<i>In Vivo</i> PET Imaging of Adenosine 2A Receptors in Neuroinflammatory and Neurodegenerative Disease

Vuorimaa, Anna; Rissanen, Eero; Airas, Laura

doi:https://doi.org/10.1155/2017/6975841

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In Vivo Imaging of Inflammation and Infection

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Review Article | Open Access

Volume 2017 | Article ID 6975841 | https://doi.org/10.1155/2017/6975841

In Vivo PET Imaging of Adenosine 2A Receptors in Neuroinflammatory and Neurodegenerative Disease

Anna Vuorimaa,^1,2Eero Rissanen,^1,2and Laura Airas^1,2

Academic Editor: Weibo Cai

Received10 Aug 2017

Accepted18 Oct 2017

Published20 Nov 2017

Abstract

Adenosine receptors are G-protein coupled P1 purinergic receptors that are broadly expressed in the peripheral immune system, vasculature, and the central nervous system (CNS). Within the immune system, adenosine 2A () receptor-mediated signaling exerts a suppressive effect on ongoing inflammation. In healthy CNS, receptors are expressed mainly within the neurons of the basal ganglia. Alterations in receptor function and expression have been noted in movement disorders, and in Parkinson’s disease pharmacological receptor antagonism leads to diminished motor symptoms. Although receptors are expressed only at a low level in the healthy CNS outside striatum, pathological challenge or inflammation has been shown to lead to upregulation of receptors in extrastriatal CNS tissue, and this has been successfully quantitated using in vivo positron emission tomography (PET) imaging and receptor-binding radioligands. Several radioligands for PET imaging of receptors have been developed in recent years, and receptor-targeting PET imaging may thus provide a potential additional tool to evaluate various aspects of neuroinflammation in vivo. This review article provides a brief overview of receptors in healthy brain and in a selection of most important neurological diseases and describes the recent advances in receptor-targeting PET imaging studies.

1. Introduction

Adenosine is a highly bioactive molecule, which is stored inside cells as adenosine triphosphate (ATP) and transported to the extracellular space by transporter molecules or catabolized into adenosine extracellularly by ectoenzymes CD39 and CD73 [1, 2]. It is rapidly transported back into cells and degraded into inosine or phosphorylated back to adenosine monophosphate (AMP) by adenosine deaminase and adenosine kinase, respectively [1]. Within the central nervous system (CNS), neurons and glia release adenosine, and concentration of adenosine increases in the extracellular space following ATP release during inflammation or cellular trauma [3]. Adenosine is ubiquitous, but short-lived [4]. It confers its biological effects locally via four adenosine-binding purinergic P1 receptors: A₁, , , and A₃ [1]. This leads to physiological regulation of a variety of important CNS functions, such as modulation of neuronal excitability, release and uptake of neurotransmitters, and modification of synaptic plasticity [5–9]. In addition, adenosine receptors have a vasoactive function [10] and an important role in controlling inflammatory events [11]. In particular, signaling through the adenosine 2A () receptor has been described as a potent regulator of inflammation [12]. In healthy CNS, receptor expression is the greatest in the neurons of the basal ganglia, where it is involved in motor control in conjunction with dopamine 2 (D₂) receptors, but under pathological conditions, receptor expression has been demonstrated also in brain areas outside the striatum [13]. Importantly, pharmacological targeting of receptors using antagonists or agonists may have important therapeutic implications in several CNS diseases [14]. receptor-binding radioligands have enabled in vivo positron emission tomography (PET) imaging of receptor expression. The human receptor PET studies have focused either on the striatal neuronal receptor expression, relevant to movement disorders [15, 16], or on receptor upregulation in the white matter in the context of neuroinflammatory disease [13]. This review will provide a brief overview of receptors in healthy brain and will describe their involvement in a selection of most important neurological diseases, such as Parkinson’s disease (PD), Huntington’s disease (HD), stroke, and multiple sclerosis (MS). The role of in vivo PET imaging in advancing the understanding of the receptor biology within the CNS will be discussed.

2. A_2A Receptor Expression in Various CNS Compartments and Cell Types

2.1. Neurons

Adenosine receptors are far more abundant in the brain than in any other organ [17]. In healthy brain, receptor expression is most prominent in neurons of the basal ganglia (Figure 1) [18, 19]. receptors are also expressed in neurons in the neocortex and the limbic cortex [20–22], where they are predominantly present in nerve terminals, albeit with a density 20 times lower than that found in the basal ganglia [20]. The distribution of receptors is similar in rodents and humans [23, 24]. However, the level of extrastriatal receptor expression appears to be higher in humans than in rodents [18]. In the basal ganglia, the receptors are colocalized with dopamine 2 receptors in the striatopallidal gamma-aminobutyric acid (GABA)ergic neurons containing enkephalin [18, 25]. receptors are mostly localized postsynaptically [26] but are also found presynaptically on glutamatergic nerve terminals, where they contact the direct-pathway medium spiny neurons [27] and can form heteromers with A₁ receptors [9]. receptor antagonists have also been found to modify the N-methyl-D-aspartic acid (NMDA) receptor subunit composition in transgenic R6/2 mice [28]. The ability of receptors to control the release of glutamate in the cerebral cortex [8, 29, 30], hippocampus [21, 22, 31], and striatum [32–38] has led to the hypothesis that the reduction in glutamate release might be the explanation for the neuroprotective effects of receptor antagonism [39, 40]. The inhibition of glutamate release by receptor antagonism seems, however, strongly time dependent in relation to lesion formation and animal age. Quinolinic acid (QA) induced glutamate release is almost completely blocked in rat striatum by pretreatment with receptor antagonist SCH58261 [39] but this effect of receptor antagonist is reversed two weeks after QA lesion, when SCH58261 significantly increases glutamate outflow [37]. Similarly, spontaneous outflow of glutamate in response to SCH58261 treatment in young rats is different from that in aged ones [35]. Future studies are awaited to confirm the usefulness of receptor antagonism in protection from glutamate-related neurotoxicity in various neurodegenerative conditions.

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2.2. Endothelial Cells

Brain endothelial cells, together with astrocytes and pericytes, form the blood-brain barrier (BBB), a physical barrier that protects the CNS against blood pathogens and prevents immune cell infiltration [41]. Endothelial cells of the BBB are linked together with occludins, claudins, and junctional adhesion molecules (JAMs) that form the tight junctions that inhibit almost all the paracellular transportation through the BBB [42]. Although the BBB allows less passing than most endothelial barriers under normal circumstances, during CNS infection, trauma or autoimmunity immune cells from the periphery gain access to the CNS parenchyma [43]. One possible mediator controlling BBB permeability is the adenosine receptor [44].

receptors are expressed on human brain endothelial cells together with adenosine-forming enzymes, CD39 and CD73 [45–47]. receptor expression has also been described on mouse and rat brain endothelial cells [48]. Evidence from animal studies suggests that activation of the receptors promotes an increase in BBB permeability to macromolecules [48]. However, another study suggested that the increased production of adenosine via induction of the adenosine-generating ectoenzyme CD73 on primary human brain endothelial cells after interferon beta (IFN-β) treatment leads to improved barrier function, but the target molecule of adenosine in this particular setting remains uncertain [49]. Activation of receptors with a broad-spectrum adenosine receptor agonist 5′-N-ethylcarboxamidoadenosine (NECA) or receptor-specific agonist Lexiscan (regadenoson, FDA approved for use as a pharmacological stress agent for radionuclide myocardial perfusion imaging) increased BBB permeability to macromolecules such as 10 kD dextrans (NECA and Lexiscan) and 70 kD dextrans (NECA) and antibodies to β-amyloid (NECA) in vivo [48]. Increase in barrier permeability after receptor agonist treatment was linked to changes in cell cytoskeleton structure, measured as decreased transendothelial cell electrical resistance (TEER) and actomyosin stress fiber formation, as well as decreased expression of tight junctions molecules, most strongly occludin [48]. Similar cytoskeletal changes were observed in primary human brain endothelial cells after treatment with receptor agonist [45]. Furthermore, receptor agonist treatment has been shown to promote paracellular transendothelial migration of lymphocytes through a model of human BBB [45]. In peripheral blood vessels the role of receptors in the control of vessel permeability remains less clear, as receptor agonists have been shown, depending on conditions, to either increase or decrease endothelial permeability [50–54].

2.3. A_2A Receptor in Choroid Plexus

In order for immune cells to gain access to the CNS, they need to cross either of the protective barriers between the periphery and CNS: the BBB or the blood-cerebrospinal fluid barrier (BCSFB). The BCSFB is formed by the choroid plexus and is made up of fenestrated capillaries, which are surrounded by parenchyma covered with epithelial cells that, like the BBB endothelial cells, are joined together by tight junctions [55, 56]. receptors are expressed on choroid plexus endothelial cells, where they seem to regulate lymphocyte migration into the CNS [57, 58]. This was also shown to contribute to the development of experimental autoimmune encephalomyelitis (EAE), the animal model of MS [57]. Here, ATP released from damaged cells within the CNS is hydrolyzed to adenosine by choroid-plexus-expressing ectoenzymes CD39 and CD73. Adenosine binds to the receptor and facilitates the lymphocyte entry via enhancing CX3CL1 expression at the choroid plexus [59]. Lack of receptors results in reduced lymphocyte entry [57].

2.4. A_2A Receptors in Glia

A role for receptors has been described in oligodendrocyte differentiation. receptor expression has been demonstrated on oligodendrocyte precursor cells [60], and receptor signaling seems to inhibit oligodendrocyte progenitor cell maturation, whereas A₁ receptor signaling promotes it [61, 62]. Under chronic inflammatory or neurodegenerative conditions, receptor expression has been demonstrated also in other CNS areas and cell types, such as microglia [63, 64] and astrocytes [65]. In several neurodegenerative CNS diseases astrogliosis can contribute to the disease pathogenesis by contributing to cellular death. Interestingly, receptor antagonism might contribute to control of astrogliosis, as antagonists SCH58261 and KW6002 were shown to significantly inhibit signs of astrogliosis in a primary cell culture of striatal rat astrocytes [66]. Similarly, receptor activation led to morphological changes in cultured microglia indicative of further microglial activation, a phenomenon which could be blocked using receptor antagonists [63]. Hence, astrocytes and microglia might provide the central link between receptor-mediated effects in neuroinflammatory and neurodegenerative diseases, which will be discussed in the next chapters.

3. A_2A Receptors in Neurodegenerative Disease

3.1. Parkinson’s Disease

receptors are abundantly expressed on neurons in the striatum [18, 19], where they colocalize with dopamine 2 receptors on the GABAergic striatopallidal neurons of the “indirect pathway” [25, 67]. In the classical model, direct and indirect pathways work together in fine-tuning movement by exciting and inhibiting the cerebral motor cortex, respectively. Presently, it is acknowledged that complex interplay is likely to occur between these two pathways [68]. and D₂ receptors are functionally antagonistic, as receptor antagonist can exert a similar effect on motor control as D₂ agonists. This effect is explained by the receptors’ opposing effect on adenylyl cyclase and by their ability to form heteromers [69, 70]. In PD, loss of dopaminergic input from substantia nigra leads to unbalance of the sensitive motor behavior controlling system. Initially effective solution to depletion of dopamine in PD has been dopamine replacement therapy by levodopa. However, in chronic levodopa treatment, patients start experiencing dyskinesias and symptoms of “wearing-off”; that is, there will be motor fluctuations as the effective time of the medication shortens [71]. Because receptor antagonists exert suppression similar to D₂ receptor activation on the medium spiny neurons of the indirect pathway, they have been studied as an add-on therapy to levodopa in PD [72].

PET imaging using receptor-binding radioligands has been used to evaluate striatal receptor expression in PD in vivo. Distribution volume ratio (DVR) of [¹¹C]TMSX ([7-N-methyl-¹¹C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine) binding in the putamen was shown to be higher in PD patients with dyskinesias (disease duration: 11.1 ± 7.2 years) compared to healthy controls [16]. On the other hand, in drug-naïve patients (disease duration: 2.0 ± 1.2 years) there was no significant difference in [¹¹C]TMSX binding compared to healthy controls. [¹¹C]TMSX DVR was, however, increased in the putamen in a follow-up scan after approximately a year of induction of antiparkinsonian therapy compared to the baseline scans, despite the absence of clinical dyskinesias [16]. Similarly, using another receptor-binding radioligand, [¹¹C]SCH442416, and PET imaging, a significant increase was found in the binding potential in the putamen and the nucleus caudatus in PD patients with levodopa-induced dyskinesias (disease duration: 13.2 ± 5.6) compared to PD patients with levodopa treatment without dyskinesias (disease duration: 6.2 ± 3.4) and to healthy controls [15].

3.2. Huntington’s Disease

Brain pathology in HD is characterized by striatal atrophy with a selective loss of medium spiny neurons [73]. Interestingly, neuropathological studies have demonstrated a marked loss of striatal receptors in early stages of HD [23, 74], and similar loss of receptors is reported in transgenic mouse models of HD [75–77]. Moreover, expression of mutant Huntingtin was shown to lead to reduced receptor expression in cell cultures by regulating transcription of the receptor gene [78]. Finally, receptor gene (ADORA2A) rs 5751876 genotype was shown to affect the age of onset of HD in humans [79]. In transgenic HD animal models, blockade of receptors rescues cognitive performance impaired by the disease [80, 81]. receptor agonists on the other hand have shown to reverse motor deficits [77], whereas blockade of the receptor worsens motor performance [76, 82]. In vivo receptor-targeting PET imaging using [¹¹C]KF18446 has been used to demonstrate reduced receptor expression in an animal model of HD [83]. Here, the binding potential of KF18446 was significantly decreased in the quinolinic acid-lesioned striatum. Thus, in vivo imaging of receptors in HD patients might provide insight into the pathologic changes in receptors in different stages of the disease. Moreover, PET imaging of receptors could be availed for interrogating treatment response to possible adenosine signaling targeting therapies in HD. To our knowledge, no receptor-targeting PET imaging has yet been performed in HD patients.

3.3. Alzheimer’s Disease

receptors are upregulated in the frontal cortex and hippocampus in Alzheimer’s disease (AD) [65, 84] and likewise in animal models of AD [5, 85]. In vitro, receptor antagonists prevent amyloid β () induced neurotoxicity and synaptotoxicity [5, 86–88], whereas receptor agonists increase production [89]. In various animal models of AD, blockade or genetic deletion of receptors enhances memory function [5, 90–92]. receptor activation is in fact sufficient to disrupt memory even in healthy rats [93, 94]. On the other hand, treatment of APP/PS1 mice with receptor antagonist was shown to increase accumulation in cortical neurons (but not in the hippocampus) [95]. receptor activation specifically in the hippocampus was shown to impair memory, whereas in the nucleus accumbens it only induced locomotor activity instead [94]. Interestingly, activation of chimeric rhodopsin- receptor by light stimulated the cAMP-PKA pathway and increased CREB and c-Fos expression in the hippocampus but stimulated the MAPK signaling pathway in the nucleus accumbens [94]. Finally, Orr et al. showed that selective deletion of receptors from astrocytes enhanced memory in an AD animal model [65]. Even though receptor antagonism or deletion in animal models of AD mainly appears to exert neuroprotective effects, the causal relationship between adenosine signaling and amyloid deposition, as well as disease progression, remains unclear. More efficient therapies for halting or slowing down the course of the disease in AD are sorely needed, and anti- therapy appears as an intriguing option in this field. Before this, however, additional evidence of the role of receptors in AD as well as in other neurodegenerative diseases would be needed. Imaging receptors in different stages of the disease and in studying treatment response to novel emerging therapies would shed more light on the understanding of the disease pathology. Still, to our knowledge, there are as yet no in vivo PET studies of receptor expression in AD or in animal models of AD.

4. A_2A Receptors in Multiple Sclerosis

4.1. Pathological Characteristics of Progressive Multiple Sclerosis

MS is traditionally considered an autoimmune disease, where an immune attack towards myelin leads to demyelination and bouts of neurological symptoms [96]. Neuropathological studies have demonstrated that, in addition to the active focal inflammation, there is also an ongoing neurodegenerative process, which starts already early on in the relapsing remitting multiple sclerosis (RRMS) phase of the disease, in both the gray matter and the white matter, and leads to gradual axonal damage, neuronal loss, and CNS atrophy [97]. With time, the RRMS disease advances to a secondary progressive phase (SPMS), with an alteration in neuropathological findings [98]. In addition to the focal inflammatory lesions, increased spreading of the inflammatory process into the so-called normal appearing white matter (NAWM) with involvement of brain resident glial cells is seen [98]. This inflammation can be measured in vivo using translocator protein-18 kDa (TSPO) PET imaging [99, 100]. The widespread microglial activation presumably contributes to the ongoing neurodegenerative process leading to clinical disease progression, but in general the mechanisms of neurodegeneration in progressive MS are presently relatively poorly understood. Importantly, better understanding and better alternatives for in vivo measurement of the pathological processes leading to disease progression would enhance therapeutic development for this undertreated condition [101].

4.2. Evidence of the Role of A_2A Receptors in Multiple Sclerosis Pathogenesis

Direct data on the role of receptors in MS is still scarce, but in vivo PET imaging studies using the receptor-binding radioligand [¹¹C]TMSX have demonstrated that receptor expression is increased in the NAWM of patients with SPMS compared to age- and sex-matched controls (Figure 2) [13]. Importantly, increased binding in the NAWM correlated with increased clinical disability score (EDSS) and decreased fractional anisotropy (FA) in diffusion tensor imaging (DTI) of SPMS patients, suggesting that the receptors have a likely role in the disease pathogenesis. In respective areas of normal appearing MS brain, increased microglial activation has been demonstrated using TSPO-binding radioligand [¹¹C]PK11195 and PET [99]. The identity of receptor-expressing cells in the context of MS is yet to be confirmed. It is nevertheless plausible to hypothesize that activated glia could be among the cell types expressing receptor in the SPMS NAWM, as receptor expression on activated glia has been demonstrated in other settings involving an inflammatory or neurodegenerative environment [63, 65, 102]. Interestingly, increased adenosine levels have been demonstrated in the cerebrospinal fluid and serum of MS patients compared to controls [103, 104]. Moreover, high consumption of coffee (caffeine is a nonspecific antagonist of A₁ and receptors) associates with decreased susceptibility risk of MS [105] and with reduced risk of progression of RRMS [106], also suggesting that receptor signaling might have a role in evolvement of MS. No clinical trials targeting receptors in MS have been performed, but EAE studies suggest that adenosine signaling might have a robust effect on CNS inflammation, as discussed below.

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Figure 2

Brain MRI and [¹¹C]TMSX PET images from a 45-year-old healthy female (a and b, resp.) and of a 48-year-old female with SPMS (disease duration: 6 years, EDSS 7.5) (c and d, resp.). The images represent axial views from gadolinium-enhanced T1 images (a and c) and parametric [¹¹C]TMSX PET images with each voxel’s intensity representing the distribution volume (V_T, ml/cm3) value of the ligand fused with the T1 image (b and d). A pattern of increased [¹¹C]TMSX binding can be observed around the T1 hypointense lesions (white arrows) and within the mildly active plaque in the frontal white matter (yellow arrow) of the SPMS patient compared to the lower, homogeneous binding in the white matter of the healthy control. Figure reprinted with permission from Rissanen et al. (2013) [13].

4.3. Evidence of the Role of A_2A Receptors in EAE

Treatment of EAE with receptor antagonists such as caffeine or SCH58261 has been shown to significantly reduce clinical scores in multiple mice and rat models of EAE [57, 58, 107–109]. Accordingly, infiltration of inflammatory cells is decreased in the cerebral cortex and spinal cord [58, 107, 109], and demyelination is reduced in these animals [107, 109]. Moreover, mice deficient in CD73 molecule, an ectoenzyme that catalyzes ATP into adenosine, have significantly milder EAE disease and little immune cell infiltration [58]. This supports the notion that preventing stimulation of the receptors within the CNS helps ameliorate EAE.

Conversely and surprisingly, other studies show that genetic removal of receptors results in initial worsening of EAE, after which disease score returns to level of wild type controls [57, 102]. Here histopathology accordingly shows initial increased infiltration of CD4+ T lymphocytes and increased reactivity of microglial activation markers CD11b+/F480+ and Iba-1 in the brain and spinal cord [57, 110]. Interestingly, treatment with receptor agonists from time of immunization (day 0) reduces EAE scores [102, 111], but delayed treatment causes an opposite effect and exacerbates the disease. The opposite is seen with receptor antagonists: treatment with caffeine from day 0 leads to higher mean EAE scores and treatment from day 10 results in lower mean EAE scores [109].

5. A_2A Receptors in Ischemia and Stroke

Adenosine is excessively released from cells under ischemic conditions [3]. receptor expression in rat brain is increased in the striatum on neurons and microglia following cerebral ischemia [112]. receptors can be beneficially targeted under ischemic conditions, as receptor blockade by genetic deletion of the receptor or pharmacological inhibition protects against cerebral ischemia and ischemia-reperfusion injury in multiple animal studies [113–123]. The protective effect is possibly due to inhibition of glutamate outflow [30, 119]. Because global deletion of receptors seemed protective against ischemia, Yu et al. [124] tested the effect of selective deletion of receptors from bone marrow-derived cells (BMDC) and found that selective reconstitution of receptors on BMDCs reinstated the ischemic brain injury in global receptor knockout mice. Accordingly, selective lack of receptors in the BMDC compartment was sufficient to abolish the protective effect of receptor genetic deletion.

Although the literature on the beneficial effect of the receptor antagonists in ischemia is abundant, some studies suggest that the protective effect of the receptor blockade is lost following excessive reperfusion injury. A recent study suggests that, although receptor antagonists initially protect against transient ischemic injury, the protective effect is lost 7 days after ischemia despite chronic treatment with the antagonist (twice a day) [125]. Similarly, chronic 8-(3-chlorostyryl) caffeine treatment (s.c.) did not show any effect on infarct volume at 72 hours after permanent occlusion of the middle cerebral artery (MCAo) [126] and genetic deletion even worsened ischemic injury in young mice when assessed at 5 days after permanent occlusion of the common carotid artery [127]. Interestingly, receptor agonist CGS21680 (i.p.) was shown to reduce infarct volume (rat cortex but not striatum), microglial activation, and granulocyte infiltration into the brain following transient MCAo when assessed 7 days after ischemia [128].

6. A_2A Receptor-Binding Radioligands in Human PET Studies

PET imaging of receptors has been used in clinical research in humans but is not generally available or utilized in routine clinical practice. In the clinical diagnostics of neurodegenerative diseases, [¹²³I]β-CIT-SPECT (single-photon emission computed tomography) can be used for imaging dopamine transporter availability for differential diagnostics of early or atypical PD, [¹¹C]PIB for identifying amyloid pathology in early AD if routine morphological imaging is normal, and [¹⁸F]FDG (2-deoxy-2-[fluorine-18]fluoro-D-glucose) for detecting hypometabolism and differentiating dementia with Lewy bodies (DLB) or frontotemporal lobe degeneration (FTD) from AD. In addition, [¹²³I]β-CIT-SPECT may aid in differentiating between DLB and AD. For imaging neuroinflammation, [¹⁸F]FDG could theoretically be used for detecting hypermetabolism, but due to its unspecificity, it is of limited value in clinical practice compared to routine MRI imaging and cerebrospinal fluid (CSF) analyses. Thus, when imaging the detailed mechanisms of receptors in neuroinflammation, more specific probes, such as receptor-binding radioligands, are needed.

In the healthy CNS, human in vivo PET studies demonstrate greatest receptor ligand binding in the basal ganglia, whereas low radiotracer accumulation was shown in cortical areas and cerebellum [19, 129–131]. Subject age does not seem to affect striatal receptor radioligand binding [132]. Regarding evaluation of disease-related receptor expression in vivo, interest in PD therapy development has clearly been the driving force. Here, the main focus has been the variation in the receptor level within the striatum, according to disease stage and medication, as discussed above [15, 16, 133]. Several ligands for imaging the receptors have been developed and five of them, that is, [¹¹C]TMSX, [¹¹C]Preladenant, [¹¹C]SCH442416, [¹⁸F]MNI-444, and [¹¹C]KW6002, have been tested in human subjects. Their chemical structures are presented in Figure 3. Below, we discuss the characteristics and the usability of these five radioligands.

6.1. [¹¹C]TMSX

[¹¹C]TMSX is a methylxanthine analog of KF17387. It is the most widely used receptor radioligand and its binding to receptors in humans has been described in the brain [134], myocardium [135, 136], and skeletal muscle [137, 138]. [¹¹C]TMSX (previously named KF18446) was first developed by Ishiwata et al. [139] in search of more 2A receptor selective ligands after previously tested xanthine-type ligands had proven poor selectivity over A₁ and high nonspecific binding [140]. In the rat, [¹¹C]TMSX shows relatively low affinity for the receptor (Table 1) and about 270-fold selectivity to receptors over A₁ [139]. In human brain, receptor antagonist theophylline reduced [¹¹C]TMSX binding in the putamen by 4.5% and in the nucleus caudatus by 8%, but not in other areas outside of striatum [134]. Specific binding is highest in the striatum, with reported binding potential (BP) of 1.2–1.25 in the putamen [19] and DVR 1.67 in the striatum [141], followed by lower binding in the thalamus, cerebellum, brainstem, and the cortex [19]. Both the centrum semiovale [142] and the cerebral cortex [132] have been used as reference for calculating TMSX binding. In addition, a semiautomated method using supervised clustering for the extraction of gray matter reference region has been developed [141].

Acquiring metabolite corrected plasma input function via arterial cannulation and repeated arterial sampling for the measurement of the radioligand activity and metabolism is considered the golden standard in brain PET image analyses especially with novel ligands without a priori knowledge of the ligand’s kinetics and metabolism. However, this methodology can be unpleasant for the study subjects, may be prone to errors, and requires more expert personnel. Therefore, optional methods for obtaining plasma input function have been developed, including independent component analysis [142] and intersectional searching algorithm with averaging and clustering of PET data (robust EPISA) [150]. Importantly, plasma input methods can be affected by the fraction of radioactive metabolites. Using nonmetabolite corrected input has been reported to underestimate the [¹¹C]TMSX distribution volume (V_T) by approximately 5% when compared with metabolite corrected plasma input [142]. Consequently, a noninvasive, validated method for obtaining metabolite corrected population-based plasma input function for [¹¹C]TMSX has been developed and validated [141]. Dosing and blood sampling under dimmed light is required due to [¹¹C]TMSX photoisomerization.

6.2. [¹¹C]SCH442416

[¹¹C]SCH442416 (5-amino-7-(3-(4-[¹¹C]methoxy)phenylpropyl)-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine) was the first suitable nonxanthine radioligand for the imaging of receptors. In a blocking study with vipadenant (an receptor antagonist), the highest radioligand binding measured as metabolite corrected V_T was seen in putamen ( ml/cm³), followed by caudate, nucleus accumbens, thalamus, and cerebellum ( ml/cm³) [149]. receptor blocking with vipadenant resulted in notable 3-4-fold reduction in total [¹¹C]SCH442416 binding (V_T) in striatal ROIs and also in about up to 2-fold reduction in cerebellum. Two later studies have shown very different specific binding potentials in the putamen when using the cerebellum as a reference region for the estimation of specific radioligand binding. Grachev et al. [148] reported the average binding potential () of five healthy subjects in the putamen as 2.47 ± 0.84, whereas Ramlackhansingh et al. [15] reported the average of six healthy controls (control group in a PD study) to be as low as 0.99 ± 0.21. The intersubject variability was, however, fairly large in the aforementioned study ( 1.12–3.82 in the putamen) [148]. In both studies spectral analysis with metabolite corrected arterial plasma input and cerebellum as a reference region were used for the quantification of specific radiotracer binding. Whether or not the region of interest (ROI) for cerebellum as reference region was defined in a similar manner in both studies—a possible source of discrepancy in the results—is not known. Finally, neither study reported the use of coffee or other caffeine-rich beverages prior to imaging session. In PET imaging studies using other ligands [13, 132], abstinence from caffeinated drinks has been required at least for 12 hours before the scan in order to rule out the possible blocking effect by caffeine.

6.3. [¹¹C]Preladenant

[¹¹C]Preladenant has high affinity for the receptor and >1000-fold selectivity to the over the other adenosine receptor subtypes [143]. First human study with [¹¹C]Preladenant was recently published [129]. Here, eight healthy male subjects were tested. Approximately 78% of Preladenant was unmetabolized at 60 minutes. In a rat study, 17% of the total radioactivity in the brain was due to radioactive metabolites at 60 minutes [151]. It will be thus necessary to take these radiometabolites into consideration in the kinetic modeling, with metabolite corrected input function. [¹¹C]Preladenant has a DVR of 7.9 ± 2.3 in the putamen and shows lower binding in the frontal cortex, thalamus, and cerebellum [129]. In rhesus monkeys, pretreatment with Preladenant before PET imaging with [¹¹C]Preladenant reduced striatal binding to extrastriatal levels but also reduced extrastriatal binding [144]. Cerebellum was nevertheless used as a reference region.

6.4. [¹⁸F]MNI-444

[¹⁸F]MNI-444 is the only [¹⁸F]-labeled radioligand used in humans. It has relatively high affinity ( = 2.8 nM) for the human recombinant receptor [145]. Reported to putamen is 4.7 ± 0.63, to globus pallidus 3.67 ± 0.69, and to caudate 2.69 ± 0.74 [130]. Also in these studies, cerebellum was used as a reference region although a dose-independent reduction in cerebellar binding was found in preblocking with Tozadenant and Preladenant in the rhesus monkey [146].

6.5. [¹¹C]KW6002

In rodent and human studies, [¹¹C]KW6002 shows high binding in the striatum, but binding is also detected in the cerebellum and thalamus. In addition, preblocking with receptor antagonist KW6002 reduced [¹¹C]KW6002 binding to receptors in all studied brain regions [152, 153]. The authors concluded that the extrastriatal binding could be explained by binding to A₁ and receptors, although no effect of receptor antagonist on [¹¹C]KW6002 binding was found [153]. Due to its inadequate specificity, this ligand has not been further developed.

6.6. Challenges in A_2A Receptor PET Imaging

Even though the highest specific [¹¹C]TMSX binding occurs in putamen and caudate, there appears to be some specific, albeit lower, receptor binding in extrastriatal tissues such as cortical gray matter and cerebellum. The rate of specific binding, calculated as BP/V_T, has been reported to be as high as 53% in cerebellum and 37.8–42.7% in cerebral cortex for [¹¹C]TMSX [19]. Similarly, the previously mentioned blocking studies with newer receptor radioligands demonstrate the presence of some specific receptor binding in extrastriatal gray matter. Therefore, both cerebellum and cerebral cortex appear as less than optimal reference regions. Moreover, in diseases with widely spread pathology, such as MS, a common, anatomically defined reference region that is presumably free of disease pathology, inflammatory activity, and possible specific binding is difficult to find. Also, when studying diseases with predominant white matter affliction, such as MS, centrum semiovale is not a feasible reference region either, even though in healthy controls the receptor binding in central white matter is negligible. In order to overcome these issues, a method for supervised clustering of the reference region has been developed and validated for [¹¹C]TMSX based on the same algorithm used for [¹¹C]PK11195 studies (SuperPK software) [154]. Importantly, this method is based on predefined kinetic classes, where the shape of the time activity curve (TAC) in the gray matter reference region is considered to represent nonspecific binding as opposed to the high specific binding with different TAC shape [141].

7. Conclusion

There is increasing interest in the therapeutic development of receptor antagonists and agonists in a variety of neurological conditions. receptors are ubiquitously expressed in various areas of the CNS, but their significance in the context of the different CNS diseases still needs clarification. Pathological processes in CNS diseases are particularly difficult to investigate for reasons such as the difficulties in obtaining representative biopsies from the brain. PET imaging, on the other hand, provides an excellent opportunity to evaluate disease-specific pathology in vivo, by allowing quantitative study of the receptors of interest in an appropriate pathological environment in situ. With the increasing variety of receptor-binding PET ligands available for use in human in vivo PET imaging, there is good likelihood that PET imaging will improve our understanding of the involvement of receptors in the pathophysiology and pathogenesis of brain diseases, both in the neuronal compartment of the basal ganglia and in relation to inflammation, such as in progressive MS. Groups of patients can be studied cross sectionally at various stages of a given disease or, alternatively, PET imaging can be applied longitudinally to evaluate alterations in the receptor in the course of the disease or in response to treatment. PET imaging of neuroinflammation has relied heavily on TSPO-binding radioligands, but methodological challenges related to TSPO-imaging has directed the field to actively seek alternative imaging probes. receptor PET imaging provides one such alternative that is worth further exploring.

Conflicts of Interest

The authors declare that there are no conflicts of interest regarding the publication of this article.

Acknowledgments

This work was supported by the Finnish Academy, Sigrid Juselius Foundation, and the Finnish Parkinson Foundation.

References

B. B. Fredholm, A. P. Ijzerman, K. A. Jacobson, K. Klotz, and J. Linden, “International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors,” Pharmacological Reviews, vol. 53, no. 4, pp. 527–552, 2001.
View at: Google Scholar
B. B. Fredholm, Y. Chern, R. Franco, and M. Sitkovsky, “Aspects of the general biology of adenosine A2A signaling,” Progress in Neurobiology, vol. 83, no. 5, pp. 263–276, 2007.
View at: Publisher Site | Google Scholar
M. Idzko, D. Ferrari, and H. K. Eltzschig, “Nucleotide signalling during inflammation,” Nature, vol. 509, no. 7500, pp. 310–317, 2014.
View at: Publisher Site | Google Scholar
G. H. Möser, J. Schrader, and A. Deussen, “Turnover of adenosine in plasma of human and dog blood,” American Journal of Physiology, vol. 256, no. 4 Pt 1, pp. C799–C806, 1989.
View at: Google Scholar
S. V. Da Silva, M. G. Haberl, P. Zhang et al., “Early synaptic deficits in the APP/PS1 mouse model of Alzheimer's disease involve neuronal adenosine A2A receptors,” Nature Communications, vol. 7, Article ID 11915, 2016.
View at: Publisher Site | Google Scholar
B. M. Fontinha, J. M. Delgado-García, N. Madroñal, J. A. Ribeiro, A. M. Sebastião, and A. Gruart, “Adenosine A(2A) receptor modulation of hippocampal CA3-CA1 synapse plasticity during associative learning in behaving mice,” Neuropsychopharmacology, vol. 34, no. 7, pp. 1865–1874, 2009.
View at: Publisher Site | Google Scholar
D. Boison, “Adenosine dysfunction in epilepsy,” Glia, vol. 60, no. 8, pp. 1234–1243, 2012.
View at: Publisher Site | Google Scholar
M. H. O'Regan, R. E. Simpson, L. M. Perkins, and J. W. Phillis, “The selective A2 adenosine receptor agonist CGS 21680 enhances excitatory transmitter amino acid release from the ischemic rat cerebral cortex,” Neuroscience Letters, vol. 138, no. 1, pp. 169–172, 1992.
View at: Publisher Site | Google Scholar
F. Ciruela, V. Casadó, R. J. Rodrigues et al., “Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers,” The Journal of Neuroscience, vol. 26, no. 7, pp. 2080–2087, 2006.
View at: Publisher Site | Google Scholar
V. Ralevic and W. R. Dunn, “Purinergic transmission in blood vessels,” Autonomic Neuroscience: Basic and Clinical, vol. 191, pp. 48–66, 2015.
View at: Publisher Site | Google Scholar
C. Cekic and J. Linden, “Purinergic regulation of the immune system,” Nature Reviews Immunology, vol. 16, no. 3, pp. 177–192, 2016.
View at: Publisher Site | Google Scholar
A. Ohta and M. Sitkovsky, “Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage,” Nature, vol. 414, no. 6866, pp. 916–920, 2001.
View at: Publisher Site | Google Scholar
E. Rissanen, J. R. Virta, T. Paavilainen et al., “Adenosine A2A receptors in secondary progressive multiple sclerosis: a [11C]TMSX brain PET study,” Journal of Cerebral Blood Flow & Metabolism, vol. 33, no. 9, pp. 1394–1401, 2013.
View at: Publisher Site | Google Scholar
J. Chen, P. K. Sonsalla, F. Pedata et al., “Adenosine A2A receptors and brain injury: broad spectrum of neuroprotection, multifaceted actions and “fine tuning” modulation,” Progress in Neurobiology, vol. 83, no. 5, pp. 310–331, 2007.
View at: Publisher Site | Google Scholar
A. F. Ramlackhansingh, S. K. Bose, I. Ahmed, F. E. Turkheimer, N. Pavese, and D. J. Brooks, “Adenosine 2A receptor availability in dyskinetic and nondyskinetic patients with Parkinson disease,” Neurology, vol. 76, no. 21, pp. 1811–1816, 2011.
View at: Publisher Site | Google Scholar
M. Mishina, K. Ishiwata, M. Naganawa et al., “Adenosine A2A receptors measured with [11C]TMSX pet in the striata of parkinson's disease patients,” PLoS ONE, vol. 6, no. 2, Article ID e17338, 2011.
View at: Publisher Site | Google Scholar
R. A. Cunha, “Adenosine Neuromodulation and Neuroprotection,” in Handbook of Neurochemistry and Molecular Neurobiology, A. Lajtha and E. S. Vizi, Eds., pp. 255–273, Springer, Boston, Mass, USA, 2008.
View at: Publisher Site | Google Scholar
P. Svenningsson, H. Hall, G. Sedvall, and B. B. Fredholm, “Distribution of adenosine receptors in the postmortem human brain: An extended autoradiographic study,” Synapse, vol. 27, no. 4, pp. 322–335, 1997.
View at: Publisher Site | Google Scholar
M. Mishina, K. Ishiwata, Y. Kimura et al., “Evaluation of distribution of adenosine A2A receptors in normal human brain measured with [11C]TMSX PET,” Synapse, vol. 61, no. 9, pp. 778–784, 2007.
View at: Publisher Site | Google Scholar
L. V. Lopes, L. Halldner, N. Rebola et al., “Binding of the prototypical adenosine A 2A receptor agonist CGS 21680 to the cerebral cortex of adenosine A 1 and A 2A receptor knockout mice,” British Journal of Pharmacology, vol. 141, no. 6, pp. 1006–1014, 2004.
View at: Publisher Site | Google Scholar
N. Rebola, C. R. Oliveira, and R. A. Cunha, “Transducing system operated by adenosine A2A receptors to facilitate acetylcholine release in the rat hippocampus,” European Journal of Pharmacology, vol. 454, no. 1, pp. 31–38, 2002.
View at: Publisher Site | Google Scholar
N. Rebola, A. M. Sebastião, A. De Mendonca, C. R. Oliveira, J. A. Ribeiro, and R. A. Cunha, “Enhanced adenosine A2A receptor facilitation of synaptic transmission in the hippocampus of aged rats,” Journal of Neurophysiology, vol. 90, no. 2, pp. 1295–1303, 2003.
View at: Publisher Site | Google Scholar
M. I. Martinez-Mir, A. Probst, and J. M. Palacios, “Adenosine A2 receptors: Selective localization in the human basal ganglia and alterations with disease,” Neuroscience, vol. 42, no. 3, pp. 697–706, 1991.
View at: Publisher Site | Google Scholar
S. N. Schiffmann, F. Libert, G. Vassart, and J.-J. Vanderhaeghen, “Distribution of adenosine A2 receptor mRNA in the human brain,” Neuroscience Letters, vol. 130, no. 2, pp. 177–181, 1991.
View at: Publisher Site | Google Scholar
S. N. Schiffmann, O. Jacobs, and J. J. Vanderhaeghen, “Striatal restricted adenosine A2 receptor (RDC8) is expressed by enkephalin but not by substance P neurons: an in situ hybridization histochemistry study,” Journal of Neurochemistry, vol. 57, no. 3, pp. 1062–1067, 1991.
View at: Publisher Site | Google Scholar
B. D. Hettinger, A. Lee, J. Linden, and D. L. Rosin, “Ultrastructural localization of adenosine A2A receptors suggests multiple cellular sites for modulation of GABAergic neurons in rat striatum,” Journal of Comparative Neurology, vol. 431, no. 3, pp. 331–346, 2001.
View at: Publisher Site | Google Scholar
C. Quiroz, R. Luján, M. Uchigashima et al., “Key modulatory role of presynaptic adenosine A2A receptors in cortical neurotransmission to the striatal direct pathway,” The Scientific World Journal, vol. 9, pp. 1321–1344, 2009.
View at: Publisher Site | Google Scholar
A. Martire, A. Ferrante, R. L. Potenza et al., “Remodeling of striatal NMDA receptors by chronic A(2A) receptor blockade in Huntington's disease mice,” Neurobiology of Disease, vol. 37, no. 1, pp. 99–105, 2010.
View at: Publisher Site | Google Scholar
M. Marchi, L. Raiteri, F. Risso et al., “Effects of adenosine A1 and A2A receptor activation on the evoked release of glutamate from rat cerebrocortical synaptosomes,” British Journal of Pharmacology, vol. 136, no. 3, pp. 434–440, 2002.
View at: Publisher Site | Google Scholar
M. Marcoli, L. Raiteri, A. Bonfanti et al., “Sensitivity to selective adenosine A1 and A2A receptor antagonists of the release of glutamate induced by ischemia in rat cerebrocortical slices,” Neuropharmacology, vol. 45, no. 2, pp. 201–210, 2003.
View at: Publisher Site | Google Scholar
M.-R. Nikbakht and T. W. Stone, “Suppression of presynaptic responses to adenosine by activation of NMDA receptors,” European Journal of Pharmacology, vol. 427, no. 1, pp. 13–25, 2001.
View at: Publisher Site | Google Scholar
R. J. Rodrigues, T. M. Alfaro, N. Rebola, C. R. Oliveira, and R. A. Cunha, “Co-localization and functional interaction between adenosine A(2A) and metabotropic group 5 receptors in glutamatergic nerve terminals of the rat striatum,” Journal of Neurochemistry, vol. 92, no. 3, pp. 433–441, 2005.
View at: Publisher Site | Google Scholar
M. T. Tebano, M. R. Domenici, and P. Popoli, “SCH 58261 differentially influences quinolinic acid-induced effects in striatal and in hippocampal slices,” European Journal of Pharmacology, vol. 450, no. 3, pp. 253–257, 2002.
View at: Publisher Site | Google Scholar
C. Corsi, A. Melani, L. Bianchi, G. Pepeu, and F. Pedata, “Striatal A2A adenosine receptors differentially regulate spontaneous and K+-evoked glutamate release in vivo in young and aged rats,” NeuroReport, vol. 10, no. 4, pp. 687–691, 1999.
View at: Publisher Site | Google Scholar
C. Corsi, A. Melani, L. Bianchi, and F. Pedata, “Striatal A2A adenosine receptor antagonism differentially modifies striatal glutamate outflow in vivo in young and aged rats,” NeuroReport, vol. 11, no. 11, pp. 2591–2595, 2000.
View at: Publisher Site | Google Scholar
A. Pintor, D. Quarta, A. Pèzzola, R. Reggio, and P. Popoli, “SCH 58261 (an adenosine A2A receptor antagonist) reduces, only at low doses, K+-evoked glutamate release in the striatum,” European Journal of Pharmacology, vol. 421, no. 3, pp. 177–180, 2001.
View at: Publisher Site | Google Scholar
M. Gianfriddo, C. Corsi, A. Melani et al., “Adenosine A2A antagonism increases striatal glutamate outflow in the quinolinic acid rat model of Huntington's disease,” Brain Research, vol. 979, no. 1-2, pp. 225–229, 2003.
View at: Publisher Site | Google Scholar
M. T. Tebano, A. Pintor, C. Frank et al., “Adenosine A_2A receptor blockade differentially influences excitotoxic mechanisms at pre- and postsynaptic sites in the rat striatum,” Journal of Neuroscience Research, vol. 77, no. 1, pp. 100–107, 2004.
View at: Publisher Site | Google Scholar
P. Popoli, A. Pintor, M. R. Domenici et al., “Blockade of striatal adenosine A2A receptor reduces, through a presynaptic mechanism, quinolinic acid-induced excitotoxicity: possible relevance to neuroprotective interventions in neurodegenerative diseases of the striatum,” The Journal of Neuroscience, vol. 22, no. 5, pp. 1967–1975, 2002.
View at: Google Scholar
P. Popoli, C. Frank, M. T. Tebano et al., “Modulation of glutamate release and excitotoxicity by adenosine A 2A receptors,” Neurology, vol. 61, no. 11, pp. S69–S71, 2003.
View at: Publisher Site | Google Scholar
N. J. Abbott, L. Rönnbäck, and E. Hansson, “Astrocyte-endothelial interactions at the blood-brain barrier,” Nature Reviews Neuroscience, vol. 7, no. 1, pp. 41–53, 2006.
View at: Publisher Site | Google Scholar
J. Keaney and M. Campbell, “The dynamic blood-brain barrier,” FEBS Journal, vol. 282, no. 21, pp. 4067–4079, 2015.
View at: Publisher Site | Google Scholar
C. Larochelle, J. I. Alvarez, and A. Prat, “How do immune cells overcome the blood-brain barrier in multiple sclerosis?” FEBS Letters, vol. 585, no. 23, pp. 3770–3780, 2011.
View at: Publisher Site | Google Scholar
M. S. Bynoe, C. Viret, A. Yan, and D.-G. Kim, “Adenosine receptor signaling: A key to opening the blood-brain door,” Fluids and Barriers of the CNS, vol. 12, no. 1, article no. 20, 2015.
View at: Publisher Site | Google Scholar
D.-G. Kim and M. S. Bynoe, “A2A Adenosine Receptor Regulates the Human Blood-Brain Barrier Permeability,” Molecular Neurobiology, vol. 52, no. 1, pp. 664–678, 2015.
View at: Publisher Site | Google Scholar
L. Airas, J. Niemelä, G. Yegutkin, and S. Jalkanen, “Mechanism of action of IFN-beta in the treatment of multiple sclerosis: a special reference to CD73 and adenosine,” Annals of the New York Academy of Sciences, vol. 1110, pp. 641–648, 2007.
View at: Publisher Site | Google Scholar
J. H. Mills, L. Alabanza, B. B. Weksler, P.-O. Couraud, I. A. Romero, and M. S. Bynoe, “Human brain endothelial cells are responsive to adenosine receptor activation,” Purinergic Signalling, vol. 7, no. 2, pp. 265–273, 2011.
View at: Publisher Site | Google Scholar
A. J. Carman, J. H. Mills, A. Krenz, D.-G. Kim, and M. S. Bynoe, “Adenosine receptor signaling modulates permeability of the blood-brain barrier,” The Journal of Neuroscience, vol. 31, no. 37, pp. 13272–13280, 2011.
View at: Publisher Site | Google Scholar
J. Niemelä, I. Ifergan, G. G. Yegutkin, S. Jalkanen, A. Prat, and L. Airas, “IFN-β regulates CD73 and adenosine expression at the blood-brain barrier,” European Journal of Immunology, vol. 38, no. 10, pp. 2718–2726, 2008.
View at: Publisher Site | Google Scholar
H. Watanabe, W. Kuhne, P. Schwartz, and H. M. Piper, “A2-adenosine receptor stimulation increases macromolecule permeability of coronary endothelial cells,” American Journal of Physiology-Heart and Circulatory Physiology, vol. 262, no. 4, pp. H1174–H1181, 1992.
View at: Google Scholar
A. Hempel, T. Noll, A. Muhs, and H. M. Piper, “Functional antagonism between cAMP and cGMP on permeability of coronary endothelial monolayers,” American Journal of Physiology-Heart and Circulatory Physiology, vol. 270, no. 4, pp. H1264–H1271, 1996.
View at: Google Scholar
Q. Lu, E. O. Harrington, J. Newton et al., “Adenosine protected against pulmonary edema through transporter- and receptor A2-mediated endothelial barrier enhancement,” American Journal of Physiology-Lung Cellular and Molecular Physiology, vol. 298, no. 6, pp. L755–L767, 2010.
View at: Publisher Site | Google Scholar
F. R. Haselton, J. S. Alexander, and S. N. Mueller, “Adenosine decreases permeability of in vitro endothelial monolayers,” Journal of Applied Physiology, vol. 74, no. 4, pp. 1581–1590, 1985.
View at: Google Scholar
L. F. Richard, T. E. Dahms, and R. O. Webster, “Adenosine prevents permeability increase in oxidant-injured endothelial monolayers,” American Journal of Physiology, vol. 274, no. 1, pp. H35–H42, 1998.
View at: Google Scholar
R. M. Ransohoff and B. Engelhardt, “The anatomical and cellular basis of immune surveillance in the central nervous system,” Nature Reviews Immunology, vol. 12, no. 9, pp. 623–635, 2012.
View at: Publisher Site | Google Scholar
M. A. Lopes Pinheiro, G. Kooij, M. R. Mizee et al., “Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke,” Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, vol. 1862, no. 3, pp. 461–471, 2016.
View at: Publisher Site | Google Scholar
J. H. Mills, D.-G. Kim, A. Krenz, J.-F. Chen, and M. S. Bynoe, “A2A adenosine receptor signaling in lymphocytes and the central nervous system regulates inflammation during experimental autoimmune encephalomyelitis,” The Journal of Immunology, vol. 188, no. 11, pp. 5713–5722, 2012.
View at: Publisher Site | Google Scholar
J. H. Mills, L. F. Thompson, C. Mueller et al., “CD73 is required for efficient entry of lymphocytes into the central nervous system during experimental autoimmune encephalomyelitis,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 105, no. 27, pp. 9325–9330, 2008.
View at: Publisher Site | Google Scholar
J. H. Mills, L. M. Alabanza, D. A. Mahamed, and M. S. Bynoe, “Extracellular adenosine signaling induces CX3CL1 expression in the brain to promote experimental autoimmune encephalomyelitis,” Journal of Neuroinflammation, vol. 9, article no. 193, 2012.
View at: Publisher Site | Google Scholar
B. Stevens, S. Porta, L. L. Haak, V. Gallo, and R. D. Fields, “Adenosine: a neuron-glial transmitter promoting myelination in the CNS in response to action potentials,” Neuron, vol. 36, no. 5, pp. 855–868, 2002.
View at: Publisher Site | Google Scholar
E. Coppi, L. Cellai, G. Maraula et al., “Role of adenosine in oligodendrocyte precursor maturation,” Frontiers in Cellular Neuroscience, vol. 9, 2015.
View at: Publisher Site | Google Scholar
E. Coppi, L. Cellai, G. Maraula, A. M. Pugliese, and F. Pedata, “Adenosine A2A receptors inhibit delayed rectifier potassium currents and cell differentiation in primary purified oligodendrocyte cultures,” Neuropharmacology, vol. 73, pp. 301–310, 2013.
View at: Publisher Site | Google Scholar
A. G. Orr, A. L. Orr, X. Li, R. E. Gross, and S. F. Traynelis, “Adenosine A2A receptor mediates microglial process retraction,” Nature Neuroscience, vol. 12, no. 7, pp. 872–878, 2009.
View at: Publisher Site | Google Scholar
M. C. Wittendorp, H. W. G. M. Boddeke, and K. Biber, “Adenosine A3 receptor-induced CCL2 synthesis in cultured mouse astrocytes,” Glia, vol. 46, no. 4, pp. 410–418, 2004.
View at: Publisher Site | Google Scholar
A. G. Orr, E. C. Hsiao, M. M. Wang et al., “Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory,” Nature Neuroscience, vol. 18, no. 3, pp. 423–439, 2015.
View at: Publisher Site | Google Scholar
R. Brambilla, L. Cottini, M. Fumagalli, S. Ceruti, and M. P. Abbracchio, “Blockade of A2A adenosine receptors prevents basic fibroblast growth factor-induced reactive astrogliosis in rat striatal primary astrocytes,” Glia, vol. 43, no. 2, pp. 190–194, 2003.
View at: Publisher Site | Google Scholar
J. S. Fink, D. R. Weaver, S. A. Rivkees et al., “Molecular cloning of the rat A₂ adenosine receptor: selective co-expression with D₂ dopamine receptors in rat striatum,” Brain Research, vol. 14, no. 3, pp. 186–195, 1992.
View at: Publisher Site | Google Scholar
P. Calabresi, B. Picconi, A. Tozzi, V. Ghiglieri, and M. Di Filippo, “Direct and indirect pathways of basal ganglia: a critical reappraisal,” Nature Neuroscience, vol. 17, no. 8, pp. 1022–1030, 2014.
View at: Publisher Site | Google Scholar
A. Mori, “Mode of action of adenosine A2A receptor antagonists as symptomatic treatment for Parkinson's disease,” International Review of Neurobiology, vol. 119, pp. 87–116, 2014.
View at: Publisher Site | Google Scholar
M. Canals, D. Marcellino, F. Fanelli et al., “Adenosine A2A-dopamine D2 receptor-receptor heteromerization: Qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer,” The Journal of Biological Chemistry, vol. 278, no. 47, pp. 46741–46749, 2003.
View at: Publisher Site | Google Scholar
P. Calabresi, M. D. Filippo, V. Ghiglieri, N. Tambasco, and B. Picconi, “Levodopa-induced dyskinesias in patients with Parkinson's disease: filling the bench-to-bedside gap,” The Lancet Neurology, vol. 9, no. 11, pp. 1106–1117, 2010.
View at: Publisher Site | Google Scholar
P. Jenner, “An Overview of adenosine A2A receptor antagonists in Parkinson's disease,” International Review of Neurobiology, vol. 119, pp. 71–86, 2014.
View at: Publisher Site | Google Scholar
G. A. Graveland, R. S. Williams, and M. DiFiglia, “Evidence for degenerative and regenerative changes in neostriatal spiny neurons in Huntington's disease,” Science, vol. 227, no. 4688, pp. 770–773, 1985.
View at: Publisher Site | Google Scholar
M. Glass, M. Dragunow, and R. L. M. Faull, “The pattern of neurodegeneration in Huntington's disease: a comparative study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations in the human basal ganglia in Huntington's disease,” Neuroscience, vol. 97, no. 3, pp. 505–519, 2000.
View at: Publisher Site | Google Scholar
J.-H. J. Cha, A. S. Frey, S. A. Alsdorf et al., “Altered neurotransmitter receptor expression in transgenic mouse models of Huntington's disease,” Philosophical Transactions of the Royal Society B: Biological Sciences, vol. 354, no. 1386, pp. 981–989, 1999.
View at: Publisher Site | Google Scholar
S. Mievis, D. Blum, and C. Ledent, “A2A receptor knockout worsens survival and motor behaviour in a transgenic mouse model of Huntington's disease,” Neurobiology of Disease, vol. 41, no. 2, pp. 570–576, 2011.
View at: Publisher Site | Google Scholar
S.-Y. Chou, Y.-C. Lee, H.-M. Chen et al., “CGS21680 attenuates symptoms of Huntington's disease in a transgenic mouse model,” Journal of Neurochemistry, vol. 93, no. 2, pp. 310–320, 2005.
View at: Publisher Site | Google Scholar
M.-C. Chiang, Y.-C. Lee, C.-L. Huang, and Y. Chern, “cAMP-response element-binding protein contributes to suppression of the A2A adenosine receptor promoter by mutant huntingtin with expanded polyglutamine residues,” The Journal of Biological Chemistry, vol. 280, no. 14, pp. 14331–14340, 2005.
View at: Publisher Site | Google Scholar
C.-M. Dhaenens, S. Burnouf, C. Simonin et al., “A genetic variation in the ADORA2A gene modifies age at onset in Huntington's disease,” Neurobiology of Disease, vol. 35, no. 3, pp. 474–476, 2009.
View at: Publisher Site | Google Scholar
S. Tyebji, A. Saavedra, P. M. Canas et al., “Hyperactivation of D1 and A2A receptors contributes to cognitive dysfunction in Huntington's disease,” Neurobiology of Disease, vol. 74, pp. 41–57, 2015.
View at: Publisher Site | Google Scholar
W. Li, H. B. Silva, J. Real et al., “Inactivation of adenosine A2A receptors reverses working memory deficits at early stages of Huntington's disease models,” Neurobiology of Disease, vol. 79, pp. 70–80, 2015.
View at: Publisher Site | Google Scholar
M. R. Domenici, M. L. Scattoni, A. Martire et al., “Behavioral and electrophysiological effects of the adenosine A2A receptor antagonist SCH 58261 in R6/2 Huntington's disease mice,” Neurobiology of Disease, vol. 28, no. 2, pp. 197–205, 2007.
View at: Publisher Site | Google Scholar
K. Ishiwata, N. Ogi, N. Hayakawa et al., “Adenosine A2A receptor imaging with [11C]KF18446 PET in the rat brain after quinolinic acid lesion: Comparison with the dopamine receptor imaging,” Annals of Nuclear Medicine, vol. 16, no. 7, pp. 467–475, 2002.
View at: Publisher Site | Google Scholar
J. L. Albasanz, S. Perez, M. Barrachina, I. Ferrer, and M. Martín, “Up-regulation of adenosine receptors in the frontal cortex in Alzheimer's disease,” Brain Pathology, vol. 18, no. 2, pp. 211–219, 2008.
View at: Publisher Site | Google Scholar
G. W. Arendash, W. Schleif, K. Rezai-Zadeh et al., “Caffeine protects Alzheimer's mice against cognitive impairment and reduces brain β-amyloid production,” Neuroscience, vol. 142, no. 4, pp. 941–952, 2006.
View at: Publisher Site | Google Scholar
O. P. Dall'lgna, L. O. Porciúncula, D. O. Souza, R. A. Cunha, and D. R. Lara, “Neuroprotection by caffeine and adenosine A 2A receptor blockade of β-amyloid neurotoxicity,” British Journal of Pharmacology, vol. 138, no. 7, pp. 1207–1209, 2003.
View at: Publisher Site | Google Scholar
S. Giunta, V. Andriolo, and A. Castorina, “Dual blockade of the A1 and A_2A adenosine receptor prevents amyloid beta toxicity in neuroblastoma cells exposed to aluminum chloride,” The International Journal of Biochemistry & Cell Biology, vol. 54, pp. 122–136, 2014.
View at: Publisher Site | Google Scholar
P. M. Canas, L. O. Porciúncula, G. M. A. Cunha et al., “Adenosine A2A receptor blockade prevents synaptotoxicity and memory dysfunction caused by β-amyloid peptides via p38 mitogen-activated protein kinase pathway,” The Journal of Neuroscience, vol. 29, no. 47, pp. 14741–14751, 2009.
View at: Publisher Site | Google Scholar
B. V. Nagpure, J. Bian, and S. Strack, “Hydrogen Sulfide Inhibits A2A Adenosine Receptor Agonist Induced β-Amyloid Production in SH-SY5Y Neuroblastoma Cells via a cAMP Dependent Pathway,” PLoS ONE, vol. 9, no. 2, p. e88508, 2014.
View at: Publisher Site | Google Scholar
O. P. Dall'Igna, P. Fett, M. W. Gomes, D. O. Souza, R. A. Cunha, and D. R. Lara, “Caffeine and adenosine A_2a receptor antagonists prevent β-amyloid (25–35)-induced cognitive deficits in mice,” Experimental Neurology, vol. 203, no. 1, pp. 241–245, 2007.
View at: Publisher Site | Google Scholar
G. M. A. Cunha, P. M. Canas, C. S. Melo et al., “Adenosine A2A receptor blockade prevents memory dysfunction caused by β-amyloid peptides but not by scopolamine or MK-801,” Experimental Neurology, vol. 210, no. 2, pp. 776–781, 2008.
View at: Publisher Site | Google Scholar
C. Laurent, S. Burnouf, B. Ferry et al., “Erratum: A2A adenosine receptor deletion is protective in a mouse model of Tauopathy (Molecular Psychiatry (2016) 21 149 (doi:10.1038/mp.2015.115)),” Molecular Psychiatry, vol. 21, no. 1, p. 149, 2016.
View at: Publisher Site | Google Scholar
N. Pagnussat, A. S. Almeida, D. M. Marques et al., “Adenosine A(2A) receptors are necessary and sufficient to trigger memory impairment in adult mice,” British Journal of Pharmacology, vol. 172, no. 15, pp. 3831–3845, 2015.
View at: Publisher Site | Google Scholar
P. Li, D. Rial, P. M. Canas et al., “Optogenetic activation of intracellular adenosine A2A receptor signaling in the hippocampus is sufficient to trigger CREB phosphorylation and impair memory,” Molecular Psychiatry, vol. 20, no. 11, pp. 1481–1481, 2015.
View at: Publisher Site | Google Scholar
J. Lu, J. Cui, X. Li et al., “An Anti-Parkinson's Disease Drug via Targeting Adenosine A2A Receptor Enhances Amyloid-ß Generation and γ-Secretase Activity,” PLoS One, vol. 11, no. 11, Article ID e0166415, 2016.
View at: Google Scholar
R. M. Ransohoff, D. A. Hafler, and C. F. Lucchinetti, “Multiple sclerosis - A quiet revolution,” Nature Reviews Neurology, vol. 11, no. 3, pp. 134–142, 2015.
View at: Publisher Site | Google Scholar
B. F. G. Popescu and C. F. Lucchinetti, “Meningeal and cortical grey matter pathology in multiple sclerosis,” BMC Neurology, vol. 12, article 11, 2012.
View at: Publisher Site | Google Scholar
J. M. Frischer, S. Bramow, A. Dal-Bianco et al., “The relation between inflammation and neurodegeneration in multiple sclerosis brains,” Brain, vol. 132, no. 5, pp. 1175–1189, 2009.
View at: Publisher Site | Google Scholar
E. Rissanen, J. Tuisku, J. Rokka et al., “In vivo detection of diffuse inflammation in secondary progressive multiple sclerosis using PET imaging and the radioligand11C-PK11195,” Journal of Nuclear Medicine, vol. 55, no. 6, pp. 939–944, 2014.
View at: Publisher Site | Google Scholar
L. Airas, E. Rissanen, and J. O. Rinne, “Imaging neuroinflammation in multiple sclerosis using TSPO-PET,” Clinical and Translational Imaging, vol. 3, no. 6, pp. 461–473, 2015.
View at: Publisher Site | Google Scholar
A. J. Thompson, “Challenge of progressive multiple sclerosis therapy,” Current Opinion in Neurology, vol. 30, no. 3, pp. 237–240, 2017.
View at: Publisher Site | Google Scholar
J. Ingwersen, B. Wingerath, J. Graf et al., “Dual roles of the adenosine A2a receptor in autoimmune neuroinflammation,” Journal of Neuroinflammation, vol. 13, no. 1, article no. 48, 2016.
View at: Publisher Site | Google Scholar
A. M. Amorini, A. Petzold, B. Tavazzi et al., “Increase of uric acid and purine compounds in biological fluids of multiple sclerosis patients,” Clinical Biochemistry, vol. 42, no. 10-11, pp. 1001–1006, 2009.
View at: Publisher Site | Google Scholar
C. R. N. Polachini, R. M. Spanevello, E. A. Casali et al., “Alterations in the cholinesterase and adenosine deaminase activities and inflammation biomarker levels in patients with multiple sclerosis,” Neuroscience, vol. 266, pp. 266–274, 2014.
View at: Publisher Site | Google Scholar
A. K. Hedström, E. M. Mowry, M. A. Gianfrancesco et al., “High consumption of coffee is associated with decreased multiple sclerosis risk; results from two independent studies,” Journal of Neurology, Neurosurgery & Psychiatry, vol. 87, no. 5, pp. 454–460, 2016.
View at: Publisher Site | Google Scholar
M. B. D'hooghe, P. Haentjens, G. Nagels, and J. De Keyser, “Alcohol, coffee, fish, smoking and disease progression in multiple sclerosis,” European Journal of Neurology, vol. 19, no. 4, pp. 616–624, 2012.
View at: Publisher Site | Google Scholar
G. Q. Chen, Y. Y. Chen, X. S. Wang et al., “Chronic caffeine treatment attenuates experimental autoimmune encephalomyelitis induced by guinea pig spinal cord homogenates in Wistar rats,” Brain Research, vol. 1309, pp. 116–125, 2010.
View at: Publisher Site | Google Scholar
S. Tsutsui, J. Schnermann, F. Noorbakhsh et al., “A1 adenosine receptor upregulation and activation attenuates neuroinflammation and demyelination in a model of multiple sclerosis,” The Journal of Neuroscience, vol. 24, no. 6, pp. 1521–1529, 2004.
View at: Publisher Site | Google Scholar
T. Wang, N.-N. Xi, Y. Chen et al., “Chronic caffeine treatment protects against experimental autoimmune encephalomyelitis in mice: therapeutic window and receptor subtype mechanism,” Neuropharmacology, vol. 86, pp. 203–211, 2014.
View at: Publisher Site | Google Scholar
S. Yao, Z. Li, Q. Huang et al., “Genetic inactivation of the adenosine A(2A) receptor exacerbates brain damage in mice with experimental autoimmune encephalomyelitis,” Journal of Neurochemistry, vol. 123, no. 1, pp. 100–112, 2012.
View at: Publisher Site | Google Scholar
Y. Liu, H. Zou, P. Zhao et al., “Activation of the adenosine A2A receptor attenuates experimental autoimmune encephalomyelitis and is associated with increased intracellular calcium levels,” Neuroscience, vol. 330, pp. 150–161, 2016.
View at: Publisher Site | Google Scholar
M. L. Trincavelli, A. Melani, S. Guidi et al., “Regulation of A(2A) adenosine receptor expression and functioning following permanent focal ischemia in rat brain,” Journal of Neurochemistry, vol. 104, no. 2, pp. 479–490, 2008.
View at: Publisher Site | Google Scholar
J. W. Phillis, “The effects of selective A1 and A2a adenosine receptor antagonists on cerebral ischemic injury in the gerbil,” Brain Research, vol. 705, no. 1-2, pp. 79–84, 1995.
View at: Publisher Site | Google Scholar
Y. Gao and J. W. Phillis, “CGS 15943, An adenosine A2 receptor antagonist, reduces cerebral ischemic injury in the mongolian gerbil,” Life Sciences, vol. 55, no. 3, pp. PL61–PL65, 1994.
View at: Google Scholar
A. Monopoli, G. Lozza, A. Forlani, A. Mattavelli, and E. Ongini, “Blockade of adenosine A2A receptors by SCH 58261 results in neuroprotective effects in cerebral ischaemia in rats,” NeuroReport, vol. 9, no. 17, pp. 3955–3959, 1998.
View at: Publisher Site | Google Scholar
K. Jo, R. Derin, M. Li, and D. S. Bredt, “Characterization of MALS/Velis-1, -2, and -3: a family of mammalian LIN-7 homologs enriched at brain synapses in association with the postsynaptic density-95/NMDA receptor postsynaptic complex,” The Journal of Neuroscience, vol. 19, no. 11, pp. 4189–4199, 1999.
View at: Google Scholar
H. Higashi, J. R. Meno, A. S. Marwaha, and H. R. Winn, “Hippocampal injury and neurobehavioral deficits following hyperglycemic cerebral ischemia: effect of theophylline and ZM 241385,” Journal of Neurosurgery, vol. 96, no. 1, pp. 117–126, 2002.
View at: Publisher Site | Google Scholar
A. Melani, S. Cipriani, M. G. Vannucchi et al., “Selective adenosine A2a receptor antagonism reduces JNK activation in oligodendrocytes after cerebral ischaemia,” Brain, vol. 132, no. 6, pp. 1480–1495, 2009.
View at: Publisher Site | Google Scholar
L. Gui, W. Duan, H. Tian et al., “Adenosine A 2A receptor deficiency reduces striatal glutamate outflow and attenuates brain injury induced by transient focal cerebral ischemia in mice,” Brain Research, vol. 1297, pp. 185–193, 2009.
View at: Publisher Site | Google Scholar
R. A. Mohamed, A. M. Agha, and N. N. Nassar, “SCH58261 the selective adenosine A 2A receptor blocker modulates ischemia reperfusion injury following bilateral carotid occlusion: Role of inflammatory mediators,” Neurochemical Research, vol. 37, no. 3, pp. 538–547, 2012.
View at: Publisher Site | Google Scholar
Z. J. Yang, B. Wang, H. Kwansa et al., “Adenosine A2A receptor contributes to ischemic brain damage in newborn piglet,” Journal of Cerebral Blood Flow & Metabolism, vol. 33, pp. 1612–1620, 2013.
View at: Publisher Site | Google Scholar
A. Melani, M. Gianfriddo, M. G. Vannucchi et al., “The selective A2A receptor antagonist SCH 58261 protects from neurological deficit, brain damage and activation of p38 MAPK in rat focal cerebral ischemia,” Brain Research, vol. 1073-1074, no. 1, pp. 470–480, 2006.
View at: Publisher Site | Google Scholar
A. Melani, L. Pantoni, F. Bordoni et al., “The selective A2A receptor antagonist SCH 58261 reduces striatal transmitter outflow, turning behavior and ischemic brain damage induced by permanent focal ischemia in the rat,” Brain Research, vol. 959, no. 2, pp. 243–250, 2003.
View at: Publisher Site | Google Scholar
L. Yu, Z. Huang, J. F. Mariani, Y. Wang, M. Moskowitz, and J. Chen, “Selective inactivation or reconstitution of adenosine A2A receptors in bone marrow cells reveals their significant contribution to the development of ischemic brain injury,” Nature Medicine, vol. 10, no. 10, pp. 1081–1087, 2004.
View at: Publisher Site | Google Scholar
A. Melani, I. Dettori, F. Corti, L. Cellai, and F. Pedata, “Time-course of protection by the selective A2A receptor antagonist SCH58261 after transient focal cerebral ischemia,” Neurological Sciences, vol. 36, no. 8, pp. 1441–1448, 2015.
View at: Publisher Site | Google Scholar
U. Fronz, A. Deten, F. Baumann et al., “Continuous adenosine A2A receptor antagonism after focal cerebral ischemia in spontaneously hypertensive rats,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 387, no. 2, pp. 165–173, 2014.
View at: Publisher Site | Google Scholar
U. Ådén, L. Halldner, H. Lagercrantz, I. Dalmau, C. Ledent, and B. B. Fredholm, “Aggravated brain damage after hypoxic ischemia in immature adenosine A2A knockout mice,” Stroke, vol. 34, no. 3, pp. 739–744, 2003.
View at: Publisher Site | Google Scholar
A. Melani, F. Corti, L. Cellai, M. Giuliana Vannucchi, and F. Pedata, “Low doses of the selective adenosine A2A receptor agonist CGS21680 are protective in a rat model of transient cerebral ischemia,” Brain Research, vol. 1551, pp. 59–72, 2014.
View at: Publisher Site | Google Scholar
M. Sakata, K. Ishibashi, and M. Imai, “Initial Evaluation of a Novel Adenosine A2A Receptor Ligand, (11)C-Preladenant, in Healthy Human Subjects,” Journal of Nuclear Medicine, 2017.
View at: Google Scholar
O. Barret, J. Hannestad, C. Vala et al., “Characterization in humans of ¹⁸F-MNI-444, a PET radiotracer for brain adenosine 2A receptors,” Journal of Nuclear Medicine, vol. 56, no. 4, pp. 586–591, 2015.
View at: Publisher Site | Google Scholar
I. Grachev, M. Doder, D. Brooks, and R. Hinz, “Quantitative in vivo Imaging of Adenosine A2A Receptors in the Human Brain Using 11C-SCH442416 PET: A Pilot Study,” Journal of Diagnostic Imaging in Therapy, vol. 1, no. 1, pp. 1–19, 2014.
View at: Publisher Site | Google Scholar
M. Mishina, Y. Kimura, M. Naganawa et al., “Differential effects of age on human striatal adenosine A1 and A2A receptors,” Synapse, vol. 66, no. 9, pp. 832–839, 2012.
View at: Publisher Site | Google Scholar
K. Varani, F. Vincenzi, A. Tosi et al., “A_2A adenosine receptor overexpression and functionality, as well as TNF-α levels, correlate with motor symptoms in Parkinson's disease,” The FASEB Journal, vol. 24, no. 2, pp. 587–598, 2010.
View at: Publisher Site | Google Scholar
K. Ishiwata, M. Mishina, Y. Kimura, K. Oda, T. Sasaki, and K. Ishii, “First visualization of adenosine A2A receptors in the human brain by positron emission tomography with [11C]TMSX,” Synapse, vol. 55, no. 2, pp. 133–136, 2005.
View at: Publisher Site | Google Scholar
I. Heinonen, S. V. Nesterov, K. Liukko et al., “Myocardial blood flow and adenosine A2A receptor density in endurance athletes and untrained men,” The Journal of Physiology, vol. 586, no. 21, pp. 5193–5202, 2008.
View at: Publisher Site | Google Scholar
K. Ishiwata, K. Kawamura, Y. Kimura, K. Oda, and K. Ishii, “Potential of an adenosine A2A receptor antagonist [ 11C]TMSX for myocardial imaging by positron emission tomography: A first human study,” Annals of Nuclear Medicine, vol. 17, no. 6, pp. 457–462, 2003.
View at: Publisher Site | Google Scholar
K. Ishiwata, M. Mizuno, Y. Kimura et al., “Potential of [11C]TMSX for the evaluation of adenosine A 2A receptors in the skeletal muscle by positron emission tomography,” Nuclear Medicine and Biology, vol. 31, no. 7, pp. 949–956, 2004.
View at: Publisher Site | Google Scholar
M. Mizuno, Y. Kimura, K. Tokizawa et al., “Greater adenosine A2A receptor densities in cardiac and skeletal muscle in endurance-trained men: A [11C]TMSX PET study,” Nuclear Medicine and Biology, vol. 32, no. 8, pp. 831–836, 2005.
View at: Publisher Site | Google Scholar
K. Ishiwata, J. Noguchi, and S. Wakabayashi, “11C-labeled KF18446: a potential central nervous system adenosine A2a receptor ligand,” Journal of Nuclear Medicine, vol. 41, no. 2, pp. 345–354, 2000.
View at: Google Scholar
S. Stone-Elander, J.-O. Thorell, L. Eriksson, B. B. Fredholm, and M. Ingvar, “In vivo biodistribution of [N-11C-methyl]KF 17837 using 3-D-PET: Evaluation as a ligand for the study of adenosine A(2A) receptors,” Nuclear Medicine and Biology, vol. 24, no. 2, pp. 187–191, 1997.
View at: Publisher Site | Google Scholar
E. Rissanen, J. Tuisku, P. Luoto et al., “Automated reference region extraction and population-based input function for brain [11C]TMSX PET image analyses,” Journal of Cerebral Blood Flow & Metabolism, vol. 35, no. 1, pp. 157–165, 2015.
View at: Publisher Site | Google Scholar
M. Naganawa, Y. Kimura, M. Mishina et al., “Quantification of adenosine A2A receptors in the human brain using [11C]TMSX and positron emission tomography,” European Journal of Nuclear Medicine and Molecular Imaging, vol. 34, no. 5, pp. 679–687, 2007.
View at: Publisher Site | Google Scholar
B. R. Neustadt and e. a. et al., “Potent, Selective, and Orally Active Adenosine A2A Receptor Antagonists: Arylpiperazine Derivatives of Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines.,” ChemInform, vol. 38, no. 29, 2007.
View at: Publisher Site | Google Scholar
X. Zhou, R. Boellaard, K. Ishiwata et al., “In Vivo Evaluation of,” Journal of Nuclear Medicine, vol. 58, no. 5, pp. 762–767, 2017.
View at: Publisher Site | Google Scholar
C. Vala, T. J. Morley, X. Zhang et al., “Synthesis and in vivo Evaluation of Fluorine-18 and Iodine-123 Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine Derivatives as PET and SPECT Radiotracers for Mapping A2A Receptors,” ChemMedChem, pp. 1936–1943, 2016.
View at: Publisher Site | Google Scholar
O. Barret, J. Hannestad, D. Alagille et al., “Adenosine 2A receptor occupancy by tozadenant and preladenant in rhesus monkeys,” Journal of Nuclear Medicine, vol. 55, no. 10, pp. 1712–1718, 2014.
View at: Publisher Site | Google Scholar
S. Todde, R. M. Moresco, P. Simonelli et al., “Design, radiosynthesis, and biodistribution of a new potent and selective ligand for in vivo imaging of the adenosine A2A receptor system using positron emission tomography [2],” Journal of Medicinal Chemistry, vol. 43, no. 23, pp. 4359–4362, 2000.
View at: Publisher Site | Google Scholar
I. Grachev, M. Doder, D. Brooks, and R. Hinz, “An in vivo Positron Emission Tomography Study of Adenosine 2A Receptor Occupancy by Preladenant using 11C-SCH442416 in Healthy Subjects,” Journal of Diagnostic Imaging in Therapy, vol. 1, no. 1, pp. 20–48, 2014.
View at: Publisher Site | Google Scholar
D. J. Brooks, S. Papapetropoulos, F. Vandenhende et al., “An open-label, positron emission tomography study to assess adenosine A2A brain receptor occupancy of vipadenant (BIIB014) at steady-state levels in healthy male volunteers,” Clinical Neuropharmacology, vol. 33, no. 2, pp. 55–60, 2010.
View at: Publisher Site | Google Scholar
M. Naganawa, Y. Kimura, J. Yano et al., “Robust estimation of the arterial input function for Logan plots using an intersectional searching algorithm and clustering in positron emission tomography for neuroreceptor imaging,” NeuroImage, vol. 40, no. 1, pp. 26–34, 2008.
View at: Publisher Site | Google Scholar
X. Zhou, S. Khanapur, J. R. De Jong et al., “In vivo evaluation of [11C]preladenant positron emission tomography for quantification of adenosine A2A receptors in the rat brain,” Journal of Cerebral Blood Flow & Metabolism, vol. 37, no. 2, pp. 577–589, 2016.
View at: Publisher Site | Google Scholar
E. Hirani, J. Gillies, A. Karasawa et al., “Evaluation of [4-O-methyl-11C]KW-6002 as a potential PET ligand for mapping central adenosine A2A receptors in rats,” Synapse, vol. 42, no. 3, pp. 164–176, 2001.
View at: Publisher Site | Google Scholar
D. J. Brooks, M. Doder, S. Osman et al., “Positron emission tomography analysis of [11C]KW-6002 binding to human and rat adenosine A2A receptors in the brain,” Synapse, vol. 62, no. 9, pp. 671–681, 2008.
View at: Publisher Site | Google Scholar
D. A. Mankoff, “A definition of molecular imaging,” Journal of Nuclear Medicine, vol. 48, no. 6, pp. 18N–21N, 2007.
View at: Google Scholar

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Copyright © 2017 Anna Vuorimaa et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Contrast Media & Molecular Imaging

In Vivo Imaging of Inflammation and Infection

In Vivo PET Imaging of Adenosine 2A Receptors in Neuroinflammatory and Neurodegenerative Disease

Abstract

1. Introduction

2. A2A Receptor Expression in Various CNS Compartments and Cell Types

2.1. Neurons

2.2. Endothelial Cells

2.3. A2A Receptor in Choroid Plexus

2.4. A2A Receptors in Glia

3. A2A Receptors in Neurodegenerative Disease

3.1. Parkinson’s Disease

3.2. Huntington’s Disease

3.3. Alzheimer’s Disease

4. A2A Receptors in Multiple Sclerosis

4.1. Pathological Characteristics of Progressive Multiple Sclerosis

4.2. Evidence of the Role of A2A Receptors in Multiple Sclerosis Pathogenesis

4.3. Evidence of the Role of A2A Receptors in EAE

5. A2A Receptors in Ischemia and Stroke

6. A2A Receptor-Binding Radioligands in Human PET Studies

6.1. [11C]TMSX

6.2. [11C]SCH442416

6.3. [11C]Preladenant

6.4. [18F]MNI-444

6.5. [11C]KW6002

6.6. Challenges in A2A Receptor PET Imaging