Synthesis and evaluation of 7-amino-2-(2(3)-furyl)-5-phenylethylamino-oxazolo[5,4-d]pyrimidines as potential A2A adenosine receptor antagonists for positron emission tomography (PET)

• Published in: European journal of medicinal chemistry Vol. 41; no. 1; pp. 7 - 15
• Main Authors: HOLSCHBACH, Marcus H, BIER, Dirk, STÜSGEN, Stefan, WUTZ, Walter, SIHVER, Wiebke, COENEN, Heinz H, OLSSON, Ray A
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 2006
• Subjects: Adenosine A2 Receptor Antagonists; Animals; Autoradiography; Binding, Competitive; Biological and medical sciences; Brain - diagnostic imaging; Brain - metabolism; Chromatography, High Pressure Liquid; Contrast media. Radiopharmaceuticals; Ligands; Medical sciences; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Positron-Emission Tomography; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Radioligand Assay; Receptor, Adenosine A2A - metabolism; Structure-Activity Relationship; Swine; Radiolabelling; Rat; Rodentia; Benzene derivatives; Furan derivatives; Central nervous system; Oxazolo[5,4-d]pyrimidines; Tritium; Hydrogen Isotopes; In vitro; Encephalon; A2A adenosine receptor; Vertebrata; Mammalia; Position isomer; Structure activity relation; Scintigraphic agent; Animal; Bicyclic compound; Affinity; Antagonist; Chemical synthesis; PET; Oxygen nitrogen heterocycle
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2005.07.018

The brain A2A adenosine receptor (A2AAR) participates with the dopamine D2 receptor in the control of movement and also might influence behavior. Because PET is an important tool for studying the roles of receptors in disease, a ligand for imaging the brain A2AAR is desirable. This report describes the synthesis and A2AAR antagonist activities of a panel of phenyl-substituted 7-amino-2-(2-furyl)-5-phenylethylamino-oxazolo[5,4-d]pyrimidines, 11aa-af, and their 3-furyl congeners, 11ba-bd. In competitive binding studies all compounds displaced [3H]CGS21680 from the A2AAR with Ki values of 14-33 nM with selectivity for the A2AAR over the A1AR of 5- to 94-fold. Autoradiography of brain sections showed a high level of unspecific binding that obscured specific binding. Thus, these compounds are not promising PET ligands.