Abstract
The development of novel PET imaging agents for synaptic vesicle glycoprotein 2A (SV2A) allowed for the in vivo detection of synaptic density changes, which are correlated with the progression and severity of a variety of neuropsychiatric diseases. While multiple ongoing clinical investigations using SV2A PET are expanding its applications rapidly, preclinical SV2A PET imaging in animal models is an integral component of the translation research and provides supporting and complementary information. Herein, we overview preclinical SV2A PET studies in animal models of neurodegenerative disorders and discuss the opportunities and practical challenges in small animal SV2A PET imaging. At the Yale PET Center, we have conducted SV2A PET imaging studies in animal models of multiple diseases and longitudinal SV2A PET allowed us to evaluate synaptic density dynamics in the brains of disease animal models and to assess pharmacological effects of novel interventions. In this article, we discuss key considerations when designing preclinical SV2A PET imaging studies and strategies for data analysis. Specifically, we compare the brain imaging characteristics of available SV2A tracers, i.e., [11C]UCB-J, [18F]SynVesT-1, [18F]SynVesT-2, and [18F]SDM-16, in rodent brains. We also discuss the limited spatial resolution of PET scanners for small brains and challenges of kinetic modeling. We then compare different injection routes and estimate the maximum throughput (i.e., number of animals) per radiotracer synthesis by taking into account the injectable volume for each injection method, injected mass, and radioactivity half-lives. In summary, this article provides a perspective for designing and analyzing SV2A PET imaging studies in small animals.
Highlights
Synapses are the basic communication units for neurons
While numerous clinical synaptic vesicle glycoprotein 2A (SV2A) Positron emission tomography (PET) studies are ongoing in expanding the applications of SV2A PET in the study of more diseases and physiological processes, preclinical SV2A PET studies using small animal models of neuropsychiatric disorders are important, e.g., in evaluating experimental drug treatment effects longitudinally
We will focus on (1) the opportunities and challenges of SV2A PET in small animal brain PET and (2) ways to strengthen the robustness of preclinical SV2A PET studies through careful experimental design and proper data analysis strategies
Summary
Synapses are the basic communication units for neurons. The disruption of synapse homeostasis has been observed in a variety of neuropsychiatric disorders (Lepeta et al, 2016). Patients with high severity depression, schizophrenia, and cannabis use disorder showed significantly lower tracer uptake in the primary regions (Holmes et al, 2019; D’Souza et al, 2020; Onwordi et al, 2020) Based on these promising clinical imaging data, we anticipate more follow-up and larger scale investigations, as well as the use of SV2A PET in evaluating therapeutic effects in clinical trials. [18F]SynVesT-2 showed in vivo defluorination at late time window (90–120 min post-injection) in rats (Figure 1C), but not in other species (Cai et al, 2020a,b) This is not likely to influence the quantitative analysis using this tracer, as [18F]SynVesT-2 has rapid brain kinetics and only requires ∼30 min scanning time for reliable quantitative analysis based on our previous non-human primates’ results (Cai et al, 2020b). Different static imaging windows when SUVR is used instead of DVR/BPND as the outcome measurement
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