title: 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.
abstract: Cerebral adenosine A2A receptors (A2ARs) are attractive therapeutic targets for the treatment of neurodegenerative and psychiatric disorders. We developed high affinity and selective compound 8 (SCH442416) analogs as in vivo probes for A2ARs using PET. We observed the A2AR-mediated accumulation of [18F]fluoropropyl ([18F]-10b) and [18F]fluoroethyl ([18F]-10a) derivatives of 8 in the brain. The striatum was clearly visualized in PET and in vitro autoradiography images of control animals and was no longer visible after pretreatment with the A2AR subtype-selective antagonist KW6002. In vitro and in vivo metabolite analyses indicated the presence of hydrophilic (radio)metabolite(s), which are not expected to cross the blood-brain-barrier. [18F]-10b and [18F]-10a showed comparable striatum-to- cerebellum ratios (4.6 at 25 and 37 min post injection, respectively) and reversible binding in rat brains. We concluded that these compounds performed equally well, but their kinetics were slightly different. These molecules are potential tools for mapping cerebral A2ARs with PET.
authors: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen , Groningen, The Netherlands.
authors: Shivashankar
authors: S
authors: Khanapur
authors: Soumen
authors: S
authors: Paul
authors: Anup
authors: A
authors: Shah
authors: Suresh
authors: S
authors: Vatakuti
authors: Michel J B
authors: MJ
authors: Koole
authors: Rolf
authors: R
authors: Zijlma
authors: Rudi A J O
authors: RA
authors: Dierckx
authors: Gert
authors: G
authors: Luurtsema
authors: Prabha
authors: P
authors: Garg
authors: Aren
authors: A
authors: van Waarde
authors: Philip H
authors: PH
authors: Elsinga
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism*; D005462:Fluorine Radioisotopes; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D062105:Molecular Docking Simulation; D049268:Positron-Emission Tomography; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D005462:Fluorine Radioisotopes; D011720:Pyrazoles; D011743:Pyrimidines; D019275:Radiopharmaceuticals; D043705:Receptor, Adenosine A2A; C416650:SCH 442416