Validation, kinetic modeling, and test-retest reproducibility of [18F]SynVesT-1 for PET imaging of synaptic vesicle glycoprotein 2A in mice.

Alterations in synaptic vesicle glycoprotein 2 A (SV2A) have been associated with several neuropsychiatric and neurodegenerative disorders. Therefore, SV2A positron emission tomography (PET) imaging may provide a unique tool to investigate synaptic density dynamics during disease progression and after therapeutic intervention. This study aims to extensively characterize the novel radioligand [18F]SynVesT-1 for preclinical applications. In C57Bl/6J mice (n = 39), we assessed the plasma profile of [18F]SynVesT-1, validated the use of a noninvasive image-derived input function (IDIF) compared to an arterial input function (AIF), performed a blocking study with levetiracetam (50 and 200 mg/kg, i.p.) to verify the specificity towards SV2A, examined kinetic models for volume of distribution (VT) quantification, and explored test-retest reproducibility of [18F]SynVesT-1 in the central nervous system (CNS). Plasma availability of [18F]SynVesT-1 decreased rapidly (13.4 ± 1.5% at 30 min post-injection). VT based on AIF and IDIF showed excellent agreement (r2 = 0.95, p < 0.0001) and could be reliably estimated with a 60-min acquisition. The blocking study resulted in a complete blockade with no suitable reference region. Test-retest analysis indicated good reproducibility (mean absolute variability <10%). In conclusion, [18F]SynVesT-1 is selective for SV2A with optimal kinetics representing a candidate tool to quantify CNS synaptic density non-invasively.

SV2A PET Imaging Is a Noninvasive Marker for the Detection of Spinal Damage in Experimental Models of Spinal Cord Injury.

Traumatic spinal cord injury (SCI) is a neurologic condition characterized by long-term motor and sensory neurologic deficits as a consequence of an external physical impact damaging the spinal cord. Anatomic MRI is considered the gold-standard diagnostic tool to obtain structural information for the prognosis of acute SCI; however, it lacks functional objective information to assess SCI progression and recovery. In this study, we explored the use of synaptic vesicle glycoprotein 2A (SV2A) PET imaging to detect spinal cord lesions noninvasively after SCI. Methods: Mice (n = 7) and rats (n = 8) subjected to unilateral moderate cervical (C5) contusion were euthanized 1 wk after SCI for histologic and autoradiographic (3H-labeled (4R)-1-[(3-methylpyridin-4-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one [UCB-J]) investigation of SV2A levels. Longitudinal 11C-UCB-J PET/CT imaging was performed in sham (n = 7) and SCI rats (n = 8) 1 wk and 6 wk after SCI. Animals also underwent an 18F-FDG PET scan during the latter time point. Postmortem tissue SV2A analysis to corroborate in vivo PET findings was performed 6 wk after SCI. Results: A significant SV2A loss (ranging from -70.3% to -87.3%; P < 0.0001) was measured at the epicenter of the impact in vitro in both mouse and rat contusion SCI models. Longitudinal 11C-UCB-J PET imaging detected SV2A loss in SCI rats (-49.0% ± 8.1% at 1 wk and -52.0% ± 12.9% at 6 wk after SCI), with no change observed in sham rats. In contrast, 18F-FDG PET imaging measured only subtle hypometabolism (-17.6% ± 14.7%). Finally, postmortem 3H-UCB-J autoradiography correlated with the in vivo SV2A PET findings (r = 0.92, P < 0.0001). Conclusion:11C-UCB-J PET/CT imaging is a noninvasive marker for SV2A loss after SCI. Collectively, these findings indicate that SV2A PET may provide an objective measure of SCI and thus represent a valuable tool to evaluate novel therapeutics. Clinical assessment of SCI with SV2A PET imaging is highly recommended.