Adenosine Receptor PET Imaging in Human Brain

CHAPTER TWO

Adenosine Receptor PET Imaging in Human Brain Masahiro Mishina*,†,1, Kiich Ishiwata† *Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan † Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 1 Corresponding author: e-mail address: [email protected]

Contents 1. Introduction 2. PET Imaging of Adenosine A1 Receptors 2.1 PET ligands for adenosine A1 receptors 2.2 Adenosine A1 receptors in normal subjects 2.3 Adenosine A1 receptors in brain diseases 3. PET Imaging of Adenosine A2A Receptors 3.1 Ligands for adenosine A2A receptors 3.2 Adenosine A2A receptors in normal subjects 3.3 Adenosine A2A receptors in brain diseases 4. Conclusions References

51 55 55 56 57 59 59 60 61 63 63

Abstract Positron emission tomography (PET) is a nuclear medicine imaging technique that allows in vivo imaging of regional receptor-binding capacity. Advances in radiotracer chemistry have led to the development of novel imaging probes for adenosine receptors, especially adenosine A1 and A2A receptors. In this chapter, we discuss brain PET imaging for adenosine receptors and comparison of radioligands for PET imaging in health and diseases.

1. INTRODUCTION Positron emission tomography (PET) is a nuclear medicine imaging technique that allows imaging and quantifying of cellular and molecular processes in humans. A small amount of radiopharmaceutical is introduced into a subject usually by intravenous injection. During its decay process, the radioisotope emits a positron (Fig. 2.1). After traveling a short distance, International Review of Neurobiology, Volume 119 ISSN 0074-7742 http://dx.doi.org/10.1016/B978-0-12-801022-8.00002-7

#

2014 Elsevier Inc. All rights reserved.

51

52

Masahiro Mishina and Kiich Ishiwata

11C

+

+

+

+

n

11B

+ +

n n

+

+

+

n

n

n n

+ +

n n

n n

+ –

γ-ray

γ-ray

– 11

Figure 2.1 Decay process of C. During its decay process, 11C emits a positron, and changes to 11B. The positron travels a short distance and annihilates on contact with an electron. The annihilation produces two γ-rays traveling in opposite directions.

the positron annihilates on contact with an electron from the surrounding environment. The annihilation produces two γ-rays traveling in opposite directions. The PET scanner detects the pairs of γ-rays emitted indirectly by positron-emitting radioisotopes. After an appropriate uptake period, a PET scanner measures the concentration of tracer in tissue. Thus, PET allows in vivo imaging of regional cerebral functions, including cerebral blood flow, molecular metabolism, and receptor-binding capacity. Since 1995, a number of radioligands for mapping adenosine receptors by PET have been reported. Most of them are focused on the ligands for adenosine A1 and A2A receptors. Radiolabeled adenosine derivatives such as N6-cyclohexyladenosine (Fastbom, Pazos, Probst, & Palacios, 1987) for adenosine A1 receptor and 2-p-(2-carboxyethyl)-phenethylamino-50 -Nethylcarboxamidoadenosine (CGS 21680) (Martinez-Mir, Probst, & Palacios, 1991) for adenosine A2A receptor are used in vitro; however, these hydrophilic compounds are not appropriate for in vivo imaging adenosine receptors in the central nervous system. Lipophilic xanthine and nonxanthine derivatives are candidates for in vivo imaging (Table 2.1). A comprehensive overview of PET tracers for the different adenosine receptor subtypes has been presented in some recent reviews (Bauer & Ishiwata, 2009; Ishiwata, Kimura, de Vries, & Elsinga, 2007; Khanapur et al., 2013; Paul, Elsinga, Ishiwata, Dierckx, & van Waarde, 2011). The binding properties of PET ligands are used clinically and related ligands are summarized in Table 2.1.

Table 2.1 In vitro affinity of PET ligands for adenosine receptors Affinity (Ki nM) Selectivity A1

A2A

6.4 (g, 1)

590 (g, 4)

Affinity (Ki nM) Selectivity

A2A/A1 or A1/A2A A3

A2B/A2A

References A3/A2A

A1 receptor ligand

DPCPX

92

Shimada et al. (1991)

0.17 (b, Kd)

Holschbach et al. (1998)

2.58 (h, Kd)

Maemoto et al. (2004)

11

3.0 (g, 1)

430 (g, 4)

11

4.2 (r, 1)

>100 (r, 5) >24

Noguchi et al. (1997)

18

0.18 (b, 2)

812 (r, 5)

Holschbach et al. (1998)

[ C]KF15372 [ C]MPDX [ F]CPFPX

140

Shimada et al. (1991)

4500

0.63 (r, Kd)

[11C]FR194921

Holschbach et al. (2002)

1.26 (h, Kd)

940 (h, Kd) >700

Holschbach et al. (2002)

4.96 (r, 2)

>100 (r, 5)

Maemoto et al. (2004)

2.91 (h, 2)

>100 (h, 5) >34

>100 (h, 4)

Maemoto et al. (2004) Continued

Table 2.1 In vitro affinity of PET ligands for adenosine receptors—cont'd Affinity (Ki nM) Selectivity Affinity (Ki nM) Selectivity A2A/A1 or A1/A2A A3

A2B/A2A

References

A1

A2A

A3/A2A

62 (r, 1)

1.0 (r, 5)

62

[ C]TMSX ([ C] KF18446)

1600 (r, 1)

5.9 (r, 5)

270

Ishiwata, Noguchi, et al. (2000)

[11C]KF21213

>10,000 (r, 1) 3.0 (r, 5)

>3300

Wang et al. (2000) Hirani et al. (2001)

A2A receptor ligand

[11C]KF17837 11

11

Nonaka et al. (1994)

[ C]KW-6002

150 (r, 1)

2.2 (r, 5)

68

SCH 58261

121 (r, 1)

2.3 (r, 5)

53

[11C]SCH 442416

1800 (r, 2)

0.50 (r, 6)

1111 (h, 2)

0.048 (h, 6) 23,000

>10,000 (h, 8) >200,000 >200,000 Todde et al. (2000)

11,500 (r, 3)

7330 (r, 7)

600 (r, 8)

11

3600

>1000 (r, 8)

Zocchi, Ongini, Conti, et al. (1996)

>10,000 (r, 8)

>20,000

Todde et al. (2000)

A3 receptor ligand

[18F]FE@SUPPYa

4.22 (h, 8) a

18

19 2700

12

Li et al. (1999) Li et al. (1999)

Recently developed [ F] 5-(2-fluoroethyl) 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (FE@SUPPY) may be a candidate radioligand for A3 subtype (Wadsak et al., 2008) but has not been applied to humans and nonhuman primates. Radioligands used for binding assay: 1, [3H] N6-cyclohexyladenosine; 2, [3H]DPCPX; 3, [3H] R-N6-(phenylisopropyl)-adenosine (R-PIA); 4, [3H]NECA; 5, [3H]CGS 21680; 6, [3H]SCH 58261; 8, [125I] N6-(4-amino-3-iodobenzyl)-50 -N-methylcarbamoyladenosine. Receptor membrane source used for binding assay: b, bovine; g, guinea pig; h, human; r, rat.

55

Human Adenosine Receptor PET

PET studies of adenosine receptors in human brain are limited to adenosine A1 and A2A receptors, but not adenosine A2B and A3 receptors. In this chapter, therefore, we discuss brain PET imaging for adenosine A1 and A2A receptors and comparison of radioligands for PET imaging in health and diseases.

2. PET IMAGING OF ADENOSINE A1 RECEPTORS 2.1. PET ligands for adenosine A1 receptors Two xanthine derivatives with high affinity and high selectivity for adenosine A1 receptor, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) (Lohse et al., 1987) and its analog 8-dicyclopropylmethyl-1,3-dipropylxanthine (KF15372) (Shimada et al., 1991), were selected as lead compounds for in vivo imaging. First, KF15372 was labeled with positron-emitter 11C in the propyl group (Ishiwata et al., 1995). Then, its ethyl and methyl derivatives, 11C-8-dicyclopropylmethyl-1-ethyl-3-propylxanthine (11C-EPDX) and 11C-8-dicyclopropylmethyl-1-methyl-3-propylxanthine (11C-MPDX; Fig. 2.2A), were developed and the latter was applied to humans (Fukumitsu et al., 2003). On the other hand, the replacement of the propyl group of DPCPX with fluoroalkyl groups was investigated (Holschbach et al., 2002), and 18F-labeled fluoropropyl analog 18F-8-cyclopentyl-3-(3fluoropropyl)-1-propylxanthine (18F-CPFPX; Fig. 2.2B) was applied to humans (Bauer et al., 2003). 18F-CPFPX has a higher affinity for A1R than 11C-MPDX, but in humans, 11C-MPDX was much more stable than 18 F-CPFPX (Bauer et al., 2003; Fukumitsu et al., 2005). As a nonxanthine ligand, 11C-2-(1-methyl-4-piperidinyl)-6-(2phenylpyrazolo[1,5-a]pyridin-3-yl)-3(2H)-pyridazinone (11C-FR194921) was evaluated in rats and nonhuman primates (Matsuya et al., 2005), but further studies have not been reported.

A

B

O

O H N

11

C N O

O

N

N

H N

N N

N 18

Figure 2.2 Structures of

11

C-MPDX (A) and

18

F-CPFPX (B).

F

56

Masahiro Mishina and Kiich Ishiwata

In the search for single photon emission computed tomography (SPECT) ligands, radioiodinated DPCPX was evaluated but found to lack promising properties (Sihver et al., 2003).

2.2. Adenosine A1 receptors in normal subjects We successfully visualized adenosine A1 receptors in living humans with 11 C-MPDX PET (Fukumitsu et al., 2003; Ishiwata et al., 2002). Kimura et al. (2004) confirmed that the nondisplaceable-binding potential (BPND) was suitable to evaluate the density of adenosine A1 receptors for kinetic analysis for 11C-MPDX in human brain. Figure 2.3 demonstrates that the density of adenosine A1 receptors was large in the striatum and thalamus, moderate in the cerebral cortices and pons, and small in the cerebellum in the 11C-MPDX PET image (Fukumitsu et al., 2005). Bauer et al. (2003) also successfully performed imaging of adenosine A1 receptors in the human brain using 18F-CPFPX PET. They also confirmed the specific binding of 18F-CPFPX to adenosine A1 receptors using unlabeled CPFPX (Meyer et al., 2006). A study using autoradiography reported that the binding ability of adenosine A1 receptor in the striatum was reduced in aged rats (Meerlo et al., 2004). Human PET studies reported that the binding ability of 18F-CPFPX and 11C-MPDX was negatively correlated with age, an effect that has previously been demonstrated with regard to dopamine D1 and D2 receptors (Ishibashi et al., 2009; Meyer et al., 2007; Mishina et al., 2012). As described

0.6

0.3

0.0 R

L

Figure 2.3 Brain images for 51-year-old man of distribution volume ratio (DVR) of 11 C-MPDX. Adenosine A1 receptors are enriched in the striatum and thalamus as well as adenosine A2A receptors. Unlike the adenosine A2A receptors, however, the adenosine A1 receptors are also widely distributed in the cerebral cortex. The pixel values for the [11C]MPDX PET image are visualized as the DVR, because the brain anatomy is unclear in the nondisplaceable-binding potential (BPND ¼ DVR  1.0) images of [11C] MPDX. Note that we use the values for the BPND in the kinetic analysis for [11C]MPDX PET (Kimura et al., 2004).

Human Adenosine Receptor PET

57

below, we reported that age-related changes were different between adenosine A1 receptors and adenosine A2A receptors (Mishina et al., 2012). A 18F-CPFPX PET study showed that the density of adenosine A1 receptors in the orbitofrontal cortex was increased in subjects who were deprived of sleep for 24 h compared with that in controls with regular sleep, and suggested that changes of expression of adenosine A1 receptor contribute to homeostatic sleep regulation (Elmenhorst et al., 2007).

2.3. Adenosine A1 receptors in brain diseases Alzheimer’s disease is the most frequent form of dementia. The pathological features are senile plaques composed of amyloid-β peptide fibrils, neurofibrillary tangles of hyperphosphorylated tau, and neurotransmitter deficits (Ferri et al., 2005). Several studies have been reported for adenosine receptors in Alzheimer’s disease (Rahman, 2009). Postmortem studies in patients with Alzheimer’s disease reported a reduced density of adenosine A1 receptors in the hippocampus ( Jaarsma, Sebens, & Korf, 1991; Jansen, Faull, Dragunow, & Synek, 1990; Kalaria, Sromek, Wilcox, & Unnerstall, 1990; Ulas, Brunner, Nguyen, & Cotman, 1993), although the reduction was also observed in vascular dementia (Deckert et al., 1998). Another postmortem study reported that the density of adenosine A1 receptors in the striatum was also decreased in patients with Alzheimer’s disease (Ikeda, Mackay, Dewar, & McCulloch, 1993). A PET study for Alzheimer’s disease (Fukumitsu et al., 2008) showed that low density of adenosine A1 receptors by 11C-MPDX PET was observed in the temporal cortex and thalamus, while hypometabolism of glucose by 2-18F-fluoro2-deoxy-D-glucose (18F-FDG) PET was observed in the parietotemporal cortex and posterior cingulate gyrus. The cerebral glucose metabolism is thought to reflect regional neuronal activities such as synaptic function (Magistretti & Pellerin, 1996; Pellerin & Magistretti, 1994; Tsacopoulos & Magistretti, 1996). Alteration of the density of adenosine A1 receptors may be different with that of other neurotransmitter system in Alzheimer’s disease. Parkinson’s disease is a progressive degenerative neurological disorder characterized clinically by resting tremor, bradykinesia, cogwheel rigidity, and postural instability (Lees, Hardy, & Revesz, 2009). These symptoms result primarily from the loss of dopaminergic neurons in the substantia nigra and can be reduced by levodopa and dopamine agonists. Adenosine A1 receptors interact negatively with dopamine D1 receptors in direct pathway

58

Masahiro Mishina and Kiich Ishiwata

neurons (Ferre et al., 1994; Yabuuchi et al., 2006) and are also presynaptic receptors that regulate the dopaminergic system (Yabuuchi et al., 2006). However, the roles of adenosine A1 receptors remain unclear in patients with Parkinson’s disease unlike adenosine A2A receptors (Kelsey, Langelier, Oriel, & Reedy, 2009). In our 11C-MPDX PET study, adenosine A1 receptors seem monotonous in the putamen of Parkinson’s disease compared with adenosine A2A receptors (in preparation). In young patients with Parkinson’s disease, chronic dopamine replacement therapy often leads to involuntary movements known as dyskinesia, which is one of the most inconvenient side effects. A recent study suggested that the dyskinesia might involve not only in adenosine A2A receptors but also in adenosine A1 receptors (Xiao et al., 2011). The adenosine and its receptors have attracted attention as potential therapeutic targets for stroke (Williams-Karnesky & Stenzel-Poore, 2009). Although human PET studies were not available for adenosine A1 receptors in patients with stroke, Nariai et al. (2003) has found that decreased 11CMPDX binding to adenosine A1 receptors after reperfusion was a sensitive predictor of severe ischemic damage in an animal study. A postmortem study found that the adenosine A1 receptors were reduced in the epileptic temporal cortex in patients with temporal lobe epilepsy (Glass et al., 1996), although upregulation of adenosine A1 receptor was found in the specimens of epileptogenic neocortex by surgical resection (Angelatou et al., 1993). In patients with temporal lobe epilepsy, binding of 11C-MPDX was significantly decreased in the mesial temporal lobe of the focus side outside the hippocampus, whereas it was significantly increased in the frontal cortex of the focus side (in preparation). The regional abnormality observed by 11C-MPDX PET was different from that observed by already established PET methods measuring central benzodiazepine receptor density by 11C-flumazenil PET and glucose metabolism by 18 F-FDG PET. In the improving patients with hemianopia caused by brain damage, a 11 C-MPDX PET study reported a compensatory increase in density of adenosine A1 receptors in the injured portion of the primary visual cortex, while cerebral glucose metabolism and benzodiazepine receptor density were low in the primary visual cortex and visual association cortex (Suzuki et al., 2012). An 18F-CPFPX PET study reported that the density of adenosine A1 receptors was decreased in the cerebral cortex of patients with liver cirrhosis and hepatic encephalopathy (Boy et al., 2008).

59

Human Adenosine Receptor PET

3. PET IMAGING OF ADENOSINE A2A RECEPTORS 3.1. Ligands for adenosine A2A receptors Several ligands with high affinity and high selectivity for adenosine A2A receptor are lead compounds for in vivo imaging radioligands: (E)-8-(3,4dimethoxystyryl)-1,3-dipropyl-7-methylxanthine (KF17837) (Shimada, Suzuki, Nonaka, Ishii, & Ichikawa, 1992), 7-(2-phenylethyl)-5amino-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4- triazolo[1,5-c]pyrimidine (SCH 58261) (Zocchi, Ongini, Ferrara, Baraldi, & Dionisotti, 1996), and 4(2-[7-amino-2-{2-furyl}1{1,2,4}triazolo{2,3-a}{1,3,5}triazin-5-yl- amino] ethyl)phenol (ZM241385) (Poucher et al., 1995). First, KF17837 with a xanthine structure was labeled with 11C (Ishiwata et al., 1996; StoneElander, Thorell, Eriksson, Fredholm, & Ingvar, 1997). Thereafter, Ishiwata et al. (2005) prepared and evaluated several analogs of 11CKF17837, and 11C-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine (11C-TMSX, formally designated as 11C-KF18446; Fig. 2.4A) was chosen for clinical application. A similar xanthine derivative, KW-6002 designated as istradefylline, is a nondopaminergic therapeutic agent for Parkinson’s disease (Factor et al., 2010; Mizuno, Hasegawa, Kondo, Kuno, & Yamamoto, 2010). Istradefylline was approved for use of Parkinson’s disease by the Ministry of Health, Labour, and Welfare, Japan, and has been available in Japan since March 2013. 11C-KW-6002 PET (Fig. 2.4B) was applied for measuring A

O

11CH

N

N

C

3

OCH3 H311 CO

N

N

O

OCH3 NH2

OCH3

B

N

N

N

O

O N N

N

O

OCH3

N N

N

N

O11 CH3

Figure 2.4 Structures of 11C-TMSX (11C-KF18446) (A), [4-O-methyl-11C]KW-6002 (B), and 11 C-SCH442416 (C).

60

Masahiro Mishina and Kiich Ishiwata

receptor occupancy by cold KW-6002 (Brooks et al., 2008). 11C-KF21213 showed a slightly higher affinity and much greater selectivity than 11C-TMSX (Wang et al., 2000); however, it has not been applied to human studies. 11 C-(E)-8-(3-bromostyryl)-3,7-dimethyl-1-propargylxanthine (11C-BSDMPX) and 11C-(E)-3,7-dimethyl-8-(3-iodostyryl)-1-propargylxanthine (11C-IS-DMPX) (Ishiwata, Shimada, et al., 2000) can potentially be labeled with longer half-life bromines (75Br, half-life of 1.7 h, or 76Br, half-life of 16.1 h) and iodines (124I, half-life of 4.18 days, and 123I, half-life of 13.3 h), but did not show preferable characteristics (Ishiwata, Shimada, et al., 2000) for PET or SPECT. One of the disadvantages of xanthine-type radioligands such as TMSX and KW-6002 is photoisomerization. It was noted that photoisomerization occurred in the styryl group at the eight positions of xanthine-type adenosine A2A receptor-selective ligands (Ishiwata, Wang, Kimura, Kawamura, & Ishii, 2003; Nonaka et al., 1993). Consequently, all procedures in PET studies were carried out under dim light until injection and also during plasma metabolite analysis (Ishiwata et al., 2005; Mishina et al., 2007, 2011). From nonxanthine-type SCH 58261 as the lead, 11C-5-amino-7-(3(4-methoxyphenyl)propyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5c]pyrimidine (11C-SCH 442416; Fig. 2.4C) was radiolabeled (Todde et al., 2000) and recently applied to humans (Ramlackhansingh et al., 2011). This ligand showed the highest affinity and selectivity among the PET ligands investigated so far, and it is noted that its affinity in vitro is 10 times higher in human adenosine receptors than in the receptors of rat. A ligand of 18 F-labeled fluoroethyl derivative of SCH 442416, 18F-MRS5425, was also developed (Bhattacharjee et al., 2011). For SPECT ligands, 123I-7-(2-(4-(2-fluoro-4-iodophenyl)piperazin-1-yl) ethyl)-2-(furan-2-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin5-amine (123I-MNI-420) was recently developed and used to measure an adenosine A2A receptor occupancy by caffeine (Tavares, Batis, Barret, et al., 2013), and then the first human study was reported (Tavares, Batis, Papin, et al., 2013).

3.2. Adenosine A2A receptors in normal subjects We successfully visualized adenosine A2A receptors in the human brain with PET and 11C-TMSX (Bauer & Ishiwata, 2009; Ishiwata et al., 2007, 2010; Mishina et al., 2007). The specific binding of 11C-TMSX to adenosine A2A receptors was confirmed with a theophylline challenge

61

Human Adenosine Receptor PET

ml/mg 2

1

R

L

0

Figure 2.5 A parametric image for the distribution volume ratio (DVR) of 11C-TMSX PET image for a 21-year-old man. The image demonstrates that density of adenosine A2A receptors was high in the putamen and low in the cerebral cortex.

(Ishiwata et al., 2005). We performed test–retest studies and optimized the kinetics for 11C-TMSX PET in normal subjects, thus confirming good reproducibility of 11C-TMSX PET in the striatum (in preparation). In the 11C-TMSX PET image (Fig. 2.5), the density of adenosine A2A receptors is largest in the putamen, followed by the head of the caudate nucleus and the thalamus, but is low in the cerebral cortex, especially the frontal lobe (Ishiwata et al., 2005; Mishina et al., 2007). 11C-TMSX PET has shown a large binding potential in the striatum where adenosine A2A receptors are abundant, as found in postmortem and nonhuman studies, but the binding of 11C-TMSX is larger in the human thalamus than in other mammals. The effects of aging on adenosine A1 and adenosine A2A receptor may be different. Our 11C-TMSX PET study did not demonstrate an effect of aging on levels of adenosine A2A receptors in the human striatum (Mishina et al., 2012), although several studies reported that adenosine A1 receptors decrease with age as mentioned above (Meerlo et al., 2004; Meyer et al., 2007; Mishina et al., 2012). On the other hand, an animal study reported that the bindings of the adenosine A2A receptor agonist and antagonist in the cortical membranes were increased in aged rats compared with those in young rats (Lopes, Cunha, & Ribeiro, 1999).

3.3. Adenosine A2A receptors in brain diseases A postmortem study reported that the density of adenosine A2A receptorbinding sites in Parkinson’s disease was comparable to that found in normal subjects (Martinez-Mir et al., 1991). Using reverse transcription polymerase chain reaction and postmortem brain tissue, Hurley, Mash, and Jenner (2000) reported that mRNA levels for adenosine A2A receptor of patients with Parkinson’s disease were decreased in the caudate nucleus and anterior dorsal putamen, and were increased in the substantia nigra pars reticulata. Another postmortem study suggested that adenosine A2A receptors were

62

Masahiro Mishina and Kiich Ishiwata

involved in the development of dyskinesia following long-term levodopa therapy in Parkinson’s disease (Calon et al., 2004). Our 11C-TMSX PET study with Parkinson’s disease (Mishina et al., 2011) demonstrates that the putaminal density of adenosine A2A receptors was increased in the patients with dyskinesia and that there was no significant difference in the striatal density of adenosine A2A receptors between de novo patients and normal controls (Fig. 2.6). Another PET study with 11C-SCH 44241 also reported that binding potentials for adenosine A2A receptors were increased in patients with dyskinesia compared with those in patients without dyskinesia (Ramlackhansingh et al., 2011). In drawing attention to the asymmetrical symptoms in de novo patients, our study suggests that adenosine A2A receptors were asymmetrically downregulated in the putamen but not in the head of the caudate nucleus. We speculate that the asymmetrical regulation of adenosine A2A receptors was involved in compensation for the decrease in dopamine because the function of adenosine A2A receptor is thought to be opposite to that of dopamine D2 receptor (Fredholm & Svenningsson, 2003). We also found that the density of adenosine A2A receptors was increased in the putamen after antiparkinsonian therapy in the de novo patients with Parkinson’s disease. They did not developed dyskinesia during the period of this study. The finding may reflect alteration in compensation for the decreased dopamine by the antiparkinsonian therapy in the patients with Parkinson’s disease. Our study suggested that the increase in putaminal adenosine A2A receptors after antiparkinsonian therapy

A

R

B

L

C

DVR 2.0

0.0

Figure 2.6 11C-TMSX PET images for a healthy man (A), a de novo patient with Parkinson's disease (B), and a patient with dyskinesia (C). The normal subject is a 56-year-old man (A). The de novo patient with Parkinson's disease is a 56-year-old man with left-dominant parkinsonism (B). The distribution volume ratio (DVR) of 11 C-TMSX was smaller in the right putamen than in the left. The patient with mild dyskinesia and Parkinson's disease is a 66-year-old **woman with left-dominant parkinsonism (C). Compared with the normal subject and de novo patient, the DVR of 11C-TMSX in the striata was increased in the patient with dyskinesia.

Human Adenosine Receptor PET

63

preceded the development of dyskinesia in patients with Parkinson’s disease (Mishina et al., 2011). The density of adenosine A2A receptors in the basal ganglia was lower in patients with Huntington’s disease than in normal subjects (Martinez-Mir et al., 1991). The loss of adenosine A2A receptors in the caudate nucleus, putamen, and external globus pallidus was more dominant than that of dopamine D2 receptor binding in the patients with Huntington’s disease (Glass, Dragunow, & Faull, 2000). In patients with schizophrenia, postmortem studies using [3H] CGS21680 reported that the adenosine A2A receptors were increased in the striatum (Deckert et al., 2003; Kurumaji & Toru, 1998) and that the increase of the receptor density correlated with the dose of antipsychotic medication (Deckert et al., 2003).

4. CONCLUSIONS Recently, adenosine receptors have attracted attention as potential therapeutic strategy ( Jacobson & Gao, 2006). Although little information was available for adenosine receptors in the living human brain to date, molecular imaging for adenosine receptors was successful in several studies for developing PET ligands and is being applied to research on physiology and neurological disorders. The imaging techniques may be applied to various drug developments. Continued efforts to identify high-affinity and selective ligands should lead to PET probes suitable for these binding sites in the near future.

REFERENCES Angelatou, F., Pagonopoulou, O., Maraziotis, T., Olivier, A., Villemeure, J. G., Avoli, M., et al. (1993). Upregulation of A1 adenosine receptors in human temporal lobe epilepsy: A quantitative autoradiographic study. Neuroscience Letters, 163(1), 11–14. http://dx.doi. org/10.1016/0304-3940(93)90217-9. Bauer, A., Holschbach, M. H., Meyer, P. T., Boy, C., Herzog, H., Olsson, R. A., et al. (2003). In vivo imaging of adenosine A1 receptors in the human brain with [18F]CPFPX and positron emission tomography. NeuroImage, 19(4), 1760–1769. http://dx.doi.org/ 10.1016/S1053-8119(03)00241-6. Bauer, A., & Ishiwata, K. (2009). Adenosine receptor ligands and PET imaging of the CNS. Handbook of Experimental Pharmacology, 193, 617–642. http://dx.doi.org/10.1007/9783-540-89615-9_19. Bhattacharjee, A. K., Lang, L., Jacobson, O., Shinkre, B., Ma, Y., Niu, G., et al. (2011). Striatal adenosine A2A receptor-mediated positron emission tomographic imaging in 6-hydroxydopamine-lesioned rats using [18F]-MRS5425. Nuclear Medicine and Biology, 38(6), 897–906. http://dx.doi.org/10.1016/j.nucmedbio.2011.01.009.

64

Masahiro Mishina and Kiich Ishiwata

Boy, C., Meyer, P. T., Kircheis, G., Holschbach, M. H., Herzog, H., Elmenhorst, D., et al. (2008). Cerebral A1 adenosine receptors (A1AR) in liver cirrhosis. European Journal of Nuclear Medicine and Molecular Imaging, 35(3), 589–597. http://dx.doi.org/10.1007/ s00259-007-0586-z. Brooks, D. J., Doder, M., Osman, S., Luthra, S. K., Hirani, E., Hume, S., et al. (2008). Positron emission tomography analysis of [11C]KW-6002 binding to human and rat adenosine A2A receptors in the brain. Synapse, 62(9), 671–681. http://dx.doi.org/ 10.1002/syn.20539. Calon, F., Dridi, M., Hornykiewicz, O., Bedard, P. J., Rajput, A. H., & Di Paolo, T. (2004). Increased adenosine A2A receptors in the brain of Parkinson’s disease patients with dyskinesias. Brain, 127, 1075–1084. http://dx.doi.org/10.1093/brain/awh128. Deckert, J., Abel, F., Kunig, G., Hartmann, J., Senitz, D., Maier, H., et al. (1998). Loss of human hippocampal adenosine A1 receptors in dementia: Evidence for lack of specificity. Neuroscience Letters, 244(1), 1–4. http://dx.doi.org/10.1016/S0304-3940(98)00108-6. Deckert, J., Brenner, M., Durany, N., Zochling, R., Paulus, W., Ransmayr, G., et al. (2003). Up-regulation of striatal adenosine A2A receptors in schizophrenia. Neuroreport, 14(3), 313–316. http://dx.doi.org/10.1097/01.wnr.0000058242.21747.04. Elmenhorst, D., Meyer, P. T., Winz, O. H., Matusch, A., Ermert, J., Coenen, H. H., et al. (2007). Sleep deprivation increases A1 adenosine receptor binding in the human brain: A positron emission tomography study. Journal of Neuroscience, 27(9), 2410–2415. http:// dx.doi.org/10.1523/JNEUROSCI.5066-06.2007. Factor, S., Mark, M. H., Watts, R., Struck, L., Mori, A., Ballerini, R., et al. (2010). A long-term study of istradefylline in subjects with fluctuating Parkinson’s disease. Parkinsonism & Related Disorders, 16(6), 423–426. http://dx.doi.org/10.1016/j. parkreldis.2010.02.014. Fastbom, J., Pazos, A., Probst, A., & Palacios, J. M. (1987). Adenosine A1 receptors in the human brain: A quantitative autoradiographic study. Neuroscience, 22(3), 827–839. http://dx.doi.org/10.1016/0306-4522(87)92962-9. Ferre, S., Popoli, P., Gimenez-Llort, L., Finnman, U. B., Martinez, E., Scotti de Carolis, A., et al. (1994). Postsynaptic antagonistic interaction between adenosine A1 and dopamine D1 receptors. Neuroreport, 6(1), 73–76. Ferri, C. P., Prince, M., Brayne, C., Brodaty, H., Fratiglioni, L., Ganguli, M., et al. (2005). Global prevalence of dementia: A Delphi consensus study. Lancet, 366(9503), 2112–2117. http://dx.doi.org/10.1016/S0140-6736(05)67889-0. Fredholm, B. B., & Svenningsson, P. (2003). Adenosine-dopamine interactions: Development of a concept and some comments on therapeutic possibilities. Neurology, 61(Suppl.), S5–S9. http://dx.doi.org/10.1212/01.WNL.0000095204.89871.FF. Fukumitsu, N., Ishii, K., Kimura, Y., Oda, K., Hashimoto, M., Suzuki, M., et al. (2008). Adenosine A1 receptors using 8-dicyclopropylmethyl-1-[11C]methyl-3-propylxanthine PET in Alzheimer’s disease. Annals of Nuclear Medicine, 22(10), 841–847. http://dx.doi. org/10.1007/s12149-008-0185-5. Fukumitsu, N., Ishii, K., Kimura, Y., Oda, K., Sasaki, T., Mori, Y., et al. (2003). Imaging of adenosine A1 receptors in the human brain by positron emission tomography with [11C]MPDX. Annals of Nuclear Medicine, 17(6), 511–515. http://dx.doi.org/10.1007/ BF03006445. Fukumitsu, N., Ishii, K., Kimura, Y., Oda, K., Sasaki, T., Mori, Y., et al. (2005). Adenosine A1 receptor mapping of the human brain by PET with 8-dicyclopropylmethyl-1-11Cmethyl-3-propylxanthine. Journal of Nuclear Medicine, 46(1), 32–37. Glass, M., Dragunow, M., & Faull, R. L. (2000). The pattern of neurodegeneration in Huntington’s disease: A comparative study of cannabinoid, dopamine, adenosine and GABAA receptor alterations in the human basal ganglia in Huntington’s disease. Neuroscience, 97(3), 505–519. http://dx.doi.org/10.1016/S0306-4522(00)00008-7.

Human Adenosine Receptor PET

65

Glass, M., Faull, R. L., Bullock, J. Y., Jansen, K., Mee, E. W., Walker, E. B., et al. (1996). Loss of A1 adenosine receptors in human temporal lobe epilepsy. Brain Research, 710(1–2), 56–68. http://dx.doi.org/10.1016/0006-8993(95)01313-X. Hirani, E., Gillies, J., Karasawa, A., Shimada, J., Kase, H., Opacka-Juffry, J., et al. (2001). Evaluation of [4-O-methyl-11C]KW-6002 as a potential PET ligand for mapping central adenosine A2A receptors in rats. Synapse, 42(3), 164–176. http://dx.doi.org/10.1002/ syn.1110. Holschbach, M. H., Fein, T., Krummeich, C., Lewis, R. G., Wutz, W., Schwabe, U., et al. (1998). A1 adenosine receptor antagonists as ligands for positron emission tomography (PET) and single-photon emission tomography (SPET). Journal of Medicinal Chemistry, 41(4), 555–563. http://dx.doi.org/10.1021/jm9705465. Holschbach, M. H., Olsson, R. A., Bier, D., Wutz, W., Sihver, W., Schuller, M., et al. (2002). Synthesis and evaluation of no-carrier-added 8-cyclopentyl-3-(3-[18F] fluoropropyl)-1-propylxanthine ([18F]CPFPX): A potent and selective A1-adenosine receptor antagonist for in vivo imaging. Journal of Medicinal Chemistry, 45(23), 5150–5156. http://dx.doi.org/10.1021/jm020905i. Hurley, M. J., Mash, D. C., & Jenner, P. (2000). Adenosine A2A receptor mRNA expression in Parkinson’s disease. Neuroscience Letters, 291(1), 54–58. http://dx.doi.org/10.1016/ S0304-3940(00)01371-9. Ikeda, M., Mackay, K. B., Dewar, D., & McCulloch, J. (1993). Differential alterations in adenosine A1 and kappa 1 opioid receptors in the striatum in Alzheimer’s disease. Brain Research, 616(1–2), 211–217. http://dx.doi.org/10.1016/0006-8993(93)90211-5. Ishibashi, K., Ishii, K., Oda, K., Kawasaki, K., Mizusawa, H., & Ishiwata, K. (2009). Regional analysis of age-related decline in dopamine transporters and dopamine D2-like receptors in human striatum. Synapse, 63(4), 282–290. http://dx.doi.org/10.1002/syn.20603. Ishiwata, K., Furuta, R., Shimada, J., Ishii, S., Endo, K., Suzuki, F., et al. (1995). Synthesis and preliminary evaluation of [11C]KF15372, a selective adenosine A1 antagonist. Applied Radiation and Isotopes, 46(10), 1009–1013. Ishiwata, K., Kimura, Y., de Vries, E. F. J., & Elsinga, P. H. (2007). PET tracers for mapping adenosine receptors as probes for diagnosis of CNS disorders. Central Nervous System Agents in Medicinal Chemistry, 7(1), 57–77. http://dx.doi.org/10.2174/ 187152407780059259. Ishiwata, K., Kimura, Y., Oda, K., Ishii, K., Sakata, M., Kawasaki, K., et al. (2010). Development of PET radiopharmaceuticals and their clinical applications at the positron medical center. Geriatrics & Gerontology International, 10(Suppl. 1), S180–S196. http://dx.doi. org/10.1111/j.1447-0594.2010.00594.x. Ishiwata, K., Mishina, M., Kimura, Y., Oda, K., Sasaki, T., & Ishii, K. (2005). First visualization of adenosine A2A receptors in the human brain by positron emission tomography with [11C]TMSX. Synapse, 55(2), 133–136. http://dx.doi.org/10.1002/ syn.20099. Ishiwata, K., Nariai, T., Kimura, Y., Oda, K., Kawamura, K., Ishii, K., et al. (2002). Preclinical studies on [11C]MPDX for mapping adenosine A1 receptors by positron emission tomography. Annals of Nuclear Medicine, 16(6), 377–382. Ishiwata, K., Noguchi, J., Toyama, H., Sakiyama, Y., Koike, N., Ishii, S., et al. (1996). Synthesis and preliminary evaluation of [11C]KF17837, a selective adenosine A2A antagonist. Applied Radiation and Isotopes, 47(5–6), 507–511. http://dx.doi.org/10.1016/0969-8043 (95)00295-2. Ishiwata, K., Noguchi, J., Wakabayashi, S., Shimada, J., Ogi, N., Nariai, T., et al. (2000). 11 C-labeled KF18446: A potential central nervous system adenosine A2A receptor ligand. Journal of Nuclear Medicine, 41(2), 345–354. Ishiwata, K., Shimada, J., Wang, W. F., Harakawa, H., Ishii, S., Kiyosawa, M., et al. (2000). Evaluation of iodinated and brominated [11C]styrylxanthine derivatives as in vivo

66

Masahiro Mishina and Kiich Ishiwata

radioligands mapping adenosine A2A receptor in the central nervous system. Annals of Nuclear Medicine, 14(4), 247–253. http://dx.doi.org/10.1007/BF02988206. Ishiwata, K., Wang, W. F., Kimura, Y., Kawamura, K., & Ishii, K. (2003). Preclinical studies on [11C]TMSX for mapping adenosine A2A receptors by positron emission tomography. Annals of Nuclear Medicine, 17(3), 205–211. http://dx.doi.org/10.1007/BF02990023. Jaarsma, D., Sebens, J. B., & Korf, J. (1991). Reduction of adenosine A1-receptors in the perforant pathway terminal zone in Alzheimer hippocampus. Neuroscience Letters, 121(1–2), 111–114. http://dx.doi.org/10.1016/0304-3940(91)90661-C. Jacobson, K. A., & Gao, Z. G. (2006). Adenosine receptors as therapeutic targets. Nature Reviews. Drug Discovery, 5(3), 247–264. http://dx.doi.org/10.1038/nrd1983. Jansen, K. L., Faull, R. L., Dragunow, M., & Synek, B. L. (1990). Alzheimer’s disease: Changes in hippocampal N-methyl-D-aspartate, quisqualate, neurotensin, adenosine, benzodiazepine, serotonin and opioid receptors—An autoradiographic study. Neuroscience, 39(3), 613–627. http://dx.doi.org/10.1016/0306-4522(90)90246-Z. Kalaria, R. N., Sromek, S., Wilcox, B. J., & Unnerstall, J. R. (1990). Hippocampal adenosine A1 receptors are decreased in Alzheimer’s disease. Neuroscience Letters, 118(2), 257–260. http://dx.doi.org/10.1016/0304-3940(90)90641-L. Kelsey, J. E., Langelier, N. A., Oriel, B. S., & Reedy, C. (2009). The effects of systemic, intrastriatal, and intrapallidal injections of caffeine and systemic injections of A2A and A1 antagonists on forepaw stepping in the unilateral 6-OHDA-lesioned rat. Psychopharmacology, 201(4), 529–539. http://dx.doi.org/10.1007/s00213-008-1319-0. Khanapur, S., Waarde, A., Ishiwata, K., Leenders, K. L., Dierckx, R. A., & Elsinga, P. H. (2013). Adenosine A2A receptor antagonists as positron emission tomography (PET) tracers. Current Medicinal Chemistry, 21(3), 312–328. Kimura, Y., Ishii, K., Fukumitsu, N., Oda, K., Sasaki, T., Kawamura, K., et al. (2004). Quantitative analysis of adenosine A1 receptors in human brain using positron emission tomography and [1-methyl-11C]8-dicyclopropylmethyl-1-methyl-3-propylxanthine. Nuclear Medicine and Biology, 31(8), 975–981. http://dx.doi.org/10.1016/j. nucmedbio.2004.06.005. Kurumaji, A., & Toru, M. (1998). An increase in [3H] CGS21680 binding in the striatum of postmortem brains of chronic schizophrenics. Brain Research, 808(2), 320–323. http://dx. doi.org/10.1016/S0006-8993(98)00840-3. Lees, A. J., Hardy, J., & Revesz, T. (2009). Parkinson’s disease. Lancet, 373(9680), 2055–2066. http://dx.doi.org/10.1016/S0140-6736(09)60492-X. Li, A. H., Moro, S., Forsyth, N., Melman, N., Ji, X. D., & Jacobson, K. A. (1999). Synthesis, CoMFA analysis, and receptor docking of 3,5-diacyl-2, 4-dialkylpyridine derivatives as selective A3 adenosine receptor antagonists. Journal of Medicinal Chemistry, 42(4), 706–721. http://dx.doi.org/10.1021/jm980550w. Lohse, M. J., Klotz, K. N., Lindenborn-Fotinos, J., Reddington, M., Schwabe, U., & Olsson, R. A. (1987). 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX)—A selective high affinity antagonist radioligand for A1 adenosine receptors. Naunyn-Schmiedeberg’s Archives of Pharmacology, 336(2), 204–210. http://dx.doi.org/10.1007/BF00165806. Lopes, L. V., Cunha, R. A., & Ribeiro, J. A. (1999). Increase in the number, G protein coupling, and efficiency of facilitatory adenosine A2A receptors in the limbic cortex, but not striatum, of aged rats. Journal of Neurochemistry, 73(4), 1733–1738. http://dx.doi.org/ 10.1046/j.1471-4159.1999.731733.x. Maemoto, T., Tada, M., Mihara, T., Ueyama, N., Matsuoka, H., Harada, K., et al. (2004). Pharmacological characterization of FR194921, a new potent, selective, and orally active antagonist for central adenosine A1 receptors. Journal of Pharmacological Sciences, 96(1), 42–52. Magistretti, P. J., & Pellerin, L. (1996). Cellular bases of brain energy metabolism and their relevance to functional brain imaging: Evidence for a prominent role of astrocytes. Cerebral Cortex, 6(1), 50–61. http://dx.doi.org/10.1093/cercor/6.1.50.

Human Adenosine Receptor PET

67

Martinez-Mir, M. I., Probst, A., & Palacios, J. M. (1991). Adenosine A2 receptors: Selective localization in the human basal ganglia and alterations with disease. Neuroscience, 42(3), 697–706. http://dx.doi.org/10.1016/0306-4522(91)90038-P. Matsuya, T., Takamatsu, H., Murakami, Y., Noda, A., Ichise, R., Awaga, Y., et al. (2005). Synthesis and evaluation of [11C]FR194921 as a nonxanthine-type PET tracer for adenosine A1 receptors in the brain. Nuclear Medicine and Biology, 32(8), 837–844. http://dx. doi.org/10.1016/j.nucmedbio.2005.06.008. Meerlo, P., Roman, V., Farkas, E., Keijser, J. N., Nyakas, C., & Luiten, P. G. (2004). Ageing-related decline in adenosine A1 receptor binding in the rat brain: An autoradiographic study. Journal of Neuroscience Research, 78(5), 742–748. http://dx.doi.org/ 10.1002/jnr.20314. Meyer, P. T., Elmenhorst, D., Boy, C., Winz, O., Matusch, A., Zilles, K., et al. (2007). Effect of aging on cerebral A1 adenosine receptors: A [18F]CPFPX PET study in humans. Neurobiology of Aging, 28(12), 1914–1924. http://dx.doi.org/10.1016/j. neurobiolaging.2006.08.005. Meyer, P. T., Elmenhorst, D., Matusch, A., Winz, O., Zilles, K., & Bauer, A. (2006). A1 adenosine receptor PET using [18F]CPFPX: Displacement studies in humans. NeuroImage, 32(3), 1100–1105. http://dx.doi.org/10.1016/j.neuroimage.2006.04.202. Mishina, M., Ishiwata, K., Kimura, Y., Naganawa, M., Oda, K., Kobayashi, S., et al. (2007). Evaluation of distribution of adenosine A2A receptors in normal human brain measured with [11C]TMSX PET. Synapse, 61(9), 778–784. http://dx.doi.org/10.1002/syn.20423. Mishina, M., Ishiwata, K., Naganawa, M., Kimura, Y., Kitamura, S., Suzuki, M., et al. (2011). Adenosine A2A receptors measured with [11C]TMSX PET in the striata of Parkinson’s disease patients. PLoS One, 6(2), e17338. http://dx.doi.org/10.1371/ journal.pone.0017338. Mishina, M., Kimura, Y., Naganawa, M., Ishii, K., Oda, K., Sakata, M., et al. (2012). Differential effects of age on human striatal adenosine A1 and A2A receptors. Synapse, 66(9), 832–839. http://dx.doi.org/10.1002/syn.21573. Mizuno, Y., Hasegawa, K., Kondo, T., Kuno, S., & Yamamoto, M. (2010). Clinical efficacy of istradefylline (KW-6002) in Parkinson’s disease: A randomized, controlled study. Movement Disorders, 25(10), 1437–1443. http://dx.doi.org/10.1002/mds.23107. Nariai, T., Shimada, Y., Ishiwata, K., Nagaoka, T., Shimada, J., Kuroiwa, T., et al. (2003). PET imaging of adenosine A1 receptors with 11C-MPDX as an indicator of severe cerebral ischemic insult. Journal of Nuclear Medicine, 44(11), 1839–1844. Noguchi, J., Ishiwata, K., Furuta, R., Simada, J., Kiyosawa, M., Ishii, S., et al. (1997). Evaluation of carbon-11 labeled KF15372 and its ethyl and methyl derivatives as a potential CNS adenosine A1 receptor ligand. Nuclear Medicine and Biology, 24(1), 53–59. http://dx. doi.org/10.1016/S0969-8051(96)00161-8. Nonaka, H., Ichimura, M., Takeda, M., Nonaka, Y., Shimada, J., Suzuki, F., et al. (1994). KF17837 ((E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine), a potent and selective adenosine A2 receptor antagonist. European Journal of Pharmacology, 267(3), 335–341. http://dx.doi.org/10.1016/0922-4106(94)90159-7. Nonaka, Y., Shimada, J., Nonaka, H., Koike, N., Aoki, N., Kobayashi, H., et al. (1993). Photoisomerization of a potent and selective adenosine A2 antagonist, (E)-1,3dipropyl-8-(3,4-dimethoxystyryl)-7-methylxanthine. Journal of Medicinal Chemistry, 36(23), 3731–3733. http://dx.doi.org/10.1021/jm00075a031. Paul, S., Elsinga, P. H., Ishiwata, K., Dierckx, R. A., & van Waarde, A. (2011). Adenosine A1 receptors in the central nervous system: Their functions in health and disease, and possible elucidation by PET imaging. Current Medicinal Chemistry, 18(31), 4820–4835. Pellerin, L., & Magistretti, P. J. (1994). Glutamate uptake into astrocytes stimulates aerobic glycolysis: A mechanism coupling neuronal activity to glucose utilization. Proceedings of the National Academy of Sciences of the United States of America, 91(22), 10625–10629.

68

Masahiro Mishina and Kiich Ishiwata

Poucher, S. M., Keddie, J. R., Singh, P., Stoggall, S. M., Caulkett, P. W., Jones, G., et al. (1995). The in vitro pharmacology of ZM 241385, a potent, non-xanthine A2A selective adenosine receptor antagonist. British Journal of Pharmacology, 115(6), 1096–1102. http:// dx.doi.org/10.1111/j.1476-5381.1995.tb15923.x. Rahman, A. (2009). The role of adenosine in Alzheimer’s disease. Current Neuropharmacology, 7(3), 207–216. http://dx.doi.org/10.2174/157015909789152119. Ramlackhansingh, A. F., Bose, S. K., Ahmed, I., Turkheimer, F. E., Pavese, N., & Brooks, D. J. (2011). Adenosine 2A receptor availability in dyskinetic and nondyskinetic patients with Parkinson disease. Neurology, 76(21), 1811–1816. http://dx.doi.org/ 10.1212/WNL.0b013e31821ccce4. Shimada, J., Suzuki, F., Nonaka, H., Ishii, A., & Ichikawa, S. (1992). (E)-1,3dialkyl-7-methyl-8-(3,4,5-trimethoxystyryl)xanthines: Potent and selective adenosine A2 antagonists. Journal of Medicinal Chemistry, 35(12), 2342–2345. http://dx.doi.org/ 10.1021/jm00090a027. Shimada, J., Suzuki, F., Nonaka, H., Karasawa, A., Mizumoto, H., Ohno, T., et al. (1991). 8-(Dicyclopropylmethyl)-1,3-dipropylxanthine: A potent and selective adenosine A1 antagonist with renal protective and diuretic activities. Journal of Medicinal Chemistry, 34(1), 466–469. http://dx.doi.org/10.1021/jm00105a072. Sihver, W., Holschbach, M. H., Bier, D., Wutz, W., Schulze, A., Olsson, R. A., et al. (2003). Evaluation of radioiodinated 8-cyclopentyl-3-[(E)-3-iodoprop-2-en-1-yl]1-propylxanthine ([*I]CPIPX) as a new potential A1 adenosine receptor antagonist for SPECT. Nuclear Medicine and Biology, 30(6), 661–668. http://dx.doi.org/ 10.1016/S0969-8051(03)00053-2. Stone-Elander, S., Thorell, J. O., Eriksson, L., Fredholm, B. B., & Ingvar, M. (1997). In vivo biodistribution of [N-11C-methyl]KF 17837 using 3-D-PET: Evaluation as a ligand for the study of adenosine A2A receptors. Nuclear Medicine and Biology, 24(2), 187–191. http://dx.doi.org/10.1016/S0969-8051(96)00216-8. Suzuki, Y., Nariai, T., Kiyosawa, M., Mochizuki, M., Kimura, Y., Oda, K., et al. (2012). Increased adenosine A1 receptor levels in hemianopia patients after cerebral injury: An application of PET using 11C-8-dicyclopropylmethyl-1-methyl-3-propylxanthine. Clinical Nuclear Medicine, 37(12), 1146–1151. http://dx.doi.org/10.1097/RLU. 0b013e31826392a7. Tavares, A. A., Batis, J., Barret, O., Alagille, D., Vala, C., Kudej, G., et al. (2013). In vivo evaluation of [123I]MNI-420: A novel single photon emission computed tomography radiotracer for imaging of adenosine 2A receptors in brain. Nuclear Medicine and Biology, 40(3), 403–409. http://dx.doi.org/10.1016/j.nucmedbio.2012.12.005. Tavares, A. A., Batis, J. C., Papin, C., Jennings, D., Alagille, D., Russell, D. S., et al. (2013). Kinetic modeling, test-retest, and dosimetry of 123I-MNI-420 in humans. Journal of Nuclear Medicine, 54(10), 1760–1767. http://dx.doi.org/10.2967/jnumed.113.119933. Todde, S., Moresco, R. M., Simonelli, P., Baraldi, P. G., Cacciari, B., Spalluto, G., et al. (2000). 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. Journal of Medicinal Chemistry, 43(23), 4359–4362. http://dx.doi.org/10.1021/ jm0009843. Tsacopoulos, M., & Magistretti, P. J. (1996). Metabolic coupling between glia and neurons. Journal of Neuroscience, 16(3), 877–885. Ulas, J., Brunner, L. C., Nguyen, L., & Cotman, C. W. (1993). Reduced density of adenosine A1 receptors and preserved coupling of adenosine A1 receptors to G proteins in Alzheimer hippocampus: A quantitative autoradiographic study. Neuroscience, 52(4), 843–854. http://dx.doi.org/10.1016/0306-4522(93)90533-L. Wadsak, W., Mien, L. K., Shanab, K., Ettlinger, D. E., Haeusler, D., Sindelar, K., et al. (2008). Preparation and first evaluation of [18F]FE@SUPPY: A new PET tracer for

Human Adenosine Receptor PET

69

the adenosine A3 receptor. Nuclear Medicine and Biology, 35(1), 61–66. http://dx.doi.org/ 10.1016/j.nucmedbio.2007.09.004. Wang, W. F., Ishiwata, K., Nonaka, H., Ishii, S., Kiyosawa, M., Shimada, J., et al. (2000). Carbon-11-labeled KF21213: A highly selective ligand for mapping CNS adenosine A2A receptors with positron emission tomography. Nuclear Medicine and Biology, 27(6), 541–546. http://dx.doi.org/10.1016/S0969-8051(00)00126-8. Williams-Karnesky, R. L., & Stenzel-Poore, M. P. (2009). Adenosine and stroke: Maximizing the therapeutic potential of adenosine as a prophylactic and acute neuroprotectant. Current Neuropharmacology, 7(3), 217–227. http://dx.doi.org/10.2174/ 157015909789152209. Xiao, D., Cassin, J. J., Healy, B., Burdett, T. C., Chen, J. F., Fredholm, B. B., et al. (2011). Deletion of adenosine A1 or A2A receptors reduces L-3,4-dihydroxyphenylalanineinduced dyskinesia in a model of Parkinson’s disease. Brain Research, 1367, 310–318. http://dx.doi.org/10.1016/j.brainres.2010.08.099. Yabuuchi, K., Kuroiwa, M., Shuto, T., Sotogaku, N., Snyder, G. L., Higashi, H., et al. (2006). Role of adenosine A1 receptors in the modulation of dopamine D1 and adenosine A2A receptor signaling in the neostriatum. Neuroscience, 141(1), 19–25. http://dx.doi. org/10.1016/j.neuroscience.2006.04.047. Zocchi, C., Ongini, E., Conti, A., Monopoli, A., Negretti, A., Baraldi, P. G., et al. (1996). The non-xanthine heterocyclic compound SCH 58261 is a new potent and selective A2A adenosine receptor antagonist. Journal of Pharmacology and Experimental Therapeutics, 276(2), 398–404. Zocchi, C., Ongini, E., Ferrara, S., Baraldi, P. G., & Dionisotti, S. (1996). Binding of the radioligand [3H]-SCH 58261, a new non-xanthine A2A adenosine receptor antagonist, to rat striatal membranes. British Journal of Pharmacology, 117(7), 1381–1386. http://dx. doi.org/10.1111/j.1476-5381.1996.tb15296.x.