The plaques of accumulated beta-amyloid (A beta) in the parenchymal brain are accepted as an important biomarker for the early diagnosis of Alzheimer's disease (AD). Many near-infrared (NIR) probes, which were based on the D-pi-A structure and bridged by conjugated double bonds, had been reported and displayed a high affinity to A beta plaques. Considering the isomerization caused by the polyethylene chain, however, the conjugated polyacetylene chain is a better choice for developing new NIR A beta probes. Hence, in this report, a new series of NIR probes with naphthyl or phenyl rings and different numbers of conjugated triple bonds were designed, synthesized, and evaluated as NIR probes for A beta plaques. Upon interaction with aggregates, these probes displayed a significant increase in fluorescence intensity (45- to 360-fold) and a high to moderate affinity (6.05-56.62 nM). Among them, probe 22b displayed excellent fluorescent properties with a 183-fold increase in fluorescence intensity and an emission maximum at 650 nm after incubated with A beta aggregates. Furthermore, 22b had a high affinity to A beta aggregates (K-d = 12.96 nM) and could efficiently detect the A beta plaques in brain sections from both transgenic mice and AD patients in vitro. In summary, this work may lead to a new direction in the development of novel NIR probes for the detection of A beta plaques.