Autoradiographic studies 18F-FDNNP and 18F-FBM in transgenic mouse models

390 Objectives: Imaging agents that target β-amyloid (Aβ) senile plaques and neurofibrillary tangles are being developed for use in Alzheimer’s disease (AD). We report evaluation of two agents, 18F-FDDNP (Agdeppa et al., 2001) and 18F-FBM (Wang et al., 2006) in two transgenic mouse models of AD that develop Aβ plaques (Tg2576) or both Aβ plaques and neurofibrillary tangles (3xTg, triple-transgenic). Findings will assist microPET studies. Methods: Tosylate precursors were labeled using 18F-fluoride to obtain 18F-FDDNP and 18F-FBM. Tg2576 (15 mo old) and 3xTg (15 and 18 mo old) mice were used and whole brain sagittal sections (10μm thick) obtained from the two transgenic models and wild-type (WT) mice of ~same age. Sections were incubated with 18F-FDDNP (3-6 μCi/cc) or 18F-FBM (3-6 μCi/cc) in 0.9% saline, pH 7.4 at 37 oC for 1 hr. Brain slices were cotreated with 10μM FDDNP and 10μM thioflavin T. Slices were washed with cold water, 70%-90%-70% alcohol, water for 2,1,1,1,1 min. Binding of 18F-FDDNP and 18F-FBM in various brain regions were quantitated using Optiquant Image program. Adjacent mice brain sections were immunostained with an anti-Aβ antibody and thioflavin to confirm presence of Aβ plaques. Results: Anti-Aβ antibody staining confirmed presence of β-amyloid plaques. Slices radiolabeled with 18F-FDDNP or 18F-FBM matched immunostained regions. Binding was reduced in the presence of 10μM FDDNP and no thioflavin. Overall 18F-FDDNP binding in 3xTg was >5 fold higher compared to 2576 because of binding to Aβ plaques and tangles in the former and only to Aβ plaques in the latter. Cerebellum (CB) is not a good reference for 18F-FDDNP in both models. Ratios of binding (using striatum (ST) as reference) were in the range of 1.4-1.6 (for hippocampus (HP), thalamus (TH) and cortex (CTX) for 3xTg and ~1.2-1.8 (HP and TH) for Tg2576, while the CTX in Tg2576 was ~1. 18F-FBM in 3xTg mice showed greater contrast compared to 18F-FDDNP. Ratios using either ST or CB were >3 for HP and >1.5 for TH. Aβ plaques within CTX regions were more easily discernible with 18F-FBM. Conclusions: 18F-FBM being less lipophilic is able to provide higher ratios than 18F-FDDNP in the mouse models. MicroPET studies with 18F-FBM may be able to use CB as a reference region. The high lipophilicity of 18F-FDDNP results in low ratios.