PET imaging of synaptic vesicle protein 2A

Abstract

The synaptic vesicle protein 2A (SV2A) is an integral 12-transmembrane domain glycoprotein located in the membrane of synaptic vesicles and widely distributed throughout the brain. In 2004, SV2A was shown to be the molecular target of the antiepileptic drug levetiracetam. High-affinity SV2A ligands have been described by the pharmaceutical company UCB more recently, and this enabled the rapid development of SV2A positron emission tomography (PET) radioligands. Because synaptic vesicle proteins, such as SV2A, have previously been used as biomarkers of synaptic density, PET imaging of SV2A may have broad utility across neuropathological diseases. In this chapter we review the current status of SV2A PET imaging. During the last few years, several SV2A radioligands have been synthesized and evaluated with PET in animals and human. Although [11C]levetiracetam was deemed an unsuitable radioligand, radiolabeled non-acetamide racetams (a class of drugs that contain the pyrrolidone moiety) such as [11C]UCB-J and more recently [18F]SynVesT-1 and [18F]SynVesT-2 provided high-quality brain PET imaging results across species. Regional brain SV2A levels were shown to closely correlate with those of synaptophysin, another commonly used marker for synaptic density. PET studies using SV2A-targeting antiepileptic drugs levetiracetam and brivaracetam confirmed that the radioligands bind specifically to SV2A and provided valuable insight in to the potential use of a reference region approach for quantification of brain PET signal. Several initial PET studies examining SV2A radioligand binding in patient groups have been reported, and SV2A was found to be reduced in disease-associated brain regions in epilepsy, Alzheimer's disease, major depressive disorder and posttraumatic stress disorder, Parkinson's disease, and schizophrenia. In conclusion, PET imaging of SV2A has rapidly developed, and qualified radioligands are now available. Initial PET studies in humans indicate that SV2A loss might be specific to disease-associated brain regions and consistent with synaptic density loss. Future studies warrant the use of fluorine-18 labeled radioligands in larger patient cohorts to establish the clinical value of SV2A PET imaging and its potential for diagnosis and progression monitoring of neuropathological diseases, as well as efficacy assessment of disease-modifying therapies.