Development and Validation of [3H]Cimbi-36 Binding in Mouse Frontal Cortex Including Affinity Constant Determination for Classical Psychedelics: Comparison to [3H]MDL100,907 Binding

Radioligand choice in competitive binding assays can affect the affinity of a ligand for the receptor.

At Sygnature Discovery, we have validated a receptor binding screen for 5-HT_2A receptors utilising agonist and antagonist radioligands, to investigate receptor pharmacology and translate cell binding data to pre-clinical behaviour, DMPK and ex vivo receptor binding.

Antagonists bind to receptors in the active and inactive state whereas agonists only bind to the active state. Cimbi-36 is a potent and selective 5-HT_2A agonist, commonly used in PET imaging studies. Sygnature Discovery has developed a radioligand binding assay using [³H]Cimbi-36 to label 5-HT_2A receptors in the mouse frontal cortex. We have demonstrated that the affinity of some psychedelic 5-HT_2A agonists differs when using an agonist or antagonist radioligand. Sygnature Discovery can advise on experimental design so that each stage of drug discovery complements the next and ensures in vitro data can be correlated with behavioural models.