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. 18 F-8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine ( 18 F-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 18 F-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 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 18 F-CPFPX binding in a concentration-dependent manner. There was no change of radioligand binding after the administration of placebo. Halfmaximal displacement was achieved at a plasma caffeine concentration of 67 mM, 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 18 F-CPFPX PET is suitable for studying the cerebral actions of caffeine, the most popular neurostimulant worldwide.

Purinergic system dysfunction in mood disorders: a key target for developing improved therapeutics

“…More than six chemicals fitting this structure have been identified as possible A1 receptor ligands, and 12 have been identified as possible A2A receptor ligands, many of them derived from similar chemicals as the A1 receptor ligands (Bauer and Ishiwata, 2009). For example, one recent study demonstrated the potential efficacy of [ 18 ]F-CPFPX, an A1 receptor ligand, by visualizing cerebral caffeine binding (Elmenhorst et al, 2012). No clinical studies in mood disorders have yet been completed using these ligands.…”

Use of 11C-MPDX and PET to Study Adenosine A1 Receptor Occupancy by Nonradioactive Agonists and Antagonists

“…Caffeine is a non-subtype-selective adenosine antagonist with moderate affinity (50% inhibitory concentration, 11-85 mM) and is widely consumed as a recreational drug (10,11). Occupancy of cerebral A 1 Rs by caffeine or the potent (dissociation constant, 0.42 nM) and highly subtype-selective A 1 R antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) (12,13) has been visualized with the tracer 18 F-CPFPX (14,15) or 11 C-MPDX (7) and PET. However, PET studies of the occupancy of cerebral A 1 Rs by agonists have never been reported.…”

Potential pitfalls when investigating the ergogenic effects of caffeine in mice

“…Caffeine's molecular mechanisms for increasing physical performance are still virtually undefined. However, due to its ability to cross the blood-brain barrier at blood concentrations generated by a moderate ergogenic dose, and because of its properties as a stimulant psychotropic drug [15,17], mechanisms involving metabolic and central effects have been proposed.Metabolic effects of caffeine have been mainly related to the enhancement of lipolysis, fatty acid oxidation and energy expenditure via the stimulation of the sympathetic nervous system [18,19] and a sequential sparing of muscle glycogen [20]. However, the main pharmacological effects of caffeine appear to be mediated via the CNS where caffeine counterbalances the inhibitory neuromodulation of adenosine in order to induce effects on both the CNS and peripheral nervous system to reduce pain and exertion perception [21], to improve motor recruitment [22] and to increase excitation-contraction coupling [23,24].…”

“…Caffeine's molecular mechanisms for increasing physical performance are still virtually undefined. However, due to its ability to cross the blood-brain barrier at blood concentrations generated by a moderate ergogenic dose, and because of its properties as a stimulant psychotropic drug [15,17], mechanisms involving metabolic and central effects have been proposed.…”