title: Synthesis and evaluation of 1-(4-[¹⁸F]fluoroethyl)-7-(4'-methyl)curcumin with improved brain permeability for β-amyloid plaque imaging.
abstract: Alzheimer's disease is characterized by the accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain. We previously developed [(18)F]fluoropropylcurcumin ([(18)F]FP-curcumin), which demonstrated excellent binding affinity (K(i)=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 (K(i)=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 [(18)F]1 was found to have an appropriate partition coefficient (logP(o/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 [(18)F]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 [(18)F]1 may hold promise as a PET radioligand for Aβ plaque imaging.
authors: Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors: Iljung
authors: I
authors: Lee
authors: Jehoon
authors: J
authors: Yang
authors: Jung Hee
authors: JH
authors: Lee
authors: Yearn Seong
authors: YS
authors: Choe
mesh_terms: D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D003474:Curcumin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D004353:Drug Evaluation, Preclinical; D005462:Fluorine Radioisotopes / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010539:Permeability; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging / Q000378:metabolism*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D012680:Sensitivity and Specificity; D014018:Tissue Distribution
chemical_list: D016229:Amyloid beta-Peptides; D005462:Fluorine Radioisotopes; D010446:Peptide Fragments; D019275:Radiopharmaceuticals; C075222:amyloid beta-protein (1-42); D003474:Curcumin