In Vivo Synaptic Density Imaging with 11 C-UCB-J Detects Treatment Effects of Saracatinib in a Mouse Model of Alzheimer Disease
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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.
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A transgenic Alzheimer's disease mouse model (APP/PS1) showed significantly lower SV2A density in hippocampus compared to wild type mice.
“a transgenic Alzheimer's disease (AD) mouse model (APP/PS1) showed significantly lower SV2A density in hippocampus compared to wild type mice.”
From Challenges and rewards of in vivo synaptic density imaging, and its application to the study of depression (2025) · cites this paper as [147]
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- Authors
- Toyonaga, T., Smith, L. M., Finnema, S. J., Gallezot, J.-D., Naganawa, M., Bini, J., Mulnix, T., Cai, Z., Ropchan, J., Huang, Y., Strittmatter, S. M., & Carson, R. E.
- Affiliations
- Yale University (US)
- ORCID
- Venue
- Journal of Nuclear Medicine
- Publisher
- Society of Nuclear Medicine
- Published
- 2019-05-17
- Volume
- 60
- Issue
- 12
- Pages
- 1780-1786
- ISSN
- 0161-5505 (ISSN-L)
- 2159-662X
- PMC
- PMC6894376
- OpenAlex
- W2945441952
- Cited by
- 79
- References
- 22
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 12 · 2023: 11 · 2022: 18 · 2021: 15 · 2020: 11 · 2019: 1 · 2018: 1
- FWCI
- 7.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Nuclear Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Society of Nuclear Medicine and Molecular Imaging
- Georgia Clinical and Translational Science Alliance (UL1TR000142)
- Vetenskapsrådet
- National Institutes of Health (1s10od010322-01a1, UL1TR000142, TR000142, UL1TR001863)
- National Institute on Aging (RF1AG053000, P50AG047270, U01AG058608, R01AG034924)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Medical Imaging Techniques and Applications
- Keywords
- [11C]UCB-J, saracatinib, Alzheimer's disease, APP/PS1 mice, hippocampus, treatment response biomarkers, amyloid precursor protein, presenilin 1, drug washout, mild cognitive impairment
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Female, Kinetics, Male, Pyridines, Pyrrolidines, Pyrrolidinones, Quinazolines, Synapses, Positron-Emission Tomography, Mice, Benzodioxoles
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