Purinergic Receptors of the Central Nervous System: Biology, PET Ligands, and Their Applications

Abstract

Purinergic receptors play important roles in central nervous system (CNS). These receptors are involved in cellular neuroinflammatory responses that regulate functions of neurons, microglial and astrocytes. Based on their endogenous ligands, purinergic receptors are classified into P1 or adenosine, P2X and P2Y receptors. During brain injury or under pathological conditions, rapid diffusion of extracellular adenosine triphosphate (ATP) or uridine triphosphate (UTP) from the damaged cells, promote microglial activation that result in the changes in expression of several of these receptors in the brain. Imaging of the purinergic receptors with selective Positron Emission Tomography (PET) radioligands has advanced our understanding of the functional roles of some of these receptors in healthy and diseased brains. In this review, we have accumulated a list of currently available PET radioligands of the purinergic receptors that are used to elucidate the receptor functions and participations in CNS disorders. We have also reviewed receptors lacking radiotracer, laying the foundation for future discoveries of novel PET radioligands to reveal these receptors roles in CNS disorders.

Purinergic signaling in infectious diseases of the central nervous system

“…However, most of the drugs described for this receptor are allosteric ligands with low potency and poor aqueous solubility (i.e., 5-BDBD and BX-430). The most exciting P2X4 antagonist to control pain by acting in glial cells is the NC-2600, which is currently in a phase II clinical trial (Zarrinmayeh and Territo, 2020). Furthermore, A-317491, a selective and competitive antagonist for both homomeric P2X3 and heteromeric P2X2/P2X3 receptors, attenuates tactile allodynia and thermal hyperalgesia in a classic neuropathic pain model (Jarvis et al, 2002).…”

“…Given the important role of purinergic signaling in infectious diseases of the CNS, therapeutic approaches targeting this signaling would represent feasible strategies to treat these diseases and their associated neurological symptoms. Brain-penetrant purinergic receptor agonists and antagonists, as well as ectonucleotidases inhibitors, have been tested in preclinical or clinical studies, as detailed in recent reviews ( Allard et al, 2017 , Bhattacharya, 2018 , Effendi et al, 2020 , Savio et al, 2018 , Zarrinmayeh and Territo, 2020 ). In this section, we discuss some examples of drugs that could modulate purinergic signaling in neuroinfections.…”

“…P2Y 2 and P2Y 4 receptors may have complementary effects by activating microglial phagocytosis and pinocytosis of soluble amyloid β protein fragments in Alzheimer’s disease ( Weisman et al, 2012 ). Diquafosol (INS365), a P2Y 2 agonist, has already been approved as a topical treatment for dry-eye disease ( Yamane et al, 2015 ), and two additional agonists are in clinical trials (INS37217 and MRS2698) ( Zarrinmayeh and Territo, 2020 ). P2Y 1 inhibition attenuates cognitive dysfunction after brain injury ( Guzman and Gerevich, 2016 ).…”

“… Pingle et al (2007) NTPDase3/CD39L3; CD73 Undefined roles in CNS infections. References used for purinergic signaling components expressed by CNS cell types: ( Brisevac et al, 2015 , Calovi et al, 2019 , del Puerto et al, 2013 , Grković et al, 2017 , Illes et al, 2020 , Sheth et al, 2014 , Zarrinmayeh and Territo, 2020 ). * Ambiguous data reporting P2X7 expression in neurons ( Illes et al, 2017 ).…”

“… References used for purinergic signaling components expressed by CNS cell types: ( Brisevac et al, 2015 , Calovi et al, 2019 , del Puerto et al, 2013 , Grković et al, 2017 , Illes et al, 2020 , Sheth et al, 2014 , Zarrinmayeh and Territo, 2020 ). …”