In Vivo Synaptic Density Imaging With C-11-Ucb-J Detects Treatment Effects Of Saracatinib In A Mouse Model Of Alzheimer Disease

C-11-UCB-J is a new PET tracer for synaptic density imaging. Recently, we conducted C-11-UCB-J PET on patients with mild cognitive impairment or early Alzheimer disease (AD) and found a 41% decrease in specific binding in the hippocampus compared with healthy subjects. We hypothesized that C-11-UCB-J may have potential to be a general biomarker for evaluating AD treatment effects via monitoring of synaptic density changes. In this study, we performed longitudinal C-11-UCB-J PET on AD mice to measure the treatment effects of saracatinib, which previously demonstrated synaptic changes with postmortem methods. Methods: Nine wildtype (WT) mice and 9 amyloid precursor protein and presenilin 1 double-transgenic (APPswe/PS1 Delta E9 [APP/PS1]) mice underwent 3 C-11-UCB-J PET measurements: at baseline, after treatment, and during drug washout. After baseline measurements, saracatinib, a Fyn kinase inhibitor currently in clinical development for AD treatment, was administered by oral gavage for 41 +/- 11 d. Treatment-phase measurements were performed on the last day of treatment, and washout-phase measurements occurred more than 27 d after the end of treatment. SUVs from 30 to 60 min after injection of C-11-UCB-J were calculated and normalized by the whole-brain (WB) or brain stem (BS) average values as SUV ratio (SUVR(WB) or SUVR-1((BS))). Results: Hippocampal SUVR(WB) at baseline was significantly lower in APP/PS1 than WT mice (APP/PS1: 1.11 +/- 0.04, WT: 1.15 +/- 0.02, P = 0.033, unpaired t test). Using SUVR-1((BS)) in the hippocampus, there was also a significant difference at baseline (APP/PS1: 0.48 +/- 0.13, WT: 0.65 +/- 0.10, P = 0.017, unpaired t test). After treatment with saracatinib, hippocampal SUVR(WB) in APP/PS1 mice was significantly increased (P = 0.037, paired t test). A trend-level treatment effect was seen with hippocampal SUVR-1((BS)). Saracatinib treatment effects may persist, as there were no significant differences between WT and APP/PS1 mice after drug washout. Conclusion: On the basis of the C-11-UCB-J PET results, hippocampal synaptic density was lower in APP/PS1 mice than in WT mice at baseline, and this deficit was normalized by treatment with saracatinib. These results support the use of C-11-UCB-J PET to identify disease-specific synaptic deficits and to monitor treatment effects in AD.