¹¹C-UCB-J is a new PET tracer for synaptic density imaging. Recently, we conducted ¹¹C-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 ¹¹C-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 ¹¹C-UCB-J PET on AD mice to measure the treatment effects of saracatinib, which previously demonstrated synaptic changes with postmortem methods. Methods: Nine wild-type (WT) mice and 9 amyloid precursor protein and presenilin 1 double-transgenic (APPswe/PS1ΔE9 [APP/PS1]) mice underwent 3 ¹¹C-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 ¹¹C-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 ¹¹C-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 ¹¹C-UCB-J PET to identify disease-specific synaptic deficits and to monitor treatment effects in AD.

¹¹ C-UCB-J是用于突触密度成像的新型PET示踪剂。最近，我们对患有轻度认知障碍或早期阿尔茨海默病（AD）的患者进行了¹¹ C-UCB-J PET，发现与健康受试者相比，海马中的特异性结合降低了41％。我们假设¹¹ C-UCB-J可能有潜力成为通过监测突触密度变化来评估AD治疗效果的一般生物标志物。在这项研究中，我们在AD小鼠上进行了纵向¹¹ C-UCB-J PET的测量，以评估saracatinib的治疗效果，该作用先前已通过验尸方法证明了突触变化。方法：九只野生型（WT）小鼠和9种淀粉样蛋白前体蛋白和早老素1双转基因（APPswe /PS1ΔE9[APP / PS1]）小鼠接受了3 ¹¹ C-UCB-J PET测量：在基线，治疗后和药物治疗期间冲刷。基线测量后，通过口服管饲法对目前在临床上正在开发用于AD治疗的Fyn激酶抑制剂saracatinib进行41±11 d的给药。在治疗的最后一天进行治疗阶段的测量，在治疗结束后超过27 d进行洗脱阶段的测量。计算¹¹ C-UCB-J注射后30至60分钟的SUV，并以全脑（WB）或脑干（BS）平均值作为SUV比（SUVR _（WB）或SUVR-1 _{（BS））进行}归一化）。结果：APP / PS1基线时的海马SUVR _（WB）显着低于WT小鼠（APP / PS1：1.11±0.04，WT：1.15±0.02，P = 0.033，未配对t检验）。在海马中使用SUVR-1 _（BS），在基线时也存在显着差异（APP / PS1：0.48±0.13，WT：0.65±0.10，P = 0.017，未配对t检验）。用萨拉卡替尼治疗后，APP / PS1小鼠的海马SUVR _（WB）显着增加（P = 0.037，配对t检验）。使用海马SUVR-1 _（BS）可以观察到趋势水平的治疗效果_。药物洗脱后，WT和APP / PS1小鼠之间无显着差异，因此Saracatinib的治疗效果可能会持续。结论：基于¹¹ C-UCB-J PET结果，APP / PS1小鼠的海马突触密度在基线时比WT小鼠低，并且该缺陷可以通过撒拉卡替尼治疗得以恢复。这些结果支持使用¹¹ C-UCB-J PET来识别疾病特异性突触缺陷并监测AD的治疗效果。