Abstract
Adenosine is a fundamental molecule of life and a main metabolite of the energy metabolism in humans and animals. The net effect of the neuromodulator adenosine on excitable tissue is inhibitory affecting the release of classical neurotransmitters. Adenosine and its receptors play an important role in the physiology and pathophysiology of the brain as well as in other organs, particularly kidney, bowel, vascular system, and in tumors. The widely used neurostimulant caffeine exerts its effects as an antagonist at adenosine receptors. Four different types of adenosine receptors have been described in mammals which are all G-protein coupled receptors. For A1 and A2A adenosine receptors PET radioligands have been used successfully in humans and animal models whereas for the A2B and A3 subtype a suitable imaging method is still lacking. Pharmacokinetic quantification of A1 and A2A adenosine receptor densities is possible. So far, these tools revealed important insights into neurologic and psychiatric disorders, sleep physiology, and cancer. The constantly increasing amount of data on adenosine and its important role in multiple organ systems as well as in the pathophysiology of frequent diseases underscores the need for further research in the field of ligand development for adenosine receptors.
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References
Balber T, Singer J, Berroteran-Infante N, Dumanic M, Fetty L, Fazekas-Singer J, Vraka C, Nics L, Bergmann M, Pallitsch K, Spreitzer H, Wadsak W, Hacker M, Jensen-Jarolim E, Viernstein H, Mitterhauser M (2018) Preclinical in vitro and in vivo evaluation of [(18)F]FE@SUPPY for cancer PET imaging: limitations of a xenograft model for colorectal cancer. Contrast Media Mol Imaging 2018:1269830
Barret O, Hannestad J, Alagille D, Vala C, Tavares A, Papin C, Morley T, Fowles K, Lee H, Seibyl J, Tytgat D, Laruelle M, Tamagnan G (2014) Adenosine 2A receptor occupancy by tozadenant and preladenant in rhesus monkeys. J Nucl Med 55:1712–1718
Barret O, Hannestad J, Vala C, Alagille D, Tavares A, Laruelle M, Jennings D, Marek K, Russell D, Seibyl J, Tamagnan G (2015) Characterization in humans of 18F-MNI-444, a PET radiotracer for brain adenosine 2A receptors. J Nucl Med 56:586–591
Bauer A, Holschbach MH, Meyer PT, Boy C, Herzog H, Olsson RA, Coenen HH, Zilles K (2003) In vivo imaging of adenosine A1 receptors in the human brain with [18F]CPFPX and positron emission tomography. NeuroImage 19:1760–1769
Bauer A, Ishiwata K (2009) Adenosine receptor ligands and PET imaging of the CNS. Handb Exp Pharmacol:617–642
Bauer A, Langen KJ, Bidmon H, Holschbach MH, Weber S, Olsson RA, Coenen HH, Zilles K (2005) 18F-CPFPX PET identifies changes in cerebral A1 adenosine receptor density caused by glioma invasion. J Nucl Med 46:450–454
Bier D, Holschbach MH, Wutz W, Olsson RA, Coenen HH (2006) Metabolism of the A1 adenosine receptor positron emission tomography ligand [18F]8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine ([18F]CPFPX) in rodents and humans. Drug Metab Dispos 34:570–576
Brooks DJ, Doder M, Osman S, Luthra SK, Hirani E, Hume S, Kase H, Kilborn J, Martindill S, Mori A (2008) Positron emission tomography analysis of [11C]KW-6002 binding to human and rat adenosine A2A receptors in the brain. Synapse 62:671–681
Brooks DJ, Papapetropoulos S, Vandenhende F, Tomic D, He P, Coppell A, O'Neill G (2010) 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. Clin Neuropharmacol 33:55–60
Ciruela F, Casado V, Rodrigues RJ, Lujan R, Burgueno J, Canals M, Borycz J, Rebola N, Goldberg SR, Mallol J, Cortes A, Canela EI, Lopez-Gimenez JF, Milligan G, Lluis C, Cunha RA, Ferre S, Franco R (2006) Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers. J Neurosci 26:2080–2087
Cristovao-Ferreira S, Navarro G, Brugarolas M, Perez-Capote K, Vaz SH, Fattorini G, Conti F, Lluis C, Ribeiro JA, McCormick PJ, Casado V, Franco R, Sebastiao AM (2011) Modulation of GABA transport by adenosine A1R-A2AR heteromers, which are coupled to both Gs- and G(i/o)-proteins. J Neurosci 31:15629–15639
Ding Y-S, Fowler J (2005) New-generation radiotracers for nAChR and NET. Nucl Med Biol 32:707–718
Dishino DD, Welch MJ, Kilbourn MR, Raichle ME (1983) Relationship between lipophilicity and brain extraction of C-11-labeled radiopharmaceuticals. J Nucl Med 24:1030–1038
Dunwiddie TV, Masino SA (2001) The role and regulation of adenosine in the central nervous system. Annu Rev Neurosci 24:31–55
Elmenhorst D, Elmenhorst EM, Hennecke E, Kroll T, Matusch A, Aeschbach D, Bauer A (2017) Recovery sleep after extended wakefulness restores elevated A1 adenosine receptor availability in the human brain. Proc Natl Acad Sci U S A 114:4243–4248
Elmenhorst D, Garibotto V, Prescher A, Bauer A (2011) Adenosine A(1) receptors in human brain and transfected CHO cells: inhibition of [(3)H]CPFPX binding by adenosine and caffeine. Neurosci Lett 487:415–420
Elmenhorst D, Kroll T, Wedekind F, Weisshaupt A, Beer S, Bauer A (2013) In vivo kinetic and steady-state quantification of 18F-CPFPX binding to rat cerebral A1 adenosine receptors: validation by displacement and autoradiographic experiments. J Nucl Med 54:1411–1419
Elmenhorst D, Meyer PT, Matusch A, Winz OH, Bauer A (2012) Caffeine occupancy of human cerebral A1 adenosine receptors: in vivo quantification with 18F-CPFPX and PET. J Nucl Med 53:1723–1729
Elmenhorst D, Meyer PT, Matusch A, Winz OH, Zilles K, Bauer A (2007a) Test-retest stability of cerebral A(1) adenosine receptor quantification using [(18)F]CPFPX and PET. Eur J Nucl Med Mol Imaging 34:1061–1070
Elmenhorst D, Meyer PT, Winz OH, Matusch A, Ermert J, Coenen HH, Basheer R, Haas HL, Zilles K, Bauer A (2007b) Sleep deprivation increases A1 adenosine receptor binding in the human brain: a positron emission tomography study. J Neurosci 27:2410–2415
Elmenhorst EM, Elmenhorst D, Benderoth S, Kroll T, Bauer A, Aeschbach D (2018) Cognitive impairments by alcohol and sleep deprivation indicate trait characteristics and a potential role for adenosine A1 receptors. Proc Natl Acad Sci U S A 115:8009–8014
Franco R, Lluis C, Canela EI, Mallol J, Agnati L, Casado V, Ciruela F, Ferre S, Fuxe K (2007) Receptor-receptor interactions involving adenosine A1 or dopamine D1 receptors and accessory proteins. J Neural Transm 114:93–104
Fredholm BB, IJzerman AP, Jacobson KA, Klotz KN, Linden J (2001) International union of pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 53:527–552
Fukumitsu N, Ishii K, Kimura Y, Oda K, Hashimoto M, Suzuki M, Ishiwata K (2008) Adenosine A(1) receptors using 8-dicyclopropylmethyl-1-[(11)C]methyl-3-propylxanthine PET in Alzheimer’s disease. Ann Nucl Med 22:841–847
Fukumitsu N, Ishii K, Kimura Y, Oda K, Sasaki T, Mori Y, Ishiwata K (2003) Imaging of adenosine A1 receptors in the human brain by positron emission tomography with [11C]MPDX. Ann Nucl Med 17:511–515
Fukumitsu N, Ishii K, Kimura Y, Oda K, Sasaki T, Mori Y, Ishiwata K (2005) Adenosine A1 receptor mapping of the human brain by PET with 8-dicyclopropylmethyl-1-11C-methyl-3-propylxanthine. J Nucl Med 46:32–37
Guo M, Gao ZG, Tyler R, Stodden T, Li Y, Ramsey J, Zhao WJ, Wang GJ, Wiers CE, Fowler JS, Rice KC, Jacobson KA, Kim SW, Volkow ND (2018) Preclinical evaluation of the first adenosine A1 receptor partial agonist radioligand for positron emission tomography imaging. J Med Chem 61:9966–9975
Haeusler D, Kuntner C, Nics L, Savli M, Zeilinger M, Wanek T, Karagiannis P, Lanzenberger RR, Langer O, Shanab K, Spreitzer H, Wadsak W, Hacker M, Mitterhauser M (2015) [18F]FE@SUPPY: a suitable PET tracer for the adenosine A3 receptor? An in vivo study in rodents. Eur J Nucl Med Mol Imaging 42:741–749
Haeusler D, Nics L, Mien LK, Ungersboeck J, Lanzenberger RR, Shanab K, Spreitzerf H, Sindelar KM, Viernstein H, Wagner KH, Dudczak R, Kletter K, Wadsak W, Mitterhauser M (2010) [18F]FE@SUPPY and [18F]FE@SUPPY:2--metabolic considerations. Nucl Med Biol 37:421–426
Halldin C, Gulyas B, Langer O, Farde L (2001) Brain radioligands--state of the art and new trends. Q J Nucl Med 45:139–152
Hayashi S, Inaji M, Nariai T, Oda K, Sakata M, Toyohara J, Ishii K, Ishiwata K, Maehara T (2018) Increased binding potential of brain adenosine A1 receptor in chronic stages of patients with diffuse axonal injury measured with [1-methyl-(11)C] 8-dicyclopropylmethyl-1-methyl-3-propylxanthine positron emission tomography imaging. J Neurotrauma 35:25–31
Heinonen I, Nesterov SV, Liukko K, Kemppainen J, Nagren K, Luotolahti M, Virsu P, Oikonen V, Nuutila P, Kujala UM, Kainulainen H, Boushel R, Knuuti J, Kalliokoski KK (2008) Myocardial blood flow and adenosine A2A receptor density in endurance athletes and untrained men. J Physiol 586:5193–5202
Herzog H, Elmenhorst D, Winz O, Bauer A (2008) Biodistribution and radiation dosimetry of the A1 adenosine receptor ligand 18F-CPFPX determined from human whole-body PET. Eur J Nucl Med Mol Imaging 35:1499–1506
Hess S (2001) Recent advances in adenosine receptor antagonist research. Expert Opin Ther Pat 11:1533–1561
Hirani E, Gillies J, Karasawa A, Shimada J, Kase H, Opacka-Juffry J, Osman S, Luthra SK, Hume SP, Brooks DJ (2001) Evaluation of [4-O-methyl-(11)C]KW-6002 as a potential PET ligand for mapping central adenosine A(2A) receptors in rats. Synapse 42:164–176
Hohoff C, Garibotto V, Elmenhorst D, Baffa A, Kroll T, Hoffmann A, Schwarte K, Zhang W, Arolt V, Deckert J, Bauer A (2014) Association of adenosine receptor gene polymorphisms and in vivo adenosine A1 receptor binding in the human brain. Neuropsychopharmacology 39:2989–2999
Holschbach M, Müller CE, Wutz W, Schüller M, Coenen HH (2000) C-11 Markierung und erste ex vivo Evaluierung des Adenosin A2A Rezeptorliganden MSX-2 an NMRI Mäusen. Nuklearmedizin 39:P154
Holschbach MH, Bier D, Sihver W, Schulze A, Neumaier B (2017) Synthesis and pharmacological evaluation of identified and putative metabolites of the A1 adenosine receptor antagonist 8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine (CPFPX). ChemMedChem 12:770–784
Holschbach MH, Olsson RA, Bier D, Wutz W, Sihver W, Schuller M, Palm B, Coenen HH (2002) Synthesis and evaluation of no-carrier-added 8-cyclopentyl-3-(3-[(18)F]fluoropropyl)-1-propylxanthine ([(18)F]CPFPX): a potent and selective A(1)-adenosine receptor antagonist for in vivo imaging. J Med Chem 45:5150–5156
Holschbach MH, Bier D, Wutz W, Willbold S, Olsson RA (2009) Synthesis of the main metabolite in human blood of the A1 adenosine receptor ligand [18F]CPFPX. Org Lett 11:4266–4269
Ishibashi K, Miura Y, Wagatsuma K, Toyohara J, Ishiwata K, Ishii K (2018) Occupancy of adenosine A2A receptors by istradefylline in patients with Parkinson's disease using (11)C-preladenant PET. Neuropharmacology 143:106–112
Ishiwata K, Furuta R, Shimada J, Ishii S, Endo K, Suzuki F, Senda M (1995) Synthesis and preliminary evaluation of [11C]KF15372, a selective adenosine A1 antagonist. Appl Radiat Isot 46:1009–1013
Ishiwata K, Kawamura K, Yanai K, Hendrikse NH (2007a) In vivo evaluation of P-glycoprotein modulation of 8 PET radioligands used clinically. J Nucl Med 48:81–87
Ishiwata K, Kimura Y, de Vries J, Erik F, Elsinga PH (2007b) PET tracers for mapping adenosine receptors as probes for diagnosis of CNS disorders. CNS Agents Med Chem (Formerly Current Medicinal Chemistry-Central Nervous System Agents) 7(1):57–77
Ishiwata K, Mishina M, Kimura Y, Oda K, Sasaki T, Ishii K (2005) First visualization of adenosine A(2A) receptors in the human brain by positron emission tomography with [11C]TMSX. Synapse 55:133–136
Ishiwata K, Mizuno M, Kimura Y, Kawamura K, Oda K, Sasaki T, Nakamura Y, Muraoka I, Ishii K (2004) Potential of [11C]TMSX for the evaluation of adenosine A2A receptors in the skeletal muscle by positron emission tomography. Nucl Med Biol 31:949–956
Ishiwata K, Noguchi J, Toyama H, Sakiyama Y, Koike N, Ishii S, Oda K, Endo K, Suzuki F, Senda M (1996) Synthesis and preliminary evaluation of [11C]KF17837, a selective adenosine A2A antagonist. Appl Radiat Isot 47:507–511
Ishiwata K, Noguchi J, Wakabayashi S, Shimada J, Ogi N, Nariai T, Tanaka A, Endo K, Suzuki F, Senda M (2000a) 11C-labeled KF18446: a potential central nervous system adenosine A2a receptor ligand. J Nucl Med 41:345–354
Ishiwata K, Ogi N, Shimada J, Nonaka H, Tanaka A, Suzuki F, Senda M (2000b) Further characterization of a CNS adenosine A2a receptor ligand [11C]KF18446 with in vitro autoradiography and in vivo tissue uptake. Ann Nucl Med 14:81–89
Ishiwata K, Ogi N, Shimada J, Wang W, Ishii K, Tanaka A, Suzuki F, Senda M (2000c) Search for PET probes for imaging the globus pallidus studied with rat brain ex vivo autoradiography. Ann Nucl Med 14:461–466
Ishiwata K, Shimada J, Wang WF, Harakawa H, Ishii S, Kiyosawa M, Suzuki F, Senda M (2000d) Evaluation of iodinated and brominated [11C]styrylxanthine derivatives as in vivo radioligands mapping adenosine A2A receptor in the central nervous system. Ann Nucl Med 14:247–253
Ishiwata K, Kawamura K, Kimura Y, Oda K, Ishii K (2003) Potential of an adenosine A2A receptor antagonist [11C]TMSX for myocardial imaging by positron emission tomography: a first human study. Ann Nucl Med 17:457–462
Jacobson KA (2009) Introduction to adenosine receptors as therapeutic targets. Handb Exp Pharmacol 193:1–24. https://doi.org/10.1007/978-3-540-89615-9_1
Jacobson KA, Gao ZG (2006) Adenosine receptors as therapeutic targets. Nat Rev Drug Discov 5:247–264
Kalla RV, Zablocki J, Tabrizi MA, Baraldi PG (2009) Recent developments in A2B adenosine receptor ligands. Handb Exp Pharmacol 193:99–122
Khanapur S, Av W, Ishiwata K, Leenders KL, Dierckx RA, Elsinga PH (2014b) Adenosine A(2A) receptor antagonists as Positron Emission Tomography (PET) tracers. Curr Med Chem 21:312–328
Khanapur S, Paul S, Shah A, Vatakuti S, Koole MJ, Zijlma R, Dierckx RA, Luurtsema G, Garg P, van Waarde A, Elsinga PH (2014a) Development of [18F]-labeled pyrazolo[4,3-e]-1,2,4- triazolo[1,5-c]pyrimidine (SCH442416) analogs for the imaging of cerebral adenosine A2A receptors with positron emission tomography. J Med Chem 57:6765–6780
Khanapur S, van Waarde A, Dierckx RA, Elsinga PH, Koole MJ (2017) Preclinical evaluation and quantification of (18)F-fluoroethyl and (18)F-fluoropropyl analogs of SCH442416 as radioligands for PET imaging of the adenosine A2A receptor in rat brain. J Nucl Med 58:466–472
Kiesewetter DO, Lang L, Ma Y, Bhattacharjee AK, Gao ZG, Joshi BV, Melman A, de Castro S, Jacobson KA (2009) Synthesis and characterization of [76Br]-labeled high-affinity A3 adenosine receptor ligands for positron emission tomography. Nucl Med Biol 36:3–10
Kimura Y, Ishii K, Fukumitsu N, Oda K, Sasaki T, Kawamura K, Ishiwata K (2004) Quantitative analysis of adenosine A1 receptors in human brain using positron emission tomography and [1-methyl-11C]8-dicyclopropylmethyl-1-methyl-3-propylxanthine. Nucl Med Biol 31:975–981
Kreft S, Bier D, Holschbach MH, Schulze A, Coenen HH (2017) New potent A1 adenosine receptor radioligands for positron emission tomography. Nucl Med Biol 44:69–77
Kroll T, Elmenhorst D, Weisshaupt A, Beer S, Bauer A (2014) Reproducibility of non-invasive A adenosine receptor quantification in the rat brain using [18F]CPFPX and Positron Emission Tomography. Mol Imaging Biol 16(5):699–709
Lahesmaa M, Oikonen V, Helin S, Luoto P, Din MU, Pfeifer A, Nuutila P, Virtanen KA (2019) Regulation of human brown adipose tissue by adenosine and A2A receptors—studies with [(15)O]H2O and [(11)C]TMSX PET/CT. Eur J Nucl Med Mol Imaging 46:743–750
Li J, Hong X, Li G, Conti PS, Zhang X, Chen K (2019) PET imaging of adenosine receptors in diseases. Curr Top Med Chem 19(16):1445–1463
Lindemann M, Hinz S, Deuther-Conrad W, Namasivayam V, Dukic-Stefanovic S, Teodoro R, Toussaint M, Kranz M, Juhl C, Steinbach J, Brust P, Muller CE, Wenzel B (2018) Radiosynthesis and in vivo evaluation of a fluorine-18 labeled pyrazine based radioligand for PET imaging of the adenosine A2B receptor. Bioorg Med Chem 26:4650–4663
Lowe PT, Dall'Angelo S, Mulder-Krieger T, IJzerman AP, Zanda M, O’Hagan D (2017) a new class of fluorinated A2A adenosine receptor agonist with application to last-step enzymatic [(18)F]fluorination for PET imaging. Chembiochem 18:2156–2164
Marian T, Boros I, Lengyel Z, Balkay L, Horvath G, Emri M, Sarkadi E, Szentmiklosi AJ, Fekete I, Tron L (1999) Preparation and primary evaluation of [11C]CSC as a possible tracer for mapping adenosine A2A receptors by PET. Appl Radiat Isot 50:887–893
Mason NS, Mathis CA (2003) Positron emission tomography radiochemistry. Neuroimaging Clin N Am 13:671–687
Matsuya T, Takamatsu H, Murakami Y, Noda A, Ichise R, Awaga Y, Nishimura S (2005) Synthesis and evaluation of [(11)C]FR194921 as a nonxanthine-type PET tracer for adenosine A(1) receptors in the brain. Nucl Med Biol 32:837–844
Matusch A, Meyer PT, Bier D, Holschbach MH, Woitalla D, Elmenhorst D, Winz OH, Zilles K, Bauer A (2006) Metabolism of the A(1) adenosine receptor PET ligand [(18)F]CPFPX by CYP1A2: implications for bolus/infusion PET studies. Nucl Med Biol 33:891–898
Matusch A, Saft C, Elmenhorst D, Kraus PH, Gold R, Hartung HP, Bauer A (2014) Cross sectional PET study of cerebral adenosine A(1) receptors in premanifest and manifest Huntington's disease. Eur J Nucl Med Mol Imaging 41:1210–1220
Meyer PT, Bier D, Holschbach MH, Boy C, Olsson RA, Coenen HH, Zilles K, Bauer A (2004) Quantification of cerebral A1 adenosine receptors in humans using [18F]CPFPX and PET. J Cereb Blood Flow Metab 24:323–333
Meyer PT, Bier D, Holschbach MH, Cremer M, Tellmann L, Bauer A (2003) Image of the month. In vivo imaging of rat brain A1 adenosine receptor occupancy by caffeine. Eur J Nucl Med Mol Imaging 30:1440
Meyer PT, Elmenhorst D, Bier D, Holschbach MH, Matusch A, Coenen HH, Zilles K, Bauer A (2005a) Quantification of cerebral A1 adenosine receptors in humans using [18F]CPFPX and PET: an equilibrium approach. NeuroImage 24:1192–1204
Meyer PT, Elmenhorst D, Boy C, Winz O, Matusch A, Zilles K, Bauer A (2006c) Effect of aging on cerebral A(1) adenosine receptors: a [(18)F]CPFPX PET study in humans. Neurobiol Aging 28:1914–1924
Meyer PT, Elmenhorst D, Matusch A, Winz O, Zilles K, Bauer A (2006a) 18F-CPFPX PET: on the generation of parametric images and the effect of scan duration. J Nucl Med 47:200–207
Meyer PT, Elmenhorst D, Zilles K, Bauer A (2005b) Simplified quantification of cerebral A1 adenosine receptors using [18F]CPFPX and PET: analyses based on venous blood sampling. Synapse 55:212–223
Meyer PT, Elmenhorst D, Matusch A, Winz O, Zilles K, Bauer A (2006b) A1 adenosine receptor PET using [18F]CPFPX: displacement studies in humans. NeuroImage 32:1100–1105
Mishina M, Ishii K, Kimura Y, Suzuki M, Kitamura S, Ishibashi K, Sakata M, Oda K, Kobayashi S, Kimura K, Ishiwata K (2017a) Adenosine A1 receptors measured with (11) C-MPDX PET in early Parkinson’s disease. Synapse 71(8):e21979
Mishina M, Ishiwata K (2014) Adenosine receptor PET imaging in human brain. Int Rev Neurobiol 119:51–69
Mishina M, Ishiwata K, Kimura Y, Naganawa M, Oda K, Kobayashi S, Katayama Y, Ishii K (2007) Evaluation of distribution of adenosine A(2A) receptors in normal human brain measured with [C-11]TMSX PET. Synapse 61:778–784
Mishina M, Ishiwata K, Naganawa M, Kimura Y, Kitamura S, Suzuki M, Hashimoto M, Ishibashi K, Oda K, Sakata M, Hamamoto M, Kobayashi S, Katayama Y, Ishii K (2011) Adenosine A(2A) receptors measured with [C]TMSX PET in the striata of Parkinson's disease patients. PLoS One 6:e17338
Mishina M, Kimura Y, Naganawa M, Ishii K, Oda K, Sakata M, Toyohara J, Kobayashi S, Katayama Y, Ishiwata K (2012) Differential effects of age on human striatal adenosine A(1) and A(2A) receptors. Synapse 66:832–839
Mishina M, Kimura Y, Sakata M, Ishii K, Oda K, Toyohara J, Kimura K, Ishiwata K (2017b) Age-Related Decrease in Male Extra-Striatal Adenosine A1 Receptors Measured Using (11)C-MPDX PET. Front Pharmacol 8:903
Mizuno M, Kimura Y, Tokizawa K, Ishii K, Oda K, Sasaki T, Nakamura Y, Muraoka I, Ishiwata K (2005) Greater adenosine A(2A) receptor densities in cardiac and skeletal muscle in endurance-trained men: a [11C]TMSX PET study. Nucl Med Biol 32:831–836
Moerlein SM, Laufer P, Stocklin G (1985) Effect of lipophilicity on the in vivo localization of radiolabelled spiperone analogues. Int J Nucl Med Biol 12:353–356
Moresco RM, Todde S, Belloli S, Simonelli P, Panzacchi A, Rigamonti M, Galli-Kienle M, Fazio F (2005) In vivo imaging of adenosine A2A receptors in rat and primate brain using [11C]SCH442416. Eur J Nucl Med Mol Imaging 32:405–413
Nabbi-Schroeter D, Elmenhorst D, Oskamp A, Laskowski S, Bauer A, Kroll T (2018) Effects of long-term caffeine consumption on the adenosine A1 receptor in the rat brain: an in vivo PET Study with [(18)F]CPFPX. Mol Imaging Biol 20:284–291
Naganawa M, Kimura Y, Mishina M, Manabe Y, Chihara K, Oda K, Ishii K, Ishiwata K (2007) Quantification of adenosine A2A receptors in the human brain using [11C]TMSX and positron emission tomography. Eur J Nucl Med Mol Imaging 34:679–687
Naganawa M, Kimura Y, Yano J, Mishina M, Yanagisawa M, Ishii K, Oda K, Ishiwata K (2008) 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 40:26–34
Naganawa M, Mishina M, Sakata M, Oda K, Hiura M, Ishii K, Ishiwata K (2014) Test-retest variability of adenosine A2A binding in the human brain with (11)C-TMSX and PET. EJNMMI Res 4:76
Nariai T, Shimada Y, Ishiwata K, Nagaoka T, Shimada J, Kuroiwa T, Ono K, Ohno K, Hirakawa K, Senda M (2003) PET imaging of adenosine A(1) receptors with (11)C-MPDX as an indicator of severe cerebral ischemic insult. J Nucl Med 44:1839–1844
Noguchi J, Ishiwata K, Furuta R, Simada J, Kiyosawa M, Ishii S, Endo K, Suzuki F, Senda M (1997) Evaluation of carbon-11 labeled KF15372 and its ethyl and methyl derivatives as a potential CNS adenosine A1 receptor ligand. Nucl Med Biol 24:53–59
Palmer TM, Stiles GL (1995) Adenosine receptors. Neuropharmacology 34:683–694
Paul S, Elsinga PH, Ishiwata K, Dierckx RA, van Waarde A (2011a) Adenosine A(1) receptors in the central nervous system: their functions in health and disease, and possible elucidation by PET imaging. Curr Med Chem 18:4820–4835
Paul S, Khanapur S, Boersma W, Sijbesma JW, Ishiwata K, Elsinga PH, Meerlo P, Doorduin J, Dierckx RA, van Waarde A (2014) Cerebral adenosine A(1) receptors are upregulated in rodent encephalitis. NeuroImage 92:83–89
Paul S, Khanapur S, Rybczynska AA, Kwizera C, Sijbesma JW, Ishiwata K, Willemsen AT, Elsinga PH, Dierckx RA, van Waarde A (2011b) Small-animal PET study of adenosine A(1) receptors in rat brain: blocking receptors and raising extracellular adenosine. J Nucl Med 52:1293–1300
Paul S, Khanapur S, Sijbesma JW, Ishiwata K, Elsinga PH, Meerlo P, Dierckx RA, van Waarde A (2014b) Use of 11C-MPDX and PET to study adenosine A1 receptor occupancy by nonradioactive agonists and antagonists. J Nucl Med 55:315–320
Petroni D, Giacomelli C, Taliani S, Barresi E, Robello M, Daniele S, Bartoli A, Burchielli S, Pardini S, Salvadori PA, Da Settimo F, Martini C, Trincavelli ML, Menichetti L (2016) Toward PET imaging of A2B adenosine receptors: a carbon-11 labeled triazinobenzimidazole tracer: Synthesis and imaging of a new A2B PET tracer. Nucl Med Biol 43:309–317
Poucher SM, Keddie JR, Singh P, Stoggall SM, Caulkett PW, Jones G, Coll MG (1995) The in vitro pharmacology of ZM 241385, a potent, non-xanthine A2a selective adenosine receptor antagonist. Br J Pharmacol 115:1096–1102
Ramlackhansingh AF, Bose SK, Ahmed I, Turkheimer FE, Pavese N, Brooks DJ (2011) Adenosine 2A receptor availability in dyskinetic and nondyskinetic patients with Parkinson disease. Neurology 76:1811–1816
Rissanen E, Tuisku J, Luoto P, Arponen E, Johansson J, Oikonen V, Parkkola R, Airas L, Rinne JO (2015) Automated reference region extraction and population-based input function for brain [(11)C]TMSX PET image analyses. J Cereb Blood Flow Metab 35:157–165
Sakata M, Ishibashi K, Imai M, Wagatsuma K, Ishii K, Zhou X, de Vries EFJ, Elsinga PH, Ishiwata K, Toyohara J (2017) Initial evaluation of an adenosine A2A receptor ligand, (11)C-preladenant, in healthy human subjects. J Nucl Med 58:1464–1470
Schneider D, Bier D, Bauer A, Neumaier B, Holschbach M (2019a) Influence of incubation conditions on microsomal metabolism of xanthine-derived A1 adenosine receptor ligands. J Pharmacol Toxicol Methods 95:16–26
Schneider D, Oskamp A, Holschbach M, Neumaier B, Bauer A, Bier D (2019b) Relevance of in vitro metabolism models to PET radiotracer development: prediction of in vivo clearance in rats from microsomal stability data. Pharmaceuticals (Basel) 12
Sihver W, Bier D, Holschbach MH, Schulze A, Wutz W, Olsson RA, Coenen HH (2004) Binding of tritiated and radioiodinated ZM241,385 to brain A2A adenosine receptors. Nucl Med Biol 31:173–177
Sihver W, Holschbach MH, Bier D, Wutz W, Schulze A, Olsson RA, Coenen HH (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. Nucl Med Biol 30:661–668
Sijbesma JW, Zhou X, Vallez Garcia D, Houwertjes MC, Doorduin J, Kwizera C, Maas B, Meerlo P, Dierckx RA, Slart RH, Elsinga PH, van Waarde A (2016) Novel approach to repeated arterial blood sampling in small animal PET: application in a test-retest study with the adenosine A1 receptor ligand [(11)C]MPDX. Mol Imaging Biol 18:715–723
Tavares AADS, Batis J, Barret O, Alagille D, Vala C, Kudej G, Koren A, Cosgrove KP, Nice K, Kordower JH, Seibyl J, Tamagnan GD (2013) In vivo evaluation of [(123)I]MNI-420: a novel single photon emission computed tomography radiotracer for imaging of adenosine 2A receptors in brain. Nucl Med Biol 40:403–409
Todde S, Moresco RM, Simonelli P, Baraldi PG, Cacciari B, Spalluto G, Varani K, Monopoli A, Matarrese M, Carpinelli A, Magni F, Kienle MG, Fazio F (2000) Design, radiosynthesis, and biodistribution of a new potent and selective ligand for in vivo imaging of the adenosine A(2A) receptor system using positron emission tomography. J Med Chem 43:4359–4362
Vala C, Morley TJ, Zhang X, Papin C, Tavares AA, Lee HS, Constantinescu C, Barret O, Carroll VM, Baldwin RM, Tamagnan GD, Alagille D (2016) 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 11:1936–1943
van Waarde A, Rajo D, Zhou X, Khanapur S, Tsukada H, Ishiwata K, Luurtsema G, de Vries EFJ, Elsinga PH (2018) Potential Therapeutic applications of adenosine A2A receptor ligands and opportunities for A2A receptor imaging. Med Res Rev 38:5–56
Vuorimaa, A., E. Rissanen, and L. Airas. 2017. In vivo PET imaging of adenosine 2A receptors in neuroinflammatory and neurodegenerative disease, Contrast Media Mol Imaging, 2017:6975841
Wadsak W, Mien LK, Shanab K, Ettlinger DE, Haeusler D, Sindelar K, Lanzenberger RR, Spreitzer H, Viernstein H, Keppler BK, Dudczak R, Kletter K, Mitterhauser M (2008) Preparation and first evaluation of [(18)F]FE@SUPPY: a new PET tracer for the adenosine A(3) receptor. Nucl Med Biol 35:61–66
Wang WF, Ishiwata K, Nonaka H, Ishii S, Kiyosawa M, Shimada J, Suzuki F, Senda M (2000) Carbon-11-labeled KF21213: a highly selective ligand for mapping CNS adenosine A(2A) receptors with positron emission tomography. Nucl Med Biol 27:541–546
Zeitzer JM, Morales-Villagran A, Maidment NT, Behnke EJ, Ackerson LC, Lopez-Rodriguez F, Fried I, Engel J, Wilson CL (2006) Extracellular adenosine in the human brain during sleep and sleep deprivation: an in vivo microdialysis study. Sleep 29:455–461
Zhou X, Doorduin J, Elsinga PH, Dierckx R, de Vries EFJ, Casteels C (2017a) Altered adenosine 2A and dopamine D2 receptor availability in the 6-hydroxydopamine-treated rats with and without levodopa-induced dyskinesia. NeuroImage 157:209–218
Zhou X, Elsinga PH, Khanapur S, Dierckx RA, de Vries EF, de Jong JR (2017b) Radiation dosimetry of a novel adenosine A2A receptor radioligand [(11)C]preladenant based on PET/CT imaging and ex vivo biodistribution in rats. Mol Imaging Biol 19:289–297
Zhou X, Khanapur S, de Jong JR, Willemsen AT, Dierckx RA, Elsinga PH, de Vries EF (2017c) In vivo evaluation of [(11)C]preladenant positron emission tomography for quantification of adenosine A2A receptors in the rat brain. J Cereb Blood Flow Metab 37:577–589
Zhou X, Khanapur S, Huizing AP, Zijlma R, Schepers M, Dierckx RA, van Waarde A, de Vries EF, Elsinga PH (2014) Synthesis and preclinical evaluation of 2-(2-furanyl)-7-[2-[4-[4-(2-[11C]methoxyethoxy)phenyl]-1-piperazinyl]ethyl]7H-pyr azolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine ([11C]Preladenant) as a PET tracer for the imaging of cerebral adenosine A2A receptors. J Med Chem 57:9204–9210
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Elmenhorst, D., Bier, D., Holschbach, M., Bauer, A. (2021). Imaging of Adenosine Receptors. In: Dierckx, R.A., Otte, A., de Vries, E.F., van Waarde, A., Lammertsma, A.A. (eds) PET and SPECT of Neurobiological Systems. Springer, Cham. https://doi.org/10.1007/978-3-030-53176-8_8
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