Probes For Β-amyloid Plaques Research Articles

(E)-5-Styryl-1H-indole and (E)-6-Styrylquinoline Derivatives Serve as Probes for β-Amyloid Plaques

We report the synthesis and biological evaluation of novel (E)-5-styryl-1H-indole and (E)-6-styrylquinoline derivatives as probes for imaging β-amyloid (Aβ) plaques. These derivatives showed binding affinities for Aβ1–40 aggregates with Ki values varying from 4.1 to 288.4 nM. (E)-5-(4-iodostyryl)-1H-indole (8) clearly stained Aβ plaques in the brain sections of Alzheimer’s disease (AD) model mice (APP/PS1). Furthermore, autoradiography for [125I]8 displayed intense and specific labeling of Aβ plaques in the brain sections mentioned above with low background. In biodistribution experiments using normal mice [125I]8 showed high initial brain uptake followed by rapid washout (4.27 and 0.64% ID/g at 2 and 30 min post injection, respectively). These findings suggests that [123I]8 may be a potential SPECT imaging agent for detecting Aβ plaques in AD brain.

Synthesis and evaluation of benzofuran-2-yl(phenyl)methanone derivatives as ligands for β-amyloid plaques

A series of benzofuran-2-yl(phenyl)methanone derivatives were synthesized and evaluated as novel probes for β-amyloid plaques. These derivatives were produced by a Rap–Stoermer condensation reaction. Compounds with a N, N-dimethylamino group displayed high affinity for Aβ 1–42 aggregates with K i values in the nanomolar range. Autoradiography with brain sections of AD model mice (APP/PS1) revealed that a radioiodinated probe, [ 125I] 10, labeled β-amyloid plaques selectively and displayed good brain uptake (3.53% ID/g) at 2 min. The results suggest that benzofuran-2-yl(phenyl)methanone derivatives should be investigated further as potential probes for detecting β-amyloid plaques in the AD brain.

Synthesis and Structure−Affinity Relationships of Novel Dibenzylideneacetone Derivatives as Probes for β-Amyloid Plaques

A new and extensive set of dibenzylideneacetone derivatives was synthesized and screened for affinity toward Aβ(1-42) aggregates. Structure-activity relationships revealed the binding of dibenzylideneacetones to be affected by various substituents. The introduction of a substituent group in the ortho position reduced or abolished the binding. However, the para position was highly tolerant of sterically demanding substitutions. Three radioiodinated ligands (6, 70, and 71) and two (18)F fluoro-pegylated (FPEG) ligands (83 and 85) were prepared, all of which displayed high affinity for Aβ(1-42) aggregates (K(i) ranging from 0.9 to 7.0 nM). In biodistribution experiments, they exhibited good initial penetration (1.59, 4.68, 4.56, 4.13, and 5.15% ID/g, respectively, at 2 min) of and fast clearance from the brain. Autoradiography with sections of postmortem AD brain and transgenic mouse brain confirmed the high affinity of these tracers. These preliminary results strongly suggest the dibenzylideneacetone structure to be a potential new scaffold for β-amyloid imaging probes.

Synthesis, Novel Crystal Structure, and β‐Amyloid Binding Property of Re(I) (tricarbonyl)+ EHIDA Analogue

A neutral compound Re(CO)3(L) (L: 2-((2-(2,6-diethylphenylamino)-2-oxoethyl)(2-ethoxy-2-oxoethyl)amino)acetic acid, an IDA analogue) has been synthesized and evaluated for in vitro imaging probes of β-amyloid (Aβ) aggregates. Results of X-ray measurement of Re(CO)3(L) demonstrated that the coordination mode of Re(CO)3(L) was different from that of classical Re/Tc(I) (tricarbonyl)-IDA analogues; the structure of Re(CO)3(L) was confirmed by means of infrared spectrum, HPLC-UV, TOF MS, and X-ray measurements (Cambridge Crystallographic Data Centre number is 732731): monoclinic P21/c, a = 15.6636 (12) Å, b = 10.9360 (8) Å, c = 27.756 (2) Å, α = 90.000 (0)°, β = 90.783 (5)°, γ = 90.000 (0)°, and Z = 8. The binding affinity for β-amyloid plaques was assessed by in vitro binding assay using preformed synthetic Aβ (1–40) aggregates. The neutral compound Re(CO)3(L) showed binding affinity to Aβ aggregates at micromolar level by fluorescence spectroscopy, and this work will encourage for further exploration of imaging agents labeled by 99mTc(CO)3 + center as probes for β-amyloid plaques in vivo.

Synthesis of Biphenyltrienes as Probes for β-Amyloid Plaques

We report a series of p-hydroxy-, p-amino-, p-monomethylamino-, and p-monofluoroethylamino-substituted biphenyltrienes that displayed high binding affinities to beta-amyloid plaques. In an in vitro binding assay using postmortem brain homogenates of Alzheimer's patients and [(125)I]9, the triene compounds showed excellent binding affinities. When labeled with suitable radionuclides, they are useful as in vivo imaging agents for detecting Abeta plaques in the brains of Alzheimer's patients.