PET technology has produced many
radiopharmaceuticals that target specific brain
proteins and other measures of brain function. Recently, a new approach has emerged to image synaptic density by targeting the synaptic vesicle
protein 2A (SV2A), an integral
glycoprotein in the membrane of synaptic vesicles and widely distributed throughout the brain. Multiple SV2A
ligands have been developed and translated to human use. The most successful of these to date is
11C-UCB-J, because of its high uptake, moderate metabolism, and effective quantification with a 1-tissue-compartment model. Further, since SV2A is the target of the
antiepileptic drug levetiracetam, human blocking studies have characterized specific binding and potential reference regions. Regional brain SV2A levels were shown to correlate with those of
synaptophysin, another commonly used marker of synaptic density, providing the basis for SV2A PET imaging to have broad utility across neuropathologic diseases. In this review, we highlight the development of SV2A tracers and the evaluation of quantification methods, including compartment modeling and simple tissue ratios. Mouse and rat models of
neurodegenerative diseases have been studied with small-animal PET, providing validation by comparison to direct tissue measures. Next, we review human PET imaging results in multiple
neurodegenerative disorders. Studies on
Parkinson disease and
Alzheimer disease have progressed most rapidly at multiple centers, with generally consistent results of patterns of SV2A or synaptic loss. In
Alzheimer disease, the synaptic loss patterns differ from those of
amyloid, tau, and
18F-FDG, although intertracer and interregional correlations have been found. Smaller studies have been reported in other disorders, including
Lewy body dementia,
frontotemporal dementia,
Huntington disease,
progressive supranuclear palsy, and
corticobasal degeneration. In conclusion, PET imaging of SV2A has rapidly developed, and qualified radioligands are available. PET studies on humans indicate that SV2A loss might be specific to disease-associated brain regions and consistent with synaptic density loss. The recent availability of new 18F tracers, 18F-SynVesT-1 and 18F-SynVesT-2, will substantially broaden the application of SV2A PET. Future studies are needed in larger patient cohorts to establish the clinical value of SV2A PET and its potential for diagnosis and progression monitoring of
neurodegenerative diseases, as well as efficacy assessment of disease-modifying
therapies.