Caffeine Occupancy of Human Cerebral A1 Adenosine Receptors: In Vivo Quantification with 18F-CPFPX and PET

Caffeine is the neuroactive agent in coffee and tea and is a broadly consumed stimulant. It is a nonselective antagonist of the neuromodulator adenosine and, if applied in commonly consumed doses, evokes its stimulating effects through the blockade of adenosine receptors. F-18-8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine (F-18-CPFPX) has been established as a highly selective and affine PET ligand for the A(1) adenosine receptor (A(1)AR). The objective of the present study was to visualize and quantify the in vivo occupancy of the human cerebral A(1)AR by caffeine using F-18-CPFPX and PET. Methods: Fifteen subjects (age range, 2468 y) underwent a 140-min bolus-plus-constant-infusion PET experiment after at least 36 h of caffeine abstinence. Metabolite-corrected blood data were used to calculate steady-state distribution volumes (V-T) during the baseline condition of the scan between 70 and 90 min. Subsequently, subjects received a 10-min infusion of varying concentrations (0.5-4.3 mg/kg of body weight) of caffeine at 90 min. Occupancy V-T of the A(1)AR was thereafter estimated using data acquired between 120 and 140 min. Occupancy levels were calculated using the Lassen plot, from which the inhibitory concentrations of 50% were derived. Plasma levels of caffeine were determined at regular intervals. One subject received an intravenous vehicle as a placebo. Results: Caffeine displaced 5%-44% of F-18-CPFPX binding in a concentration-dependent manner. There was no change of radioligand binding after the administration of placebo. Half-maximal displacement was achieved at a plasma caffeine concentration of 67 p,M, which corresponds to 450 mg in a 70-kg subject or approximately 4.5 cups of coffee. Conclusion: Given a biologic half-life of about 5 h, caffeine might therefore occupy up to 50% of the cerebral A(1)AR when caffeinated beverages are repeatedly consumed during a day. Furthermore, the present study provides evidence that F-18-CPFPX PET is suitable for studying the cerebral actions of caffeine, the most popular neurostimulant worldwide.