Review Article Molecular Imaging Volume 19: 1-26 ª The Author(s) 2020 Purinergic Receptors of the Central Article reuse guidelines: sagepub.com/journals-permissions Nervous System: Biology, PET Ligands, DOI: 10.1177/1536012120927609 and Their Applications journals.sagepub.com/home/mix Hamideh Zarrinmayeh, PhD1 and Paul R. Territo, PhD1 Abstract Purinergic receptors play important roles in central nervous system (CNS). These receptors are involved in cellular neuroin- flammatory 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 accu- mulated 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. Keywords purinergic receptors, central nervous system, PET ligands, biology, neuroinflammation Introduction dementia (FD), amyotrophic lateral sclerosis (ALS), multiple scleroses (MS), traumatic brain injury (TBI), stroke, cerebral The cell surface purinergic receptors (purinoceptors) are ischemia, epilepsy, psychiatric diseases, sleep disorder, and plasma membrane proteins found in nearly all mammalian tis- neuropathic pain.1,3,6,7 sues including the central nervous system (CNS).1 The history In the CNS, adenosine 50-triphosphate (ATP), an energy of the purinergic receptors goes back to early 20th century source for neurons and glial cells, also acts as an extracel- when, for the first time, an observation was made that purines lular purinergic signaling molecule that controls communi- effected cardiovascular physiology.2 Almost half a century cation between brain cells.8 The steady state concentration later, these receptors were classified based on their endogenous of cytosolic ATP is high, ranging between 5 and 10 mM, ligands into P1 and P2 categories.3 and very low (nM) in the extracellular space.9 Under patho- P1 or adenosine receptors (ARs) are a family of G protein– logical conditions and CNS insults such as trauma, ischemic coupled receptors (GPCRs) with 4 subtypes: A ,A ,A , 1 2A 2B stroke, epileptogenic seizures, cellular stress, neuroinflam- and A . P2 receptors are subgrouped into the ligand-gated ion 3 mation, and neurodegenerative disorders, high concentration channel receptors P2X with 7 receptor subtypes: P2X1,P2X2, P2X3,P2X4,P2X5,P2X6,P2X7, and P2Y, which are G protein-coupled metabotropic receptors with 8 subtypes: 1 Department of Radiology and Imaging Sciences, Indiana University School of P2Y1,P2Y2,P2Y4,P2Y6,P2Y11,P2Y12,P2Y13,andP2Y14 Medicine, Indianapolis, IN, USA (Figure 1).4 Burnstock has recently published an excellent Submitted: 31/10/2019. Revised: 11/03/2020. Accepted: 10/04/2020. review article on purinergic receptors, their distributions, and functions revealing the importance of these receptors in phy- Corresponding Author: siological system.5 Purinergic receptors play major roles in Hamideh Zarrinmayeh, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, 950 West Walnut Street, R2/E124, Indianapolis, CNS disorders including Alzheimer disease (AD), Parkinson IN, USA. disease (PD), Huntington disease (HD), frontotemporal Email: [email protected] Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). 2 Molecular Imaging Figure 1. Purinergic receptor subfamilies and their endogenous ligands. of ATP is released to the extracellular region as a danger of the existing PET radioligands that have been used as tools signal creating a cascade of events that eventually damages for understanding the functions of these receptors. the neurons.10,11 High level of extracellular ATP from the damaged cells enforces microglia to undergo chemotaxis to the site of injury Adenosine, Receptors and Functions in the in order to remove cell debris from these sites.12 Microglial CNS 13 14,15 activation results in upregulation of P2X4 and P2X7 and 16 Adenosine has been widely recognized as an inhibitory mod- downregulation of P2Y receptor expression. This balance 26 12 ulator of the CNS. It acts as a homeostatic modulator at between the expression of P2X4, P2X7, and P2Y12 receptors 26,27 28 17 synapses and participates in neurotransmitter release, dictate the destiny of microglia. A relative expression levels neuronal excitability, synaptic plasticity,29 and local inflamma- of P2X4 and P2X7 receptors are positive indicator of microglial 30,31 18 tory processes. Adenosine is complicated in neurobiology activation, while P2Y12 receptor is a negative predictor. of learning and memory29,32,33 by overstimulating the 34,35 Additionally, upon release of the large amount of ATP (hun- N-methyl-D-aspartic acid (NMDA) receptors that influence dreds of mmol), P2Y1 and P2X7 receptors facilitate movement long-term potentiation (LTP) and long-term depression of ramified microglia to the damage site, while P2Y6 receptor, (LTD).29 Additionally, adenosine participates in modulation a normally expressed receptor on the activated microglia, inter- of neurotransmissions exerted by dopamine (DA) and acetyl- 3,19 venes the process of phagocytosis. Furthermore, extracellu- choline (Ach).36-48 Consumption of drugs of abuse and psy- lar ATP can be converted to adenosine via ectonucleotidases chostimulants, either acutely or chronically, has shown to 20 CD39 and CD73 that are present in microglia and in turn modify adenosine level in the brain.49 As such, a more clear 21,22 activates ARs as well. understanding of the involvement of adenosine signaling path- While novel ligands of some purinergic receptors are cur- way during addiction might help to explore potential treatments rently used as pharmacological tools to define and modify for substance use dependence.50 Several reports have indicated 23 actions of these receptor subtypes in the CNS, there is still the involvement of adenosine in neuropathological conditions a growing need to clearly understand these receptors’ roles in including stroke,51,52 epilepsy,53 PD,54-57 and other neurode- the brain, specifically as it relates to neuroinflammation and generation disorders.31 neurodegeneration. Positron emission tomography (PET) ima- Extracellular adenosine binds to its 4 receptor subtypes A1, 30 ging has advanced our understanding of the functions of pur- A2A,A2B, and A3 to exert its effect in the CNS. A1R and 24,25 inergic receptors in healthy and pathological brains. A2AR have high affinities of 70 and 150 nM, respectively, Herein, we have reviewed the significance of the purinergic while A2BRandA3R have a distinctly lower affinities of receptors in the CNS and accumulated a comprehensive list 5100 and 6500 nM, respectively, for adenosine.58 All ARs are Zarrinmayeh and Territo 3 11 11 11 11 11 Figure 2. Structures of the adenosine A1 receptor [ C] PET radioligands: [ C]KF15372, [ C]MPDX, [ C]FR194921, and [ C]MMPD. PET indicates positron emission tomography. 52 59 60 present on neurons, astrocytes, oligodendrocytes, and Adenosine A1R and Functions in the CNS microglia.61 A is the most abundant AR subtype in the brain with broad In the brain, A and A are the major ARs.58 A receptor, 1 1 2A 1 distribution in neurons of the cortex, hippocampus, and cere- the most abundant subtype, is widely distributed in the cortex, bellum.31,58 Several studies have shown that activation of ade- hippocampus, and cerebellum, while A2A receptor is mainly 30 nosine A1R promoted neuroprotection, induced sedation, localized in the striatum and olfactory bulb. Presynaptically, 76 reduced anxiety, inhibited seizures, and reduced A1R exacer- A1 and A2A interact with adenosine to modulate the release of 58 62 bated neuronal damage. Significant reduction in A1R expres- neurotransmitters. Postsynaptically, adenosine decreases cel- sion was detected in layers of the dentate gyrus in the brain of lular excitability through activation of A1Rs or inhibition of 68,77 63 AD subjects, providing evidence that A1R agonists might A2ARs. Thus, A1Rs impose an inhibitory brake on excitatory be an effective therapy for treatment of AD even at late stages transmission, while A2A receptors engage in promoting excita- 78 64 of the disease. Additionally, A1R agonists or adenosine reup- tory effect. In general, A1R is considered a neuroprotective take inhibitors have shown to decrease the extent of brain dam- and A2A receptor is designated as a neurodegenerative recep- age in most brain injuries.78,79 There