Fluoro-pegylated Chalcones as Positron Emission Tomography Probes for in Vivo Imaging of β-Amyloid Plaques in Alzheimer’s Disease

Abstract

This paper describes the synthesis and biological evaluation of fluoro-pegylated (FPEG) chalcones for the imaging of beta-amyloid (Abeta) plaques in patients with Alzheimer's disease (AD). FPEG chalcone derivatives were prepared by the aldol condensation reaction. In binding experiments conducted in vitro using Abeta(1-42) aggregates, the FPEG chalcone derivatives having a dimethylamino group showed higher Ki values (20-50 nM) than those having a monomethylamino or a primary amine group. When the biodistribution of 11C-labeled FPEG chalcone derivatives having a dimethyamino group was examined in normal mice, all four derivatives were found to display sufficient uptake for imaging Abeta plaques in the brain. 18F-labeled 7c also showed good uptake by and clearance from the brain, although a slight difference between the 11C and 18F tracers was observed. When the labeling of Abeta plaques was carried out using brain sections of AD model mice and an AD patient, the FPEG chalcone derivative 7c intensely labeled Abeta plaques. Taken together, the results suggest 7c to be a useful candidate PET tracer for detecting Abeta plaques in the brain of patients with AD.

Synthesis and evaluation of ethyleneoxylated and allyloxylated chalcone derivatives for imaging of amyloid β plaques by SPECT

“…In vitro binding experiments to evaluate the binding affinity of the chalcones for Aβ were performed in suspensions of Aβ (1-42) aggregates with [ 125 I]4-dimethylamino-4'-iodochalcone (DMIC) which is a high-affinity Aβ ligand with a chalcone backbone as described in our previous papers [17][18][19][20] . The inhibition constant (Ki) values of 2-4 indicated that the binding affinity of these compounds to Aβ aggregates was affected by the length of the ethyleneoxy group in the chalcone backbone.…”

“…Indeed, it was reported that several Aβ probes with single-digit nanomolar Ki values for the Aβ aggregates successfully stained the Aβ plaques in brain sections of the Tg2576 mice by in vitro autoradiography 25,26 . In addition, it has been shown that chalcone derivatives with a dimethylamino group at the third position can be used to visualize Aβ plaques by in vitro autoradiography 19,27 . Thus, chalcone derivatives with a dimethylamino group in the 3-phenyl ring may be more suitable than those with an alkoxy group with respect to binding of the Aβ plaques in the brain.…”

“…We have previously reported Aβ imaging agents based on flavonoid derivatives, such as flavones 15,16 , chalcones [17][18][19][20] , aurones 21,22 , and styrylchromones 23 studies demonstrated that chalcone derivatives fluoro-pegylated at the p-position of the 1-phenyl ring showed a sufficient brain uptake with a good binding capacity to Aβ plaques 19 . In addition, radioiodinated flavonoids, such as flavone and aurone derivatives, with a methoxy or oligoethyleneoxy group at the p-position of the 3-phenyl ring have the properties of high brain uptake and rapid clearance from the brain without significant decrease in the binding affinity for Aβ 15,22 .…”

99mTc/Re complexes based on flavone and aurone as SPECT probes for imaging cerebral β-amyloid plaques

“…Recently, we have reported that flavonoids including chalcone, flavone, and aurone serve as useful molecular scaffolds in the development of imaging agents for β-amyloid plaques in the brain [23][24][25][26][27][28] . Initially, we designed and synthesized four 99m Tc-labeled In the present study, to develop more useful 99m Tc imaging agents for the clinical diagnosis of AD, we synthesized two flavone and aurone derivatives with BAT as a chelation ligand.…”

“…Based on this success, efforts were made to search for comparable 99m Tc imaging agents that target binding sites on -amyloid plaques in the brain of AD patients. Several 99m Tc-labeled imaging probes have been developed (Figure 1), but no clinical study of them has been reported [19][20][21][22] .Recently, we have reported that flavonoids including chalcone, flavone, and aurone serve as useful molecular scaffolds in the development of imaging agents for β-amyloid plaques in the brain [23][24][25][26][27][28] . Initially, we designed and synthesized four 99m Tc-labeled In the present study, to develop more useful 99m Tc imaging agents for the clinical diagnosis of AD, we synthesized two flavone and aurone derivatives with BAT as a chelation ligand.…”