Chalcone Based Homodimeric PET Agent, ¹¹C-(Chal)₂DEA-Me, for Beta Amyloid Imaging: Synthesis and Bioevaluation

Abstract

Homodimeric chalcone based C-PET radiotracer,C-(Chal)DEA-Me, was synthesized, and binding affinity toward beta amyloid (Aβ) was evaluated. The computational studies revealed multiple binding of the tracer at the recognition sites of Aβ fibrils. The bivalent ligand C-(Chal)DEA-Me displayed higher binding affinity compared to the corresponding monomer, C-Chal-Me, and classical Aβ agents. The radiolabeling yield with carbon-11 was 40-55% (decay corrected) with specific activity of 65-90 GBq/μmol. A significant ( p< 0.0001) improvement in the binding affinity of C-(Chal)DEA-Me with synthetic Aβ42 aggregates over the monomer, C-Chal-Me, demonstrates the utility of the bivalent approach. The PET imaging and biodistribution data displayed suitable brain pharmacokinetics of both ligands with higher brain uptake in the case of the bivalent ligand. Metabolite analysis of healthy ddY mouse brain homogenates exhibited high stability of the radiotracers in the brain with>93% intact tracer at 30 min post injection. Both chalcone derivatives were fluorescent in nature and demonstrated significant changes in the emission properties after binding with Aβ42. The preliminary analysis indicates high potential of C-(Chal)DEA-Me as in vivo Aβ42 imaging tracer and highlights the significance of the bivalent approach to achieve a higher biological response for detection of early stages of amyloidosis.

Bio-Evaluation of 99mTc-Labeled Homodimeric Chalcone Derivative as Amyloid-β-Targeting Probe

“…The docking score of DT(Ch) 2 was found higher than the currently FDA-approved tracers, such as florbetaben, florbetapir, and flutemetamol (36). Additionally, in comparison to previously reported chalcone derivatives, such as dihydrochalcone and Chal-Me, which have binding affinity to amyloid fibrils, binding energy for DT(Ch) 2 was comparable but lower than the dimeric derivative of Chal-Me, (Chal) 2 DEA-Me ligand (32,37). A similar range of binding energy was also reported for recently synthesized isoxazolone and triazole derivatives (38,39).…”

Phytochemicals toward Green (Bio)sensing

“…Considering the key role of chalcones in Aβ42 amyloids targeting, a chalcone (Figure - 9e )-based homodimeric ligand labeled with carbon-11 ( 11 C) radioisotope was developed for positron emission tomography (PET) imaging of Aβ. The results showed this bivalent ligand could be potentially applied as an in vivo Aβ imaging tracer . The derivative forms of chalcones have been frequently employed for bioimaging applications.…”

“…Given the importance of Aβ proteins biosensing/bioimaging as one of the main amyloid plaques that are thoroughly related to the pathogenesis and diagnosis of incurable Alzheimer’s disease, several phytochemicals have been utilized so far for their bioimaging in the brain. − …”

Designing drugs and chemical probes with the dualsteric approach

“…Other targets reported with dualsteric modulators include hydrolases, [163][164][165][166][167][168][169][170][171][172][173][174][175] isomerases, 176 oxidoreductases, 177,178 and transport proteins. [179][180][181][182][183][184][185][186][187][188] The small population of these cases suggests a broaden prospect for developing dualsteric modulators targeting proteins apart from GPCR and kinase.…”