Abstract
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Objectives: Previous work in humans (Kepe, 2005) has shown a 27% hippocampus (HP) decrease in serotonin 5HT1A receptors in Alzheimer’s disease (AD) using 18F-MPPF. In order to evaluate 5HT1A receptor level changes in AD we used 18F-trans-mefway (18F-MEF) in two transgenic mouse models of AD that develop β-amyloid (Aβ) plaques (Tg2576) or both Aβ plaques and neurofibrillary tangles (3xTg). Our goal is to evaluate 18F-MEF as a tool for measuring changes in serotonin receptor concentrations characterized by AD. Methods: Radiosynthesis of 18F-MEF was carried out as described previously with a specific activity of >2 Ci/μmol. Brain slices (10 μm) from male Sprague-Dawley rats and the two AD transgenic mouse models were used: Tg2576 (15 mo) and 3xTg triple transgenic (1, 2, 15 and 18 mo old) mice and wild-type (WT) mice of comparable age were used. Sagittal sections were incubated in 50 mM Tris-HCl buffer (pH 7.4) with 3.5-4.0 μCi/cc of 18F-MEF at 37 oC (1 hr). Nonspecific binding was measured using 3 μM WAY-100635. Binding of 18F-MEF in HP, cortex (CTX) and cerebellum (CB) were measured. Adjacent mice brain sections were also immunostained with anti-Aβ antibody and thioflavin to confirm presence of Aβ plaques. Results: Binding of 18F-MEF was evident in several 5HT1A receptor-rich regions, including HP, and CTX. Using CB as reference, rat brain slices gave ratios of HP=55 and CTX=17 for 18F-MEF. WT mice showed similar distribution of 18F-MEF with ratios, Hp=60 and CTX=16, suggesting a similarity in binding to 5HT1A receptors in the two rodent species. Older Tg2576 and 3xTg (15-18 mo) showed a >90% decrease in 18F-MEF binding in HP (ratios 2-3) and CTX (ratio ~1) compared to WT. Younger 3xTg showed ratios of: 1 month HP=46, a 23% decrease; 2 months HP=38, a 37% decrease. CTX in 1-2 month old 3xTg did not show a significant decrease. Conclusions: Due to the high degree of specific binding of 18F-MEF to 5HT1A receptors, it appears to be a suitable radiotracer for studying AD. Loss of 5HT1A receptor binding in the two mouse models is consistent with that found in humans- However, the losses in the older transgenic are much greater than those found in human AD.
- Society of Nuclear Medicine, Inc.