Research Projects

The currently available treatments for AD in the market provide only symptomatic relief for the initial short period of time. At present AD diagnosis and treatment are mainly based on assessing the cognitive state of the patients which means the disease is already in an advanced stage, and the neurons irreversibly degenerate. To the best of our knowledge, none of the theranostic probes have the potential to reflect the full spectrum of AD. To change the status quo and given the advantages of near infra-red fluorescent (NIRF) agents may serve as an inexpensive, handy theranostic tool to comprehend the dynamics of pathogenic progression in AD. Several literature evidence, including our publications, strongly suggest the key role played by amyloid beta and ChEs in an interdependent manner in AD pathology. A few NIRF probes for AChE, BChE, or Aβ aggregates have been reported. Conversely, imaging modalities make recording in-situ changes in ChE enzymes and Aβ activity simultaneously in the AD brain is more challenging. The lack of simple but effective theranostic agents capable of selectively detecting and inhibiting AD pathological hallmarks, such as cholinesterases ChEs and Aβ aggregates, responsible for the onset and progression of the disease, has significantly thwarted the progress toward developing clinical candidates for AD. In our continuous effort, we further successfully designed and developed a donor-pie-acceptor based core capable of detecting Aβ and AChE BChE while also serving as ChEs inhibition activity along with being able to modulate amyloid beta, and identified I-43 as lead probe MS second revision Nature Communications NCOMMS 23-59606, Patent Application 202411099768. Interesting, the lead probe I43 exhibited emission in the deep NIR range 725 nm selectivity and affinity for amyloid beta aggregates in various in-vitro AD models including AD autopsy samples, brain permeability following in-vivo fluorescence imaging in live transgenic APP/PS1 mice model in-vitro and cell-based changes in ChEs activity with AChE inhibitory activity in the low micromolar range as a therapeutic agent. In addition, the probe successfully retrieves impaired memory in the scopolamine-induced amnesia mice model. Intriguingly, I43 suffers from poor water solubility due to a high cLogP of more than 6, which is the key challenge to evaluating the developed lead molecule's efficacy in the clinic. Also, there is the potential to improve metabolic stability. We plan to carry out the systematic structural modifications without hampering the central pharmacophoric conjugation system present in I43. The structural modifications on the left side donor N,N dimethyl, replacement of ester with amide, and introduction of indole instead of benzthiazole are expected to bring the cLogP in the desired range. Therefore, the origin of our proposal is based on our results, which require further investigation. The selection of the probes for the detailed biological evaluation is based on the in vitro assays. The probes with high QY promising sensing ability on Aβ aggregation modulation and enzyme inhibition property, low IC50, with improved water solubility and metabolic stability, and desired physicochemical properties will be screened, followed by moderately potent and least potent probes exhibiting other favorable properties and drug-like nature. AChE BChE and Aβ will be detected in cell culture models using SHSY5Y or PC12 cells. The most promising candidates will then be evaluated in vivo in age-dependent APP PS1 transgenic mice. The age-dependent presence of change in soluble, or insoluble amyloid beta species, or both soluble and insoluble Aβ species, along with an increase in the level of BChE. The study aims to establish next-generation NIRF probes with improved water solubility and metabolic properties, ultimately contributing to the development of reliable fluorescence-based diagnostic tools for AD.