Author:

Keywords:

Adenosine A2 Receptor Antagonists, Animals, Autoradiography, Brain, Fluorine Radioisotopes, Humans, Male, Microsomes, Liver, Molecular Docking Simulation, Positron-Emission Tomography, Pyrazoles, Pyrimidines, Radiopharmaceuticals, Rats, Rats, Sprague-Dawley, Receptor, Adenosine A2A, Structure-Activity Relationship, Tissue Distribution, Science & Technology, Life Sciences & Biomedicine, Chemistry, Medicinal, Pharmacology & Pharmacy, CRYSTAL-STRUCTURE, SELECTIVE LIGAND, NERVOUS-SYSTEM, BINDING-SITES, BASAL GANGLIA, RAT, ANTAGONIST, BRAIN, BIODISTRIBUTION, PHARMACOLOGY, 0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, 3214 Pharmacology and pharmaceutical sciences, 3404 Medicinal and biomolecular chemistry, 3405 Organic chemistry

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.