Inhibition of P2Y6R has proven to be a potential therapeutic strategy for treatment of neuroinflammation, PD,282 feeding disorders, and systemic insulin resistance in obesity condition.283 Potent and selective nonnucleotide P2Y6R antagonist MRS2578 (IC50 = 37 nM, hP2Y6 R and IC50 = 98 nM, rP2Y6R) has shown to inhibit UDP-induced phagocytosis and prevent LPS-induced neuronal loss in mixed neuronal/glial cultures.284 MRS2578 specifically lacks any antagonist activity at P2Y1,2,4,11 receptors.285,286 Recently, a novel selective hP2Y6R antagonist TIM-38 was reported with low potency (IC50 = 4.3 μM).287 TIM-38 could be a useful pharmacological tool and a starting point for the development of therapeutic agents against P2Y6 receptor-implicated disease. Activation of P2Y6R by either its endogenous ligand UDP or selective agonist MRS-2693 has shown to promote production of pro-inflammatory cytokines IL-6 and IL-8 and contribute to phagocytosis of neurons.288,289 To the best of our knowledge, there has been no report of any PET radioligand for mapping of the P2Y6Rs.
