"Tau Protein Targeting Via Radioiodinated Azure A For Brain Theranostics: Radiolabeling, Molecular Docking, in vitro And in vivo Biological Evaluation".

Abstract

Azure-A is one of the phenothiazines (PTZs) derivatives which for decades have been used as antipsychotic drugs due to good lipophilic characteristics which enable them to pass through the blood brain barrier (BBB), besides the important property of enabeling investigation of the pathological forms of aggregated tau protein found in the neurons of the central nervous system. Radioiodination of Azure-A was carried out via an electrophilic substitution reaction using chloramine-T as oxidizing agent. The influence of various reaction parameters and conditions on radioiodination efficiency was investigated, and a high radiochemical yield of 92.07 ± 0.9 % was obtained. An in vitro cytotoxicity study of iodinated Azure-A on three cell lines (HCT-116, human colon carcinoma cell line; Hep-G2, liver carcinoma cell line and HFB-4, normal human melanocytes) was carried out, and the data revealed that ioiodinated Azure A has no to very low toxic effect. The in vivo biodistribution study of 131 I-Azure A showed a high brain uptake of 6.15 ± 0.09 % injected dose/g tissue organ at 30 minutes post-injection, and its retention in brain remained high up to 2 hours, whereas the clearance from the body appeared to proceed via the renal system. The experimental data were confirmed by the molecular docking studies to predict the effect of radioiodination on the binding affinity of the parent molecule (Azure A) to tau paired helical filaments (PHFs). Both ligands showed better binding to S2 and S3 pockets of (PHFs). Consequently, radioiodinated Azure A seems to be a good candidate as an imaging agent for taupathies such as Alzheimer's disease, chronic traumatic encephalopathy, and corticobasal degeneration. Furthermore, it could be a very potent theranostics agent for brain tumors.