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

Abstract

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. ¹⁸F-8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine (¹⁸F-CPFPX) has been established as a highly selective and affine PET ligand for the A₁ adenosine receptor (A₁AR). The objective of the present study was to visualize and quantify the in vivo occupancy of the human cerebral A₁AR by caffeine using ¹⁸F-CPFPX and PET. Methods: Fifteen subjects (age range, 24–68 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 A₁AR 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 ¹⁸F-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 μM, 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 A₁AR when caffeinated beverages are repeatedly consumed during a day. Furthermore, the present study provides evidence that ¹⁸F-CPFPX PET is suitable for studying the cerebral actions of caffeine, the most popular neurostimulant worldwide.