Dimethylamino-fluorenes: ligands for detecting beta-amyloid plaques in the brain

Formation of beta-amyloid (Abeta) plaques in the brain is a major contributing factor in the pathogenesis of Alzheimer's disease (AD). Detection of Abeta plaques in the brain will be potentially useful in early diagnosis and monitoring the progression of the disease. A series of novel Abeta aggregate-specific ligands based on fluorenes, which are simple and rigid tricyclic molecules, are synthesized and characterized. Starting with 2- or 3-aminofluorenes, 1a-1f, the amino group was converted to the N,N-dimethylamino group (2a-2f) in excellent yield. It was found that 7-iodo-2-N,N-dimethylaminofluorene (2f) showed an extremely high binding affinity to preformed Abeta40 aggregates (K(i) = 0.9 nM). In vitro autoradiography study using brain sections obtained from transgenic mice (Tg2576) with [(125)I]2f showed exquisitely high specific binding to Abeta plaques. The same section also displayed an equivalent labeling when stained by Thioflavin-S, a commonly used fluorescent dye for Abeta plaques. When [(125)I]2f was injected intravenously into normal mice, it exhibited an excellent brain uptake. Taken together the data suggest that [(125)I]2f may be useful as an in vivo imaging agent to detect Abeta plaques in the brain.