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: Iljung Lee, Jehoon Yang, Jung Hee Lee, Yearn Seong Choe
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 21 Issue 19 Pg. 5765-9 (Oct 01 2011) ISSN: 1464-3405 [Electronic] England
• PMID: 21885280 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Fluorine Radioisotopes
• Peptide Fragments
• Radiopharmaceuticals
• amyloid beta-protein (1-42)
• Curcumin

Topics

• Alzheimer Disease (diagnostic imaging, metabolism)
• Amyloid beta-Peptides (chemistry, metabolism)
• Animals
• Blood-Brain Barrier (metabolism)
• Brain (diagnostic imaging, metabolism)
• Curcumin (analogs & derivatives, chemistry, metabolism, pharmacokinetics)
• Drug Evaluation, Preclinical
• Fluorine Radioisotopes (metabolism, pharmacokinetics)
• Humans
• Mice
• Mice, Transgenic
• Peptide Fragments (chemistry, metabolism)
• Permeability
• Plaque, Amyloid (diagnostic imaging, metabolism)
• Radionuclide Imaging
• Radiopharmaceuticals (chemical synthesis, chemistry, pharmacokinetics)
• Sensitivity and Specificity
• Tissue Distribution