title: Toward PET imaging of A2B adenosine receptors: a carbon-11 labeled triazinobenzimidazole tracer: Synthesis and imaging of a new A2B PET tracer.
abstract: A2B adenosine receptors (ARs) are commonly defined as "danger" sensors because they are triggered during cell injury when the endogenous molecule, adenosine, increases rapidly. These receptors, together with the other receptor subtypes (A1, A2A and A3), exert a wide variety of immunomodulating and (cyto)protective effects, thus representing a pivotal therapeutic target for different pathologies including diabetes, tumors, cardiovascular diseases, pulmonary fibrosis and others. The limited availability of potent and selective ligands for A2B ARs has prevented this receptor to emerge both as therapeutic and diagnostic target.
  
  
  
  Recently, a new class of potent A2B ARs antagonists was developed featuring the triazinobenzimidazole scaffold. Starting from this chemotype, we synthesized a new radiotracer, [(11)C]-4 (1-[(11)C]methyl-3-phenyl triazino[4,3-a]benzimidazol-4(1H)-one), and investigated the pharmacokinetics of this compound in vivo to define its potential use in the imaging of A2B AR with positron emission tomography.
  
  
  
  [(11)C]-4 showed a very high chemical and blood stability. Results of in vivo and ex vivo experiments underlined the ability of this molecule to bind the A2B AR and correlated with the A2B AR protein and gene expression data.
  
  
  
  Although further studies are necessary, these data suggest that [(11)C]-4 may represent a good lead compound for the development of novel selective and potent A2B AR radiotracers, and a new option for the clinical investigation of several pathophysiological processes and chronic diseases.
authors.affiliation: Institute of Clinical Physiology, Consiglio Nazionale delle Ricerche (CNR), Via Moruzzi, 1, I-56124 Pisa, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Petroni
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, I-56126 Pisa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Giacomelli
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, I-56126 Pisa, Italy. Electronic address: sabrina.taliani@farm.unipi.it.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Taliani
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, I-56126 Pisa, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barresi
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, I-56126 Pisa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Robello
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, I-56126 Pisa, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Daniele
authors.affiliation: Molecular Imaging Center, Università di Torino, Via Nizza, 52, I-10125 Ivrea, Italy.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Bartoli
authors.affiliation: Fondazione Toscana G. Monasterio, Via Moruzzi, 1, I-56124, Pisa, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Burchielli
authors.affiliation: Institute of Clinical Physiology, Consiglio Nazionale delle Ricerche (CNR), Via Moruzzi, 1, I-56124 Pisa, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pardini
authors.affiliation: Institute of Clinical Physiology, Consiglio Nazionale delle Ricerche (CNR), Via Moruzzi, 1, I-56124 Pisa, Italy.
authors.forename: Piero A
authors.initials: PA
authors.lastname: Salvadori
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, I-56126 Pisa, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, I-56126 Pisa, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, I-56126 Pisa, Italy. Electronic address: maria.trincavelli@farm.unipi.it.
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Trincavelli
authors.affiliation: Institute of Clinical Physiology, Consiglio Nazionale delle Ricerche (CNR), Via Moruzzi, 1, I-56124 Pisa, Italy; Fondazione Toscana G. Monasterio, Via Moruzzi, 1, I-56124, Pisa, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Menichetti
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D016466:CHO Cells; D002247:Carbon Isotopes; D006224:Cricetinae; D003412:Cricetulus; D005786:Gene Expression Regulation; D006801:Humans; D007553:Isotope Labeling; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011854:Radiochemistry; D051381:Rats; D043704:Receptor, Adenosine A2B / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: C000618835:1-methyl-3-phenyltriazino(4,3-a)benzimidazol-4(1H)-one; D001562:Benzimidazoles; D002247:Carbon Isotopes; D012333:RNA, Messenger; D043704:Receptor, Adenosine A2B; D014227:Triazines; C031000:benzimidazole
keywords: A(2B) adenosine receptors; PET; carbon-11; radiotracer; substituted-[1,2,4]triazino[4,3-a]benzimidazoles