Pharmacophore screening finds new brain-imaging scaffold for the microglial P2Y12 receptor
- Existing P2Y12 ligands are charged or effluxed, so none has become a brain PET tracer; a pharmacophore screen of roughly three million compounds sought a new chemotype.
- The imidazo[1,2-b]pyrazolone scaffold emerged, and hit expansion with SAR work gave two ligands binding strongly to both human and rat receptors in radioligand assays.
- One analogue was labelled with fluorine-18 in workable yields as a proof of concept; brain imaging is future work.
- This is an unreviewed chemRxiv preprint.
💡 Points Based on the abstract
Binding potency is the easy part here; charge and efflux are what have sunk P2Y12 tracers. A neutral, compact imidazopyrazolone is a sensible escape from the acid-bearing, clopidogrel-type chemistry, but nothing yet shows it evades efflux or crosses into the brain, and that is the data that would make this interesting.
A Pharmacophore-Based Virtual Screening Approach for the Discovery of Novel P2Y12 Receptor Ligands ↗