Synthesis and evaluation of 1-(4-[18F]fluoroethyl)-7-(4′-methyl)curcumin with improved brain permeability for β-amyloid plaque imaging

Alzheimer’s disease is characterized by the accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain. We previously developed [18F]fluoropropylcurcumin ([18F]FP-curcumin), which demonstrated excellent binding affinity (Ki = 0.07 nM) for Aβ(1–40) aggregates and good pharmacokinetics in normal mouse brains. However, its initial brain uptake was poor (0.52% ID/g at 2 min post-injection). Therefore, in the present study, fluorine-substituted 4,4′-bissubstituted or pegylated curcumin derivatives were synthesized and evaluated. Their binding affinities for Aβ(1–42) aggregates were measured and 1-(4-fluoroethyl)-7-(4′-methyl)curcumin (1) had the highest binding affinity (Ki = 2.12 nM). Fluorescence staining of Tg APP/PS-1 mouse brain sections demonstrated high and specific labeling of Aβ plaques by 1 in the cortex region, which was confirmed with thioflavin-S staining of the same spots in the adjacent brain sections. Radioligand [18F]1 was found to have an appropriate partition coefficient (log Po/w = 2.40), and its tissue distribution in normal mice demonstrated improved brain permeability (1.44% ID/g at 2 min post-injection) compared to that of [18F]FP-curcumin by a factor of 2.8 and fast wash-out from mouse brains (0.45% ID/g at 30 min post-injection). These results suggest that [18F]1 may hold promise as a PET radioligand for Aβ plaque imaging.

Graphical abstractA double transgenic mouse (APP/PS-1) brain section stained with 1.Figure optionsDownload full-size imageDownload as PowerPoint slide