A novel SiX-dipropargyl glycerol scaffold (X: H, F, or (18) F) was developed as a versatile prosthetic group that provides technical advantages for the preparation of dimeric radioligands based on silicon fluoride acceptor pre- or post-labeling with fluorine-18. Rapid conjugation with the prosthetic group takes place in microwave-assisted click conjugation under mild conditions. Thus, a bivalent homodimeric SiX-dipropargyl glycerol derivatized radioligand, [(18) F]BMPPSiF, with enhanced affinity was developed by using click conjugation. High uptake of the radioligand was demonstrated in 5-HT1A receptor-rich regions in the brain with positron emission tomography. Molecular docking studies (rigid protein-flexible ligand) of BMPPSiF and known antagonists (WAY-100635, MPPF, and MefWAY) with monomeric, dimeric, and multimeric 5-HT1A receptor models were performed, with the highest G score obtained for docked BMPPSiF: -6.766 as compared with all three antagonists on the monomeric model. Multimeric induced-fit docking was also performed to visualize the comparable mode of binding under in vivo conditions, and a notably improved G score of -8.455 was observed for BMPPSiF. These data directly correlate the high binding potential of BMPPSiF with the bivalent binding mode obtained in the biological studies. The present study warrants wide application of the SiX-dipropargyl glycerol prosthetic group in the development of ligands for imaging with enhanced affinity markers for specific targeting based on peptides, nucleosides, and lipids.

We have synthesized six new congeners of acetamidobenzoxazolone for Translocator Protein [18 kDa, TSPO] imaging. The best in vitro binding affinity (10.8 ± 1.2 nm) for TSPO was found for N-methyl-2-(5-(naphthalen-1-yl)-2-oxobenzo[d]oxazol-3(2H)-yl)-N-phenylacetamide, (NBMP). NBMP was synthesised by Suzuki coupling reaction between 2-(5-bromo-2-oxo-1,3-benzoxazol-3(2H)-yl)-N-phenylacetamide and napthalene-1-boronic acid. Computational docking and simulation studies showed not much impact of intersubject variability on binding which is one of the major drawbacks of several TSPO ligands. These findings suggested that NBMP may become a promising marker for visualization of neuroinflammation via TSPO targeting.

Human serum albumin (HSA) is one of the most abundant plasma proteins available in blood and responsible for transport of fatty acids, drugs and metabolites at its binding sites which are very important for the assessment of pharmacokinetics profile of the polyamino-polycarboxylic ligands.

A new prospective approach for PET imaging of 5-HT7 by a small molecule ligand.

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.