Imaging fibrillar
amyloid-β deposition in the human brain in vivo by positron emission tomography has improved our understanding of the time course of
amyloid-β pathology in
Alzheimer's disease. The most widely used
amyloid-β imaging tracer so far is (11)C-Pittsburgh compound B, a thioflavin derivative but other (11)C- and (18)F-labelled
amyloid-β tracers have been studied in patients with
Alzheimer's disease and cognitively normal control subjects. However, it has not yet been established whether different
amyloid tracers bind to identical sites on
amyloid-β fibrils, offering the same ability to detect the regional
amyloid-β burden in the brains. In this study, we characterized (3)H-Pittsburgh compound B binding in autopsied brain regions from 23 patients with
Alzheimer's disease and 20 control subjects (aged 50 to 88 years). The binding properties of the
amyloid tracers FDDNP, AV-45, AV-1 and
BF-227 were also compared with those of (3)H-Pittsburgh compound B in the frontal cortices of patients with
Alzheimer's disease. Saturation binding studies revealed the presence of high- and low-affinity (3)H-Pittsburgh compound B binding sites in the frontal cortex (K(d1): 3.5 ± 1.6 nM; K(d2): 133 ± 30 nM) and hippocampus (K(d1):5.6 ± 2.2 nM; K(d2): 181 ± 132 nM) of
Alzheimer's disease brains. The relative proportion of high-affinity to low-affinity sites was 6:1 in the frontal cortex and 3:1 in the hippocampus. One control showed both high- and low-affinity (3)H-Pittsburgh compound B binding sites (K(d1): 1.6 nM; K(d2): 330 nM) in the cortex while the others only had a low-affinity site (K(d2): 191 ± 70 nM). (3)H-Pittsburgh compound B binding in
Alzheimer's disease brains was higher in the frontal and parietal cortices than in the caudate nucleus and hippocampus, and negligible in the cerebellum. Competitive binding studies with (3)H-Pittsburgh compound B in the frontal cortices of
Alzheimer's disease brains revealed high- and low-affinity binding sites for BTA-1 (Ki: 0.2 nM, 70 nM),
florbetapir (1.8 nM, 53 nM) and
florbetaben (1.0 nM, 65 nM).
BF-227 displaced 83% of (3)H-Pittsburgh compound B binding, mainly at a low-affinity site (311 nM), whereas FDDNP only partly displaced (40%). We propose a multiple binding site model for the
amyloid tracers (binding sites 1, 2 and 3), where AV-45 (
florbetapir), AV-1 (
florbetaben), and
Pittsburgh compound B, all show nanomolar affinity for the high-affinity site (binding site 1), as visualized by positron emission tomography.
BF-227 shows mainly binding to site 3 and FDDNP shows only some binding to site 2. Different
amyloid tracers may provide new insight into the pathophysiological mechanisms in the progression of
Alzheimer's disease.