Synaptic density imaging with ¹¹C-UCB-J detects treatment effects of a Fyn tyrosine kinase inhibitor on Alzheimer’s disease mice.

Objectives: ¹¹C-UCB-J is a new PET tracer targeting the synaptic vesicle glycoprotein 2A (SV2A) [1] located primarily in presynaptic terminals. In previous studies, we have showed that ¹¹C-UCB-J uptake in PET scans was well correlated with histopathological synaptic markers, and concluded that SV2A imaging can be used to evaluate synaptic density in vivo [2]. This tracer therefore has the potential to be a general biomarker for evaluating synaptic changes in neurodegenerative diseases. Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases, and is associated with aggregating β-amyloid (Aβ), hyperphosphorylated tau, synaptic dysfunction, and neuronal loss. In AD pathology, Fyn tyrosine kinase may play an important role by triggering the downstream cascade of Aβ- and tau-driven signaling [3]. Saracatinib is an inhibitor of Src family kinases, which also has activity against Fyn. Previous studies showed that Fyn inhibition by saracatinib reversed memory deficits and synaptic loss in an AD mouse model during and after treatment [3, 4]. In this study, we evaluated longitudinally the treatment effects of Fyn inhibition on AD mice in vivo with ¹¹C-UCB-J PET.

Methods: Nine wild-type (WT) mice and seven amyloid precursor protein and presenilin 1 double transgenic (APP/PS1) mice underwent three ¹¹C-UCB-J PET scans at baseline, post-treatment, and during drug wash out. The mean and standard deviations of age at baseline scans were 66 ±1.8 weeks for WT and 65 ± 1.4 weeks for APP/PS1 mice. After baseline scans, saracatinib (5 mg/kg, every 12 h) was administered by oral gavage for 41 ± 11 days. Treatment-phase scans were performed on the last day of treatment, and wash-out phase scans occurred more than 27 days after treatment. For PET scans, ¹¹C-UCB-J was administered by retro-orbital injection, and emission data were acquired for 30 min on the Inveon PET/CT, starting at ~30 min after ¹¹C-UCB-J injection. Images were reconstructed using an OSEM-3D-MAP algorithm without attenuation or scatter correction. Standardized uptake values (SUV) from 30-60 min postinjection were normalized by the whole brain average value as SUV ratio (SUVR). Previous mouse studies in our lab showed that SUVR was well correlated with binding potential (BP_ND) determined from 1-h PET scans. The Mouse M.Mirrione template was manually applied to individual PET images and region of interest analyses were performed.

Results: Hippocampal SUVR values at baseline were significantly lower for APP/PS1 than WT mice (WT: 1.15±0.02, APP/PS1: 1.11±0.06, p = 0.033, unpaired, two-tailed, t-test). After treatment, hippocampal SUVR values were significantly increased for APP/PS1 mice (p=0.037, paired, two-tailed, t-test). Hippocampal SUVR values at treatment phase were similar between WT and APP/PS1 mice (WT: 1.14±0.03, APP/PS1: 1.14±0.05, p = 0.88, unpaired, two-tailed, t-test). Hippocampal SUVR slightly decreased in APP/PS1 mice in the wash-out phase, but there was no significant difference between WT and APP/PS1 mice (WT: 1.14±0.04, APP/PS1: 1.12±0.05, p = 0.45, unpaired, two-tailed, t-test). Other regions such as cortex, amygdala and cerebellum showed no differences between groups or phases. These patterns of change were also present when cerebellum or brain stem was used as normalizing regions, but statistical significance was greatest with whole brain normalization. Conclusion: Based on ¹¹C‑UCB‑J PET, hippocampal synaptic density is lower in APP/PS1 mice compared with WT mice. Furthermore, hippocampal synaptic deficits were normalized during Fyn inhibitor treatment. These results support the use of ¹¹C-UCB-J PET not only to identify disease-specific synaptic deficits but also to monitor treatment effects in AD. References: 1. Nabulsi et al., 2016, JNMMI, 57:5:777-84. 2. Finnema et al., 2016, Sci Transl Med, 8:348:348ra96. 3. Kaufman et al., 2015, Ann Neurol, 77:6:953-71 4. Smith et al., 2018, Neuropharmacology 130:54-61.