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, 53 (3), 933-41

18F Stilbenes and Styrylpyridines for PET Imaging of A Beta Plaques in Alzheimer's Disease: A Miniperspective

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18F Stilbenes and Styrylpyridines for PET Imaging of A Beta Plaques in Alzheimer's Disease: A Miniperspective

Hank F Kung et al. J Med Chem.

Figures

Figure 1
Figure 1
A. Processes (β-amyloid cascade) participating in AD pathogenesis. Aβ peptides produced by neurons aggregate into a variety of assemblies, some of which may impair synapses and neuronal dendrites. Build-up of pathogenic Aβ aggregates could result from increased production or aggregation or from deficient clearance mechanisms. This multifactorial scenario leads to progressive disintegration of neural circuits, isolation and loss of neurons, network failure, and neurological decline. (Reproduced with permission from Science). B. A simplified model of excessive Aβ production leading to Alzheimer’s disease (AD). Normally, amyloid precursor protein (APP) is metabolized by at least three proteases (α-, β- and γ-secretases). Aβ-peptides are produced by β-secretase, cleaving at the N-terminal residue, and by γ-secretase, cleaving at the C-terminal residue of APP. The fibrillar aggregates of amyloid peptides, Aβ40 and Aβ42, are the major constituent of senile plaques in AD patients. The Aβ aggregates are believed to be responsible for initiating a cascade of events leading to neurotoxicity and AD.
Figure 2
Figure 2
Comparison of chemical structures of 4, PIB and 18, SB-13. The aromatic rings and electronically negative substitution groups, N-methylamino and hydroxyl (indicated by an arrow), overlap each other. In addition, both ligands are relatively planar due the conjugating ring systems.
Figure 3
Figure 3
A. Inhibition constants (Ki, nM) of [125I]IMPY binding to Aβ aggregates of AD brain homogenates and brain uptake in normal mice. Values (Ki, nM) are the mean ± SEM of three independent experiments, each in duplicate. The in vitro binding data suggest that when 20 n < 8, the high binding affinity was maintained (Ki < 10 nM) (as indicated by the red line). However, when n was above and beyond 8, the binding affinity showed a significant reduction. It is noted that for this series of compounds the binding data for AV-1, 9, (Ki = 6.7 nM) was slightly different from the Ki value obtained later in Table 2 (Ki = 2.22 nM). B. The 18F labeled 20, (n = 2–8) were injected (iv) into normal mice and the brain uptake (%dose/g) was measured. It was surprising to find that when n > 5, there was a significant drop off of brain penetration (red boxes). Comparable brain uptake of [11C]PIB and [125I]IMPY in mice was observed: 7 and 7.2 at 2 min and 0.6 and 0.65 %dose/g in mice at 30 min, respectively.,
Figure 4
Figure 4
PET imaging of a healthy control (HC) and an AD patient (AD) at 70–90 min after a dose of 7 mCi of [18F]Bay 94–9172 (AV1), 9. Significant uptake in the frontal cortex region of AD patients was observed; while the uptake in the normal controls showed low or no uptake. (Reproduced with permission from Nature Neurology).
Figure 5
Figure 5
Inhibition constants (Ki, nM) of stilbene derivatives: fluoro monomer, 20, hydroxyl monomer, 21, and dimer, 22. The Ki values were measured by using [125I]IMPY as the ligand and cortex homogenates of postmortem AD brain (Ki values of fluoro monomer, 20, are shown in Figure 2). The red line indicates the Ki value at 10 nM. It is important to note that for the dimer, 22, the binding affinity increases dramatically, when n > 6.
Figure 6
Figure 6
Comparative studies of four 18F PET imaging agents (10, AV-45; 23, AV-138; 24, AV-144 and 25, AV-19) targeting Aβ plaques in living human brain - AD (Alzheimer’s disease); HC (healthy control). The scale for the Y axis represents SUV value. By visual inspection one can easily translate the specific vs non-specific binding ratio in different regions of the brain. Three PET imaging tracers, 10, AV-45; 23, AV-138; and 24, AV-144, displayed the desired properties for detecting Aβ plaques in the brain of AD patients. One final candidate, 10, AV-45, was selected for commercial development.

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