[en] 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.
Research Center/Unit :
GIGA CRC (Cyclotron Research Center) In vivo Imaging-Aging & Memory - ULiège
Finnema, S.J., Nabulsi, N.B., Eid, T., Detyniecki, K., Lin, S.-F., Chen, M.-K., Dhaher, R., Holden, D., Imaging synaptic density in the living human brain (2016) Sci. Transl. Med., 8, p. 348ra96
Mercier, J., Provins, L., Valade, A., Discovery and development of SV2A PET tracers: Potential for imaging synaptic density and clinical applications (2017) Drug Discov. Today Technol., 25, pp. 45-52
Custer, K.L., Austin, N.S., Sullivan, J.M., Bajjalieh, S.M., Synaptic vesicle protein 2 enhances release probability at quiescent synapses (2006) J. Neurosci., 26, pp. 1303-1313
Van Vliet, E.A., Aronica, E., Redeker, S., Boer, K., Gorter, J.A., Decreased expression of synaptic vesicle protein 2A, the binding site for levetiracetam, during epileptogenesis and chronic epilepsy (2009) Epilepsia, 50, pp. 422-433
Bartholome, O., Van Den Ackerveken, P., Sánchez Gil, J., De La Brassinne Bonardeaux, O., Leprince, P., Franzen, R., Rogister, B., Puzzling out synaptic vesicle 2 family members functions (2017) Front. Mol. Neurosci., 10, p. 148
Crèvecoeur, J., Foerch, P., Doupagne, M., Thielen, C., Vandenplas, C., Moonen, G., Deprez, M., Rogister, B., Expression of SV2 isoforms during rodent brain development (2013) BMC Neurosci., 14, p. 87
Bajjalieh, S.M., Frantz, G.D., Weimann, J.M., McConnell, S.K., Scheller, R.H., Differential expression of synaptic vesicle protein 2 (SV2) isoforms (1994) J. Neurosci., 14, pp. 5223-5235
Janz, R., Südhof, T.C., SV2C is A synaptic vesicle protein with an unusually restricted localization: Anatomy of A synaptic vesicle protein family (1999) Neuroscience, 94, pp. 1279-1290
Bajjalieh, S.M., Peterson, K., Linial, M., Scheller, R.H., Brain contains two forms of synaptic vesicle protein 2 (1993) Proc. Natl. Acad. Sci. USA, 90, pp. 2150-2154
Stahl, S.M., Psychopharmacology of anticonvulsants: Levetiracetam as A synaptic vesicle protein modulator (2004) J. Clin. Psychiatry, 65, pp. 1162-1163
Matagne, A., Margineanu, D.-G., Kenda, B., Michel, P., Klitgaard, H., Anti-convulsive and anti-epileptic properties of brivaracetam (ucb 34714), A high-afinity ligand for the synaptic vesicle protein, SV2A (2008) Br. J. Pharmacol., 154, pp. 1662-1671
Kaminski, R.M., Gillard, M., Leclercq, K., Hanon, E., Lorent, G., Dassesse, D., Matagne, A., Klitgaard, H., Proepileptic phenotype of SV2A-deficient mice is associated with reduced anticonvulsant efficacy of levetiracetam (2009) Epilepsia, 50, pp. 1729-1740
Lynch, B.A., Lambeng, N., Nocka, K., Kensel-Hammes, P., Bajjalieh, S.M., Matagne, A., Fuks, B., The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam (2004) Proc. Natl. Acad. Sci. USA, 101, pp. 9861-9866
Bretin, F., Bahri, M.A., Bernard, C., Warnock, G., Aerts, J., Mestdagh, N., Buchanan, T., Mievis, F., Biodistribution and Radiation Dosimetry for the Novel SV2A Radiotracer [18F]UCB-H: First-in-Human Study (2015) Mol. Imaging Biol., 17, pp. 557-564
Bretin, F., Warnock, G., Bahri, M.A., Aerts, J., Mestdagh, N., Buchanan, T., Valade, A., Lemaire, C., Preclinical radiation dosimetry for the novel SV2A radiotracer [18F]UCB-H (2013) EJNMMI Res., 3, p. 35
Warnier, C., Lemaire, C., Becker, G., Zaragoza, G., Giacomelli, F., Aerts, J., Otabashi, M., Plenevaux, A., Enabling efficient Positron Emission Tomography (PET) Imaging of Synaptic Vesicle Glycoprotein 2A (SV2A) with A Robust and One-Step Radiosynthesis of A Highly Potent 18F-Labeled Ligand ([18F]UCB-H) (2016) J. Med. Chem., 59, pp. 8955-8966
Nabulsi, N.B., Mercier, J., Holden, D., Carre, S., Najafzadeh, S., Vandergeten, M.-C., Lin, S.-F., Wood, M., Synthesis and Preclinical Evaluation of 11C-UCB-J as A PET Tracer for Imaging the Synaptic Vesicle Glycoprotein 2A in the Brain (2016) J. Nucl. Med., 57, pp. 777-784
Cai, H., Mangner, T.J., Muzik, O., Wang, M.-W., Chugani, D.C., Chugani, H.T., Radiosynthesis of 11C-levetiracetam: A potential marker for PET imaging of SV2A expression (2014) ACS Med. Chem. Lett., 5, pp. 1152-1155
Estrada, S., Lubberink, M., Thibblin, A., Sprycha, M., Buchanan, T., Mestdagh, N., Kenda, B., Gillard, M., [11C]UCB-A, A novel PET tracer for synaptic vesicle protein 2 A (2016) Nucl. Med. Biol., 43, pp. 325-332
Heurling, K., Ashton, N.J., Leuzy, A., Zimmer, E.R., Blennow, K., Zetterberg, H., Eriksson, J., Schöll, M., Synaptic vesicle protein 2A as A potential biomarker in synaptopathies (2019) Mol. Cell. Neurosci.
Rabiner, E.A., Imaging Synaptic Density: A different Look at Neurologic Diseases (2018) J. Nucl. Med., 59, pp. 380-381
Cai, Z., Li, S., Matuskey, D., Nabulsi, N., Huang, Y., PET imaging of synaptic density: A new tool for investigation of neuropsychiatric diseases (2019) Neurosci. Lett., 691, pp. 44-50
Li, S., Cai, Z., Wu, X., Holden, D., Pracitto, R., Kapinos, M., Gao, H., Carson, R.E., Synthesis and in Vivo Evaluation of A Novel PET Radiotracer for Imaging of Synaptic Vesicle Glycoprotein 2A (SV2A) in Nonhuman Primates (2019) ACS Chem. Neurosci., 10, pp. 1544-1554
Bahri, M.A., Plenevaux, A., Aerts, J., Bastin, C., Becker, G., Mercier, J., Valade, A., Ledoux, D., Measuring brain synaptic vesicle protein 2A with positron emission tomography and [18F]UCB-H (2017) Alzheimer's Dement., 3, pp. 481-486
Serrano, M.E., Bahri, M.A., Becker, G., Seret, A., Mievis, F., Giacomelli, F., Lemaire, C., Plenevaux, A., Quantification of [18F]UCB-H Binding in the Rat Brain: FromKinetic Modelling to Standardised Uptake Value (2018) Mol. Imaging Biol.
Hanaya, R., Hosoyama, H., Sugata, S., Tokudome, M., Hirano, H., Tokimura, H., Kurisu, K., Arita, K., Low distribution of synaptic vesicle protein 2A and synaptotagimin-1 in the cerebral cortex and hippocampus of spontaneously epileptic rats exhibiting both tonic convulsion and absence seizure (2012) Neuroscience, 221, pp. 12-20
Clegg, N., Ferguson, C., True, L.D., Arnold, H., Moorman, A., Quinn, J.E., Vessella, R.L., Nelson, P.S., Molecular characterization of prostatic small-cell neuroendocrine carcinoma (2003) Prostate, 55, pp. 55-64
Dardou, D., Monlezun, S., Foerch, P., Courade, J.P., Cuvelier, L., De Ryck, M., Schifimann, S.N., A role for Sv2c in basal ganglia functions (2013) Brain Res., 1507, pp. 61-73
Altmann, V., Schumacher-Schuh, A.F., Rieck, M., Callegari-Jacques, S.M., Rieder, C.R., Hutz, M.H., Influence of genetic, biological and pharmacological factors on levodopa dose in Parkinson's disease (2016) Pharmacogenomics, 17, pp. 481-488
Dunn, A.R., Stout, K.A., Ozawa, M., Lohr, K.M., Hoffman, C.A., Bernstein, A.I., Li, Y., Sastry, N., Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson disease (2017) Proc. Natl. Acad. Sci. USA, 114, pp. E2253-E2262
Karp, J.S., Daube-Witherspoon, M.E., Muehllehner, G., Factors affecting accuracy and precision in PET volume imaging (1991) J. Cereb. Blood Flow Metab., 11, pp. A38-A44
Aston, J.A.D., Cunningham, V.J., Asselin, M.-C., Hammers, A., Evans, A.C., Gunn, R.N., Positron emission tomography partial volume correction: Estimation and algorithms (2002) J. Cereb. Blood Flow Metab., 22, pp. 1019-1034
Dardou, D., Dassesse, D., Cuvelier, L., Deprez, T., De Ryck, M., Schifimann, S.N., Distribution of SV2C mRNA and protein expression in the mouse brain with A particular emphasis on the basal ganglia system (2011) Brain Res., 1367, pp. 130-145
Becker, G., Warnier, C., Serrano, M.E., Bahri, M.A., Mercier, J., Lemaire, C., Salmon, E., Plenevaux, A., Pharmacokinetic Characterization of [18F]UCB-H PET Radiopharmaceutical in the Rat Brain (2017) Mol. Pharm., 14, pp. 2719-2725
Warnock, G.I., Aerts, J., Bahri, M.A., Bretin, F., Lemaire, C., Giacomelli, F., Mievis, F., Valade, A., Evaluation of 18F-UCB-H as A novel PET tracer for synaptic vesicle protein 2A in the brain (2014) J. Nucl. Med., 55, pp. 1336-1341
