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

Objective The aim of this research is to synthesize and evaluate β-amyloid (Aβ) binding probes for early diagnosis of Alzheimer's disease (AD). Methods We 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. Results Both 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. Conclusion We 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.