Synthesis and in vitro evaluation of novel indanone derivatives targeting β-amyloid

Abstract

ObjectiveThe aim of this research is to synthesize and evaluate β-amyloid (Aβ) binding probes for early diagnosis of Alzheimer's disease (AD). MethodsWe designed and synthesized two new fluorine tag Indanone derivatives (compounds a and b), and then based on the platform of ultra-high-performance liquid chromatography-mass spectrometry for its affinity with β-amyloid (Aβ) protein determination, and use of compounds a and b solution as dyes for AD brain tissue staining in vitro. To evaluate the lipid solubility and stability of the drug, the lipid-water partition coefficient was determined using n-octanol as the lipid phase, and the stability of compound b was tested in vitro to mimic the in vivo environment. ResultsBoth compounds a and b exhibit high affinity for binding to Aβ. The Kd values of compound a for Aβ1-40 and Aβ1-42 were found to be 467.40 ± 63.26, and 227.57 ± 19.08 nmol/L, respectively. Similarly, the Kd values of compound b for Aβ1-40 and Aβ1-42 were 438.13 ± 26.77 and 167.27 ± 23.70 nmol/L, respectively. In the staining experiment of human brain slices of AD, both compounds a and b were found to bind to Aβ plaques, and their staining effect was stronger than positive control (0.1 % ThS). In the lipid-water partition coefficient experiment, compound a and compound b exhibited logP values of 0.84 and 1.85, respectively, indicating good lipid solubility. In the in vitro stability experiment, compound b exhibited a concentration of 74.79 %, 80.47 %, and 70.00 % after incubation in liver, brain homogenate, and blood, respectively. ConclusionWe have successfully designed and synthesized two probes labeled with fluoride that can be used for diagnosing AD. These probes have a high affinity for Aβ protein and good lipid solubility. As A contrast agent based on Aβ protein, compound b showed greater potential than compound a.