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

in Molecular Pharmaceutics (in press)

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 detailRegiospecific radiolabelling of Nanofitin on Ni Magnetic Beads with [18F]FBEM and in vivo PET studies
Dammicco, Sylvestre ULg; Goux, Marine; Lemaire, Christian ULg et al

in Nuclear Medicine & 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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See detailComparative assessment of 6-[18F]fluoro-L-m-tyrosine and 6-[18F]fluoro-L-dopa to evaluate dopaminergic presynaptic integrity in a Parkinson’s disease rat model.
Becker, Guillaume ULg; Bahri, Mohamed Ali ULg; Michel, Anne et al

in Journal of Neurochemistry (2017), 141

Because of the progressive loss of nigro-striatal dopaminergic terminals in Parkinson’s disease (PD), in vivo quantitative imaging of dopamine (DA) containing neurons in animal models of PD is of critical ... [more ▼]

Because of the progressive loss of nigro-striatal dopaminergic terminals in Parkinson’s disease (PD), in vivo quantitative imaging of dopamine (DA) containing neurons in animal models of PD is of critical importance in the pre-clinical evaluation of highly awaited disease-modifying therapies. Among existing methods, the high sensitivity of positron emission tomography (PET) is attractive to achieve that goal. The aim of this study was to perform a quantitative comparison of brain images obtained in 6-hydroxydopamine (6-OHDA) lesioned rats using two dopaminergic PET radiotracers, namely [18F]fluoro-3,4-dihydroxyphenyl-L-alanine ([18F]FDOPA) and 6-[18F]fluoro-L-m-tyrosine ([18F]FMT). Because the imaging signal is theoretically less contaminated by metabolites, we hypothesized that the latter would show stronger relationship with behavioural and post-mortem measures of striatal dopaminergic deficiency. We used a within-subject design to measure striatal [18F]FMT and [18F]FDOPA uptake in eight partially lesioned, eight fully lesioned and ten sham-treated rats. Animals were pretreated with an L-aromatic amino acid decarboxylase (AADC) inhibitor. A catechol-O-methyl transferase inhibitor was also given before [18F]FDOPA PET. Quantitative estimates of striatal uptake were computed using conventional graphical Patlak method. Striatal dopaminergic deficiencies were measured with apomorphine-induced rotations and post-mortem striatal DA content. We observed a strong relationship between [18F]FMT and [18F]FDOPA estimates of decreased uptake in the denervated striatum using the tissue-derived uptake rate constant Kc. However, only [18F]FMT Kc succeeded to discriminate between the partial and the full 6-OHDA lesion and correlated well with the post-mortem striatal DA content. This study indicates that the [18F]FMT could be more sensitive, with respect of [18F]FDOPA, to investigate DA terminals loss in 6-OHDA rats, and open the way to in vivo AADC activity targeting in future investigations on progressive PD models. [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 ULg; Becker, Guillaume ULg; Bahri, Mohamed Ali ULg 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 ULg; Bartholomé, Odile ULg; Van Den Ackerveken, Priscilla ULg 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 ULg; Becker, Guillaume ULg; Bahri, Mohamed Ali ULg 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 ULg; Becker, Guillaume ULg; Bahri, Mohamed Ali ULg 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 ULg; Becker, Guillaume ULg; Bahri, Mohamed Ali ULg 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 detailStudy Protocol: Effect of prenatal wheel-running exercise (before and during gestation) on cocaine psychomotor sensitization expressed in the offspring in periadolescent females and males C57BL/6J mice
Lespine, Louis-Ferdinand ULg; Plenevaux, Alain ULg; Tirelli, Ezio ULg

E-print/Working paper (2017)

The present study principally aims at determining to which extent prenatal exercise (before and during gestation) could affect the initiation (establishment) and the expression of psychomotor ... [more ▼]

The present study principally aims at determining to which extent prenatal exercise (before and during gestation) could affect the initiation (establishment) and the expression of psychomotor sensitization induced by a representative dose of cocaine in young female and male mice. More specifically, we will assess cocaine-induced acute psychomotor-activating effects, psychomotor sensitization developing over 9 daily sessions (daily peritoneal injections of cocaine or saline) and the long-term expression of the sensitized response (30 days after the last sensitizing injection) in C57BL/6J mice born from mothers housed with or without a running wheel before and during gestation. Based on literature and on our prior results, the mice born from exercised mothers are expected to show significantly reduced levels of cocaine responsiveness in comparison with the control mice (born from unexercised mothers). [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 ULg; Aerts, Joël ULg; Bahri, Mohamed Ali ULg 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 detailIn Vivo Preclinical Molecular Imaging: From the Laboratory Bench to the Patient.
Plenevaux, Alain ULg

in Pharmaceuticals (2016, November 18), 9(4), 73

Preclinical molecular imaging plays a key role in the study of diseases and the development, evaluation, andvalidation of novel treatment 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, andvalidation of novel treatment and diagnostic techniques. The actual aim is to facilitate the translation of innovative 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 from the fact that in vivo data are non-invasively collected, 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 GIGA-CRC In vivo Imaging at ULg is a multidisciplinary laboratory which relies on a medical cyclotron for radioisotope productions, a radiochemistry unit for the development of new radiopharmaceuticals and process automation, a GMP unit for radiopharmaceutical productions, a preclinical imaging unit and a clinical imagingplatform (with MRI, PET, EEG, TMS, . . . ). All expertise and qualified staff are present on site. Our laboratory has all necessary permission and approval for radiopharmaceutical productions and human clinical trials. During this presentation, we will take as an example the development of the first SV2A radioligand [18F]UCB-H (a-b) to illustrate how we can bring new ideas from the laboratory bench to the patient (Bretin, F., et al. Eur. J. Nucl. Med. Mol. Imaging Res. 2013, 3, 35; Warnock, G., et al. J. Nucl. Med. 2014, 55, 1336–1341). [less ▲]

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See detailResting-state Network-specific Breakdown of Functional Connectivity during Ketamine Alteration of Consciousness in Volunteers
BONHOMME, Vincent ULg; VANHAUDENHUYSE, Audrey ULg; Demertzi, Athina ULg et al

in Anesthesiology (2016), 125(5), 873-878

Background: Consciousness-altering anesthetic agents disturb connectivity between brain regions composing the resting-state consciousness networks (RSNs). The default mode network (DMn), executive control ... [more ▼]

Background: Consciousness-altering anesthetic agents disturb connectivity between brain regions composing the resting-state consciousness networks (RSNs). The default mode network (DMn), executive control network, salience network (SALn), auditory network, sensorimotor network (SMn), and visual network sustain mentation. Ketamine modifies consciousness differently from other agents, producing psychedelic dreaming and no apparent interaction with the environment. The authors used functional magnetic resonance imaging to explore ketamine-induced changes in RSNs connectivity. Methods: Fourteen healthy volunteers received stepwise intravenous infusions of ketamine up to loss of responsiveness. Because of agitation, data from six subjects were excluded from analysis. RSNs connectivity was compared between absence of ketamine (wake state [W1]), light ketamine sedation, and ketamine-induced unresponsiveness (deep sedation [S2]). Results: Increasing the depth of ketamine sedation from W1 to S2 altered DMn and SALn connectivity and suppressed the anticorrelated activity between DMn and other brain regions. During S2, DMn connectivity, particularly between the medial prefrontal cortex and the remaining network (effect size β [95% CI]: W1 = 0.20 [0.18 to 0.22]; S2 = 0.07 [0.04 to 0.09]), and DMn anticorrelated activity (e.g., right sensory cortex: W1 = −0.07 [−0.09 to −0.04]; S2 = 0.04 [0.01 to 0.06]) were broken down. SALn connectivity was nonuniformly suppressed (e.g., left parietal operculum: W1 = 0.08 [0.06 to 0.09]; S2 = 0.05 [0.02 to 0.07]). Executive control networks, auditory network, SMn, and visual network were minimally affected. Conclusions: Ketamine induces specific changes in connectivity within and between RSNs. Breakdown of frontoparietal DMn connectivity and DMn anticorrelation and sensory and SMn connectivity preservation are common to ketamine and propofol-induced alterations of consciousness. [less ▲]

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See detailEnabling efficient PET imaging of Synaptic Vesicle glycoprotein 2A (SV2A) with a robust and one-step radiosynthesis of a highly potent 18F-labelled ligand ([18F]UCB-H)
Warnier, Corentin ULg; Lemaire, Christian ULg; Becker, Guillaume ULg et al

in Journal of Medicinal Chemistry (2016), 59

We herein describe the straightforward synthesis of a stable pyridyl(4- methoxyphenyl)iodonium salt and its [18F]radiolabelling within a one-step, fully automated and cGMP compliant radiosynthesis of [18F ... [more ▼]

We herein describe the straightforward synthesis of a stable pyridyl(4- methoxyphenyl)iodonium salt and its [18F]radiolabelling within a one-step, fully automated and cGMP compliant radiosynthesis of [18F]UCB-H ([18F]7), a PET tracer for the imaging of Synaptic Vesicle glycoprotein 2A (SV2A). Over the course of one year, 50 automated productions provided 34±2% of injectable [18F]7 from up to 285 GBq (7.7 Ci) of [18F]fluoride in 50 minutes (uncorrected radiochemical yield. Specific Activity = 815±185 GBq/μmol). The successful implementation of our synthetic strategy within routine, high-activity and cGMP productions attests to its practicality and reliability for the production of large doses of [18F]7. In addition to enabling efficient and cost-effective clinical research on a range of neurological pathologies through the imaging of SV2A, this work further demonstrates the real value of iodonium salts for the cGMP 18F-PET tracer manufacturing industry, and their ability to fulfill practical and regulatory requirements in that field. [less ▲]

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See detailBiodistribution of Novel 68Ga-Radiolabelled HER2 Aptamers in Mice
Gijs, Marlies; Becker, Guillaume ULg; Plenevaux, Alain ULg et al

in Journal of Nuclear Medicine and Radiation Therapy (2016), 7(5),

Background: Two novel HER2 aptamers were recently selected with great potential for the in vitro diagnosis of HER2-positive cancer. The goal of this study was to examine the in vivo diagnostic potential ... [more ▼]

Background: Two novel HER2 aptamers were recently selected with great potential for the in vitro diagnosis of HER2-positive cancer. The goal of this study was to examine the in vivo diagnostic potential of these HER2 aptamers. Methods: Both HER2 aptamers were radiolabelled with 68Ga, injected in mice bearing a HER2-positive and HER2-negative tumour and evaluated by PET/MRI. Results: Ex vivo bio distribution analysis revealed high uptake in the blood, tissues and organs, except the brain. Interestingly, this high uptake was explained by the slow blood clearance due to non-specific aptamer binding to blood proteins. We observed accumulation of radioactivity in both tumours in time. Although higher uptake in the HER2-positive tumour compared to the HER2-negative tumour was observed, this was accompanied with more necrosis in the HER2-negative tumour, which was observed by 18FDG PET/CT. Conclusion: This work presents a first step towards the development of 68Ga-labelled aptamers for molecular cancer imaging. [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), 43(6), 379-389

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