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A new series of fluoro-pegylated benzyloxybenzenes were designed, synthesized and evaluated as PET probes for early detection of A β plaques. Molecular docking revealed that all of the flexible benzyloxybenzenes inserted themselves into the hydrophobic Val18_Phe20 cleft on the flat spine of the A β fiber, in a manner similar to that of IMPY molecule. The most potent probe, [ 18 F] 9a , exhibited a combination of high binding affinity to A β aggregates ( K i = 21.0 ± 4.9 nM), high initial brain uptake (9.14% ID/g at 2 min), fast clearance from normal brain tissue (1.79% ID/g at 60 min), and satisfactory in vivo biostability in the brain (95% of intact form at 2 min). [ 18 F] 9a clearly labeled A β plaques in in vitro autoradiography of postmortem AD patients and Tg mice brain sections. Ex vivo autoradiography further demonstrated that [ 18 F] 9a did penetrate the intact BBB and specifically bind to A β plaques in vivo . Overall, [ 18 F] 9a may be a potential PET probe for imaging A β plaques in AD brains. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a debilitating neurodegenerative dementia that involves substantial neuronal loss. Extracellular deposition of neurotoxic β -amyloid (A β ) plaques in the brain has been recognized as the central histological characteristic of AD. In the past decade, precise detection of the A β plaques at preclinical AD with positron emission tomography (PET) or single photon emission computed tomography (SPECT) has achieved continued development. A big category of A β imaging agents was benzoheterocycles which derived from Thioflavin-T (ThT), a traditional amyloid binding dye. This review summarizes the past and current status of radioactive benzoheterocycles designed to selectively bind to A β plaques. Separate sections discuss the chemical synthesis, in vitro and in vivo investigations of radiolabeled benzothiazole, benzoxazole, benzofuran, benzothiophene, indole, imidazopyridine and quinoxaline analogs to act as PET/SPECT candidates for imaging A β plaques. [ABSTRACT FROM AUTHOR]

Abstract: Four 99mTc-labeled dibenzylideneacetone derivatives and corresponding rhenium complexes were successfully synthesized and biologically evaluated as potential imaging probes for Aβ plaques using SPECT. All rhenium complexes (5a–d) showed affinity for Aβ (1–42) aggregates (K i = 13.6–120.9 nM), and selectively stained the Aβ plaques on brain sections of transgenic mice. Biodistribution in normal mice revealed that [99mTc]5a–d exhibited moderate initial uptake (0.31%–0.49% ID/g at 2 min) and reasonable brain washout at 60 min post-injection. Although additional optimizations are still needed to facilitate it's penetration through BBB, the present results indicate that [99mTc]5a may be a potential SPECT probe for imaging Aβ plaques in Alzheimer's brains. [Copyright &y& Elsevier]

Abstract: In continuation of our study on the 2-phenylquinoxaline scaffold as potential β-amyloid imaging probes, two [18F]fluoro-pegylated 2-phenylquinoxaline derivatives, 2-(4-(2-[18F]fluoroethoxy)phenyl)-N-methylquinoxalin-6-amine ([18F]4a) and 2-(4-(2-(2-(2-[18F]fluoroethoxy)ethoxy)ethoxy)phenyl)-N-methylquinoxalin-6-amine ([18F]4b) were prepared. Both of them displayed high binding affinity to Aβ 1-42 aggregates (K i = 10.0 ± 1.4 nM for 4a, K i = 5.3 ± 3.2 nM for 4b). The specific and high binding of [18F]4a and [18F]4b to Aβ plaques was confirmed by in vitro autoradiography on brain sections of AD human and transgenic mice. In biodistribution in normal mice, [18F]4a displayed high initial brain uptake (8.17% ID/g at 2 min) and rapid washout from the brain. These preliminary results suggest [18F]4a may be a potential PET imaging agent for Aβ plaques in the living human brain. [Copyright &y& Elsevier]