CHARACTERIZATION OF A NOVEL RADIOTRACER TARGETING SYNAPTIC VESICLE PROTEIN 2A (SV2A)

Poster (2012, September)

Synaptic vesicle protein 2A (SV2A) has been identified as the binding site of the antiepileptic levetiracetam (Keppra) [1]. SV2 proteins are critical for proper nervous system function and have been ... [more ▼]

Synaptic vesicle protein 2A (SV2A) has been identified as the binding site of the antiepileptic levetiracetam (Keppra) [1]. SV2 proteins are critical for proper nervous system function and have been demonstrated to be involved in vesicle trafficking. Their implication in epilepsy makes them an interesting therapeutic target, and the widespread distribution of SV2A in particular may provide an opportunity to develop a PET-based measure of neuronal function in brain diseases. [18F]UCB-H is a fluorine-18 radiolabelled PET imaging agent with a nanomolar affinity for the human SV2A protein. Preclinical PET studies in rodents were carried out using male SD rats, imaged under isoflurane anaesthesia in a Siemens Concorde Focus 120 microPET scanner. Arterial input function was measured using an arteriovenous shunt method and beta microprobe system. [18F]UCB-H was injected IV (3.8 ± 0.54 mCi bolus, specific activity 8.5 ± 0.86 Ci/Emol immediately after synthesis) and dynamic PET data acquired in list mode for 90 min. Images were reconstructed using filtered back projection with correction for all physical effects except scatter. These scans revealed high uptake of [18F]UCB-H in brain and spinal cord, matching the expected homogeneous distribution of SV2A in the rodent brain [2]. Notably, the kinetics of [18F]UCB-H uptake in the brain were fast, peaking at up to 30 % ID/cm3 before a rapid decline. Metabolism of [18F]UCB-H in vivo followed a typical pattern of rapid initial metabolism followed by a reducing rate of metabolism over time, with less than 20% of the activity in plasma attributable to the parent compound after 30 minutes, and was highly reproducible between subjects. One major metabolite was identified. The uptake of [18F]UCB-H in the brain over time was well fitted by a classical 1-tissue compartment model. Mean parameter estimates (mean ± SD, n=7, whole brain VOI) were K1: 3.58 ± 0.65 ml/cm3/min, k2: 0.21 ± 0.03 min-1, Vt: 17.21 ± 2.52 ml/cm3. Uptake of [18F]UCB-H was blocked by pretreatment with brivaracetam (21 mg/kg IV, 10 min prior to [18F]UCB-H), a recently described high affinity SV2A ligand with a 20-fold higher affinity for SV2A than levetiracetam [3]. In contrast, pretreatment with ucb-100230-1, a diastereoisomer of brivaracetam with 3200-fold lower affinity for SV2A [3], had no clear effect of the brain uptake of [18F]UCB-H. Our results indicate that [18F]UCB-H is a suitable radiotracer for the quantification of SV2A proteins in vivo and for estimating target occupancy of drugs targeting SV2A. This is the first PET tracer for in vivo quantification of SV2A. The necessary steps for implementation of [18F]UCB-H production under GMP conditions have been completed and first in human studies are planned. References [1] Lynch, B.A. et al. (2004) PNAS 101(26):9861-6. [2] Janz, R. & Sudhof, T.C. (1999) Neuroscience 94(4):1279-1290.[3] Gillard, M. et al. (2011) Eur J Pharmacol 664:36-44. [less ▲]

Use of a beta microprobe system to measure arterial input function in PET via an arteriovenous shunt in rats

in European Journal of Nuclear Medicine and Molecular Imaging Research (2011), 1

Kinetic modeling of physiological function using imaging techniques requires the accurate measurement of the time-activity curve of the tracer in plasma, known as the arterial input function (IF). The ... [more ▼]

Kinetic modeling of physiological function using imaging techniques requires the accurate measurement of the time-activity curve of the tracer in plasma, known as the arterial input function (IF). The measurement of IF can be achieved through manual blood sampling, the use of small counting systems such as beta microprobes, or by derivation from PET images. Previous studies using beta microprobe systems to continuously measure IF have suffered from high background counts. In the present study, a light-insensitive beta microprobe with a temporal resolution of up to 1 s was used in combination with a pump-driven femoral arteriovenous shunt to measure IF in rats. The shunt apparatus was designed such that the placement of the beta microprobe was highly reproducible. The probe-derived IF was compared to that obtained from manual sampling at 5-s intervals and IF derived from a left ventricle VOI in a dynamic PET image of the heart. Probe-derived IFs were very well matched to that obtained by "gold standard" manual blood sampling, but with an increased temporal resolution of up to 1 s. The area under the curve (AUC) ratio between probe- and manually derived IFs was 1.07 ± 0.05 with a coefficient of variation of 0.04. However, image-derived IFs were significantly underestimated compared to the manually sampled IFs, with an AUC ratio of 0.76 ± 0.24 with a coefficient of variation of 0.32. IF derived from the beta microprobe accurately represented the IF as measured by blood sampling, was reproducible, and was more accurate than an image-derived technique. The use of the shunt removed problems of tissue-background activity, and the use of a light-tight probe with minimal gamma sensitivity refined the system. The probe/shunt apparatus can be used in both microprobe and PET studies. [less ▲]

Synthesis and hydrolytic stability of novel 3-[18F]fluoroethoxybis(1-methylethyl)silyl]propanaminebased prosthetic groups

Poster (2011)

Synthesis and hydrolytic stability of novel 3-[18F]fluoroethoxybis(1-methylethyl)silyl]propanamine-based prosthetic groups

in Journal of Fluorine Chemistry (2011), 132(4), 250-257

Two new silicon-based prosthetic groups, derived from 3-[ethoxybis(1-methylethyl)silyl]propanamine, have been prepd. in good yields. These silicon groups bearing an acid or an azide group were coupled to ... [more ▼]

Two new silicon-based prosthetic groups, derived from 3-[ethoxybis(1-methylethyl)silyl]propanamine, have been prepd. in good yields. These silicon groups bearing an acid or an azide group were coupled to a model tripeptide (Leu-Gly- Gly) either through a classical amide bond formation or through "click chem." via the Huisgen cycloaddn. The radiolabeling with fluorine-18 by substitution of the ethoxy group at silicon has been carried out with success in 51-54% decay cor. radiochem. yields. Radiolabeled peptides were easily prepd. by direct 18F-fluorination of the silicon-bearing tripeptide or by coupling the peptide with a radiolabeled silicon-based prosthetic group. Their stabilities in physiol. medium were studied and proved poor. [less ▲]

Controlled Memory Processes in Questionable Alzheimer's Disease: A View from Neuroimaging Research

in Journal of Alzheimer's Disease [=JAD] (2010), 20(2), 547-560

Alzheimer's disease (AD) is characterized by a progressive loss of controlled cognitive processes, and neuroimaging studies at early stages of AD provide an opportunity to tease out the neural correlates ... [more ▼]

Alzheimer's disease (AD) is characterized by a progressive loss of controlled cognitive processes, and neuroimaging studies at early stages of AD provide an opportunity to tease out the neural correlates of controlled processes. Accordingly, controlled and automatic memory performance was assessed with the Process Dissociation Procedure in 50 patients diagnosed with questionable Alzheimer's disease (QAD). The patients' brain glucose metabolism was measured using FDG-PET. After a follow-up period of 36 months, 27 patients had converted to AD, while 23 remained stable. Both groups showed a similar decrease in controlled memory processes but preserved automatic processes at entry into the study. Voxel-based cognitive and metabolic correlations showed that a decrease in controlled memory processes was preferentially correlated with lower activity in the dorsomedial prefrontal and posterior cingulate cortices in very early AD patients. In stable QAD patients, reduced controlled performance in verbal memory correlated with impaired activity in the left anterior hippocampal structure. The results demonstrated the central role of a medial frontal-posterior cingulate network for controlled processing of episodic memory in the early stages of AD. [less ▲]

Fast production of highly concentrated reactive [18F] fluoride for aliphatic and aromatic nucleophilic radiolabelling

in Tetrahedron Letters (2010), 51

The use of a polymeric solid support loaded with a long alkyl chain quaternary ammonium allows the rapid and efficient recovery of cyclotron produced [18F]F- from [18O]water to a low water content organic ... [more ▼]

The use of a polymeric solid support loaded with a long alkyl chain quaternary ammonium allows the rapid and efficient recovery of cyclotron produced [18F]F- from [18O]water to a low water content organic solution compatible with fast nucleophilic labelling of most precursors for PET radiopharmaceuticals in high yield. [less ▲]

Modified Non-Ionic Solid Supports: a Way to High Activity Fluorine-18 Radiochemistry in Microfluidic Devices

in Journal of Labelled Compounds & Radiopharmaceuticals (2009, July), 52(S1), 12

New Improvements in the Enantioselective Synthesis of 2-[18F]Fluoro-L-Tyrosine and 6-[18F]Fluoro-L-Dopa

in Journal of Labelled Compounds & Radiopharmaceuticals (2009, July), 52(S1), 196

Use of Organic Bases for 18F-Fluoride Anion Exchange Elution avoiding the Classical Azeotropic drying Step Before Labeling

in Journal of Labelled Compounds & Radiopharmaceuticals (2009, July), 52(S1), 198

Combiner les mesures métaboliques cérébrales et neuropsychologiques permet une meilleure prédiction de la conversion vers une maladie d’Alzheimer chez les patients MCI

in Revue Neurologique (2009), 165

Introduction. Une voie de recherche neurologique importante concerne la capacité de prédire sur base de l’évaluation initiale des patients avec Mild Cognitive Impairment (MCI) ceux qui vont développer une ... [more ▼]

Introduction. Une voie de recherche neurologique importante concerne la capacité de prédire sur base de l’évaluation initiale des patients avec Mild Cognitive Impairment (MCI) ceux qui vont développer une maladie d’Alzheimer (MA). Parmi les tests neuropsychologiques, le rappel indicé avec indiçage congruent lors de l’encodage et du rappel (RI48) apparaît comme le meilleur prédicteur du devenir des patients MCI (Ivanoiu et al., 2005). D’autre part, on a montré que les mesures métaboliques cérébrales (TEP-FDG), plus particulièrement l’hypométabolisme du cortex temporopariétal, prédit le déclin cognitif global dans le MCI mieux que des mesures neuropsychologiques (Chételat et al., 2005). Le but de notre étude était d’évaluer le pouvoir de prédiction pour la conversion du MCI vers une MA de deux prédicteurs robustes (performance au RI48 et métabolisme cérébral) pris soit isolément soit ensemble. Méthode. 50 patients MCI ont subi un examen en TEP-FDG au repos et ont réalisé le test de rappel indicé RI48 et le MMSE. Au terme d’un suivi neuropsychologique de 36 mois, 28 patients ont évolué vers une MA et 22 sont restés stables. Le métabolisme cérébral et les performances cognitives ont été comparés entre « convertisseurs » et MCI-stables. Des analyses discriminantes ont ensuite permis d’évaluer la capacité de classification de l’âge, du MMSE et des mesures métaboliques et mnésiques considérés individuellement ou selon diverses combinaisons. Résultat. Par comparaison avec les MCI-stables, les « convertisseurs » montraient un hypométabolisme du cortex temporal moyen bilatéralement, du cortex pariétal inférieur droit et du précuneus droit, et de plus faibles performances initiales au RI48. Prises individuellement, les différentes mesures permettaient le même taux de classification correcte (métabolisme cérébral = 76%, RI48 = 76%). L’âge et le MMSE étaient de faibles prédicteurs (exactitude de classification = 62% et 66% respectivement). Par contre, la combinaison des mesures métaboliques et des scores au RI48 prédisaient le mieux la progression vers la MA (88%). Conclusion. Les résultats suggèrent que la stratégie optimale pour identifier quels patients MCI ont plus de risque de développer une MA est de combiner les mesures métaboliques cérébrales et la performance à un test de mémoire très sensible. [less ▲]