Vesicles in presynaptic neuron terminals secrete neurotransmitters by fusing with the presynaptic membrane. One essential vesicle membrane protein is the synaptic vesicle glycoprotein 2 (SV2), with one of its isoforms, SV2A, ubiquitously expressed in virtually all synapses. Clinical and experimental data have suggested that SV2A is involved in epilepsy with decreased SV2A receptor density found in the epileptogenic zone. Animal models of epilepsy suggest that loss of SV2A could contribute to epileptogenesis and pharmacoresistance. Furthermore, SV2A has been found to be the site of action of the anticonvulsant Levetiracetam (LEV). We recently developed 11C-UCB-J as a promising radioligand for quantitative measurement of SV2A with positron emission tomography (PET). In our pilot first-in-human SV2A PET studies in healthy subjects, we found that 11C-UCB-J has the potential to be an excellent PET tracer for quantitative imaging of SV2A in the human brain. In addition, this tracer has the potential to be a general-purpose tool for measuring synaptic vesicle density. We propose to fully develop and validate 11C-UCB-J for human use and perform an initial clinical study in epilepsy. In the first aim, we will quantify SV2A using bolus/infusion delivery on the High Resolution Research Tomography (HRRT) and perform paired test/retest scans in one day in young healthy controls. In a separate cohort, we will determine the magnitude of specific binding in young healthy controls by paired studies at baseline and following IV administration of LEV. Data from these experiments will define the optimal scanning protocol and the most appropriate quantitative method. In the second aim, we will assess age effects on SV2A by assessing specific and nonspecific binding of 11C-UCB-J. MR-based partial volume correction will be performed to eliminate any artifactual effects of cortical atrophy. Such results will be important to interpret any disease-related changes, e.g., due to neurodegeneration, as a function of age.
The third aim i s to assess SV2A density in epilepsy patients with medically refractory focal epilepsies who are candidates for surgical resection. We will compare 11C-UCB-J binding in these patients to age- and sex-matched healthy controls and assess whether SV2A density is decreased at the site of origin of seizures. We will validate these results with measurements of SV2A expression in surgically removed tissue samples. 11C-UCB-J binding will also be compared to that of 18F-FDG in the same patients, to evaluate if 11C-UCB-J is more diagnostically useful than FDG for seizure focus determination.

Public Health Relevance

Patients with a variety of brain disorders, including epilepsy and Alzheimer's disease, lose nerve cells and synapses; however, there is no accurate method to measure neuronal density in the living human brain. We have developed a new PET imaging agent, which binds to a protein in the vesicles of presynaptic terminal, and scans using this tracer have the potential to be an imaging marker of synaptic density. This study will validate the use of this new PET imaging agent in young and old healthy controls, and then compare the images to those of patients with epilepsy who are candidates for surgery, in order to see if the new scans are better able to define the source location of their seizures in the brain.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Molecular Imaging and Probe Development (CMIP)
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Stewart, Randall R
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Yale University
Schools of Medicine
New Haven
United States
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