2A in relevant regions for epilepsy and appears as a valuable tool to follow in vivo SV2A through longitudinal studies. KA model in rats deserves for further development and validation as a tool for the study of epilepsy. [less ▲]

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See detailIN VIVO STUDY OF THE SV2A PROTEIN IN AN EPILEPTIC RAT MODEL
Serrano Navacerrada, Maria Elisa ULiege; Becker, Guillaume ULiege; Bahri, Mohamed Ali ULiege et al

Poster (2017)

Introduction Epilepsy is one of the commonest neurological disorders, affecting more than 60 million people worldwide [1]. New and effective antiepileptic drugs mainly target the SV2A protein [2] but its ... [more ▼]

Introduction Epilepsy is one of the commonest neurological disorders, affecting more than 60 million people worldwide [1]. New and effective antiepileptic drugs mainly target the SV2A protein [2] but its actual role is still largely unknown. [18F]UCB-H was developed as a tool to study in vivo the brain expression of this isoform [3, 4]. Due to the fact that only post-mortem studies were reported so far [5] the present pilot study was undertaken in order to evaluate for the first time in vivo in rats the SV2A expression in the validated Kaïnic Acid (KA) epilepsy model [6]. Methods Three male Sprague-Dawley were used, one injected with saline (Sham) and two with multiple KA systemic injections (5mg/kg x 3) [9]. SV2A brain levels were estimated at day 75, when spontaneous seizures started to appear. Animals were anesthetized (2.5 to 3 % isoflurane), and scanned for 1 hour with [18F]UCB-H (41 ± 5 MBq IV tail vein) in a Focus 120 microPET system and with MRI (9.4T Agilent, anatomical T2). Coregistration was done with PMOD 3.6 software. Data were expressed in SUV and areas under the curve were calculated for the different regions. Results [18F]UCB-H microPET images showed an important reduction (20-30%) for SV2A after KA injections mainly localized in amygdala, hippocampus, lateral parietal association cortex and cingulate cortex. The rest of the brain was globally unchanged. MRI revealed atrophy and inflammation in amygdala and hippocampus. Conclusions These preliminary results in KA treated rats presenting spontaneous seizures showed that [18F]UCB-H microPET was able to detect important reductions for the SV2A proteins in relevant regions for epilepsy [5]. Accordingly to this, we can infer that the KA model in rats deserves for further development and validation as a tool for the study of epilepsy. [18F]UCB-H appears as a valuable tool to follow in vivo SV2A proteins through longitudinal protocols and in turn to better understand its actual role in epilepsy. References/acknowledgements 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. [1] Alexopoulos, Epileptology, 2004 [2] Hamann et al., Eur J Pharmacol, 2008 [3] Bretin et al., Molecular Imaging and Biology, 2015 [4] Warnock et al., J Nucl Med., 2014 [5] Wang et al., J Mol Neurosci., 2014 [6] Hellier et al., Epilepsy Res., 1998 [less ▲]

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See detail[18F]UCB-H RADIOTRACER AS A TOOL TO UNDERSTAND THE ROLE OF THE SV2A PROTEIN
Serrano Navacerrada, Maria Elisa ULiege; Becker, Guillaume ULiege; Bahri, Mohamed Ali ULiege et al

Poster (2017)

Background: SV2A is the most studied isoform of the Synaptic Vesicle 2 proteins, which are involved in the synaptic vesicle trafficking, being important both in normal as in pathological process (1, 2 ... [more ▼]

Background: SV2A is the most studied isoform of the Synaptic Vesicle 2 proteins, which are involved in the synaptic vesicle trafficking, being important both in normal as in pathological process (1, 2). Until now, only one study in vivo has been reported, showing a reduction of SV2A levels in the epilepsy (3). [18F]UCB-H was developed like a current tool to study the role of SV2A with in vivo techniques (4, 5), and as a tool in clinical investigations. The objective of this research was to evaluate the radiotracer specificity to this isoform comparing with the others, through a competition assay in rats with ex-vivo autoradiography and mPET imaging. Methods: Forty male Sprague-Dawley were used in ex-vivo autoradiography experiments (N=20) and in microPET imaging (N=20). Animals were pre-treated 30 minutes before the injection of [18F]UCB-H with a dose IP either of vehicle, Keppra (SV2A ligand), UCB068 (SV2B ligand) or UCB054 (SV2C ligand). Ex-vivo autoradiography was carried out 5 minutes after radiotracer injection while mPET images were acquiring with a dynamic scanner of 1 hour. Standard Uptake Value (SUV) and Distribution Volume (VT) were calculated and the correlation between both parameters was determined. Results: In ex-vivo autoradiography, ANOVA of two-ways showed statistical significant differences in brain uptake of [18F]UCB-H among the groups pretreated with Keppra or the ligand for SV2B and the control group. Regarding mPET data, statistical significant differences were found between the group injected with keppra and the rest of groups. Pearson Correlation between SUV and VT was strong, with a value of 0.955. Conclusion: Even if a considerable affinity between the ligands UCB068 and UCB054, and the receptor for the isoform SV2A exists, it is only detected during the first 5 minutes (ex-vivo technique), being certainly due to a nonspecific binding. This binding is not strong enough to show a direct competition with the radiotracer during a mPET acquisition. These results allow us to conclude that [18F]UCB-H is a suitable radiotracer for the imaging of the isoform SV2A in vivo, allowing us the clinical study about the molecular base of a disease with a high population impact, like the epilepsy. 1) Van Vliet et al., 2009. Epilepsia 2) Crèvecœur et al., 2013. BMC Neurosci. 3) Finnema et al., 2016; Sci Transl Med. 4) Bretin et al., 2013.EJNMMI Res 5) Bretin et al., 2015.Mol Imaging Biol [less ▲]

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See detailEVALUATING THE SPECIFICITY OF [18F]UCB-H FOR THE ISOFORM SV2A, COMPARED WITH ISOFORMS SV2B AND SV2C
Serrano Navacerrada, Maria Elisa ULiege; Aerts, Joël ULiege; Bahri, Mohamed Ali ULiege et al

Poster (2016, November 18)

Background: SV2A is the most studied isoform of the Synaptic Vesicle 2 proteins, which are involved in the synaptic vesicle trafficking, being important in normal and pathological process, like the ... [more ▼]

Background: SV2A is the most studied isoform of the Synaptic Vesicle 2 proteins, which are involved in the synaptic vesicle trafficking, being important in normal and pathological process, like the epilepsy (1, 2). [18F]UCB-H was developed like a tool to study the role of this isoform with neuroimaging techniques (3, 4). The objective of this study was to evaluate its specificity to this isoform comparing with the others, through a competition assay in rats with ex-vivo autoradiography and mPET imaging. Methods: Forty male Sprague-Dawley were used in ex-vivo autoradiography experiments (N=20) and in microPET imaging (N=20). Animals were pre-treated 30 minutes before the injection of [18F]UCB-H with a dose IP either of vehicle, Keppra (SV2A ligand), UCB068 (SV2B ligand) or UCB054 (SV2C ligand). Ex-vivo autoradiography was carried out 5 minutes after radiotracer injection while mPET images were acquiring with a dynamic scanner of 1 hour. Data were expressed in Standard Uptake Value and then, the area under the curve was calculated for the total process. Results: In ex-vivo autoradiography, ANOVA of two-ways showed statistical significant differences in brain uptake of [18F]UCB-H among the groups pretreated with Keppra or the ligand for SV2B and the control group. Regarding mPET data, statistical significant differences were found between the group injected with keppra and the rest of groups. Conclusion: Even if a considerable affinity between the ligands UCB068 and UCB054, and the receptor for the isoform SV2A exists, it is only detected during the first 5 minutes (ex-vivo technique), being certainly due to a nonspecific binding. This binding is not strong enough to show a direct competition with the radiotracer during a mPET acquisition. These results allow us to conclude that [18F]UCB-H is a suitable radiotracer for the imaging of the isoform SV2A in vivo, allowing us the clinical study about the molecular base of a disease with a high population impact, like the epilepsy. [less ▲]

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See detailStudy of the SV2A protein role in Epilepsy.
Bartholomé, Odile ULiege; Van Den Ackerveken, Priscilla ULiege; Wislet, Sabine ULiege et al

Poster (2016, October)

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

Poster (2016, March 09)

Introduction Epilepsy is one of the commonest neurological disorders [1]. Antiepileptic drugs mainly target the SV2A protein [2] but its actual role is still largely unknown. [18F]UCB-H was developed to ... [more ▼]

Introduction Epilepsy is one of the commonest neurological disorders [1]. Antiepileptic drugs mainly target the SV2A protein [2] but its actual role is still largely unknown. [18F]UCB-H was developed to study in vivo SV2A brain proteins [3, 4]. The present pilot study was undertaken to evaluate for the first time in vivo in rats SV2A expression in the Kaïnic Acid (KA) epilepsy model [5]. Although this model is well studied in mice, few reports were devoted to rats. Imaging-wise, rats are very interesting thanks to a bigger brain size (reduction of the partial volume effect). Methods Three male Sprague-Dawley were used, one injected with saline and two with multiple KA injections (3 x 5mg/kg) [6]. 75 days later, when spontaneous seizures started to appear, microPET (Focus 120 ) was performed under isoflurane anesthesia (2.5-3 % in air) for 1 hour with [18F]UCB-H (41 ± 5 MBq IV tail vein) followed by MRI (9.4T Agilent, anatomical T2). Coregistration was done with PMOD 3.6 software. Data were expressed as SUV and areas under the curve were calculated for the different regions. Results [18F]UCB-H microPET images showed an important reduction (20-30%) for SV2A after KA injections mainly localized in amygdala, hippocampus, lateral parietal association cortex and cingulate cortex. The rest of the brain was globally unchanged. MRI revealed atrophy and inflammation in amygdala and hippocampus. Conclusions These preliminary results obtained in KA treated rats showed that [18F]UCB-H was able to detect important modifications for SV2A in relevant regions for epilepsy and appears as a valuable tool to follow in vivo SV2A through longitudinal studies. KA model in rats deserves for further development and validation as a tool for the study of epilepsy. [less ▲]

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See detailIn vivo evaluation of [18F]UCB-H binding at SV2A protein, through a new and efficient radiosynthesis of [18F]UCB-H.
Becker, Guillaume ULiege; Warnier, C; Serrano Navacerrada, Maria Elisa ULiege et al

Poster (2016, March 08)

Background: [18F]UCB-H is a validated radiotracer with a high affinity for the synaptic vesicle glycoprotein 2A (SV2A), known as the binding site of the antiepileptic drug levetiracetam [1, 2]. The major ... [more ▼]

Background: [18F]UCB-H is a validated radiotracer with a high affinity for the synaptic vesicle glycoprotein 2A (SV2A), known as the binding site of the antiepileptic drug levetiracetam [1, 2]. The major drawback of [18F]UCB-H was a long, multi-step radiosynthesis with limited yield of radiotracer [3]. We provide here in vivo evaluation of a new efficient single-step radiosynthesis of [18F]UCB-H, that allows us to highlight the role of the enantio-selectivity while targeting SV2A. Then, we synthetized and radiolabeled the major metabolite, namely [18F]UCB-H-N-oxyde, and investigated its impact on rat brain PET images. Methods: [18F]UCB-H was produced with a simple, one-step production strategy which consisted in radiolabeling an enantiomerically pure (S- or R-) N-heteroaryliodonium precursor [4]. 5 Sprague-Dawley (SD) rats underwent 1 dynamic PET scan (60 minutes) with each enantiomer and a third one with the racemic mixture. We used a population-based input function (PBIF) to quantify [18F]UCB-H binding with Logan graphical analysis. [18F]UCB-H-N-oxyde was produced by a direct oxidation with a large excess of pure m-CPBA in Et2O. 5 SD rats underwent 1 dynamic PET scan (60 minutes) with this radiosynthetic [18F]UCB-H-N-oxyde. Results: The radiosynthesis lasted 60 min and afforded a 34 ± 2% radiochemical yield, non-corrected for decay, with a high specific activity (820 ± 180 GBq/µmol). Time activity curves showed higher values for the [18F]UCB-H compared to both the S-[18F]UCB-H and the racemic. Distribution volume (Vt) of the [18F]UCB-H, measured with the PBIF were consistent with previous study [2]. Analysis of [18F]UCB-H-N-oxyde PET images confirmed the absence of Blood-Brain-Barrier crossing. Conclusions: This new [18F]UCB-H radiosynthesis allows us to reach high specific activities. In vivo results are consistent with previous work and emphasize the need of high enantiomeric purity to reach accurate quantitative values of radiotracer binding. The use of a PBIF to quantify [18F]UCB-H binding in the rat brain is reliable and afford longitudinal study. At the end, our study demonstrated that [18F]UCB-H fulfils an important criterion for PET radiopharmaceuticals with the lack of troublesome brain radiometabolites. [less ▲]

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See detailDevelopment and validation of a new mouse model to investigate the role of sv2a in epilepsy
MENTEN, Catherine ULiege; Serrano Navacerrada, Maria Elisa ULiege; Bartholomé, Odile ULiege et al

in PLoS ONE (2016)

SV2A is a glycoprotein present in the membranes of most synaptic vesicles. Although it has been highly conserved throughout evolution, its physiological role remains largely unknown. Nevertheless ... [more ▼]

SV2A is a glycoprotein present in the membranes of most synaptic vesicles. Although it has been highly conserved throughout evolution, its physiological role remains largely unknown. Nevertheless, Levetiracetam, a very effective anti-epileptic drug, has been recently demonstrated to bind to SV2A. At present, our understanding of the normal function of SV2A and its possible involvement in diseases like epilepsy is limited. With this study, we sought to develop a relevant model enabling analysis of SV2A's role in the occurrence or progression of epilepsy. For this purpose, we generated a floxed SV2A mouse model with conditional alleles carrying LoxP sites around exon 3 by means of a gene-targeting strategy. The SV2A lox/lox mouse line is indistinguishable from wild-type mice. When the recombination was observed in all cells, a model of mice with both SV2A alleles floxed around exon 3 recapitulated the phenotype of SV2A KO mice, including seizures. However, the specific invalidation of SV2A in the CA3 hippocampal region was not followed by epileptic seizures or decrease in the epileptic threshold on pentylenetetrazol (PTZ) test. These results demonstrate that the floxed SV2A mouse line has been successfully established. This transgenic mouse model will be useful for investigating SV2A functions related to cell types and developmental stages. [less ▲]

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