In Vivo Synaptic Density Imaging with 11C-UCB-J Detects Treatment Effects of Saracatinib in a Mouse Model of Alzheimer Disease

• Published in: The Journal of nuclear medicine (1978) Vol. 60; no. 12; pp. 1780 - 1786
• Main Authors: Toyonaga, Takuya, Smith, Levi M, Finnema, Sjoerd J, Gallezot, Jean-Dominique, Naganawa, Mika, Bini, Jason, Mulnix, Tim, Cai, Zhengxin, Ropchan, Jim, Huang, Yiyun, Strittmatter, Stephen M, Carson, Richard E
• Format: Journal Article
• Language: English
• Published: New York Society of Nuclear Medicine 01.12.2019
• Subjects: Alzheimer's disease; Amyloid precursor protein; Biomarkers; Brain stem; Cognitive ability; Density; Enzyme inhibitors; Fyn protein; Hippocampus; In vivo methods and tests; Kinases; Medical imaging; Neurodegenerative diseases; Neuroimaging; Neurology; Positron emission; Positron emission tomography; Presenilin 1; Synaptic density; Tomography
• ISSN: 0161-5505; 1535-5667; 1535-5667
• DOI: 10.2967/jnumed.118.223867

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.