Adenosine 2A receptor occupancy by tozadenant and preladenant in rhesus monkeys

Abstract

Motor symptoms in Parkinson disease (PD) are caused by a loss of dopamine input from the substantia nigra to the striatum. Blockade of adenosine 2A (A2A) receptors facilitates dopamine D2 receptor function. In phase 2 clinical trials, A2A antagonists (istradefylline, preladenant, and tozadenant) improved motor function in PD. We developed a new A2A PET radiotracer, 18F-MNI-444, and used it to investigate the relationship between plasma levels and A2A occupancy by preladenant and tozadenant in nonhuman primates (NHP). Results: 18F-MNI-444 regional uptake was consistent with A2A receptor distribution in the brain. Selectivity was demonstrated by dose-dependent blocking by tozadenant and preladenant. The specific-to-nonspecific ratio was superior to that of other A2A PET radiotracers. Pharmacokinetic modeling predicted that tozadenant and preladenant may have different profiles of A2A receptor occupancy in humans. Methods: A series of 20 PET experiments was conducted in 5 adult rhesus macaques. PET data were analyzed with both plasma-input (Logan graphical analysis) and reference-region-based (simplified reference tissue model and noninvasive Logan graphical analysis) methods. Whole-body PET images were acquired for radiation dosimetry estimates. Human pharmacokinetic parameters for tozadenant and preladenant were used to predict A2A occupancy in humans, based on median effective concentration (EC50) values estimated from the NHP PET measurements. Conclusion: 18F-MNI-444 appears to be a better PET radiotracer for A2A imaging than currently available radiotracers. Assuming that EC50 in humans is similar to that in NHP, it appears that tozadenant will provide a more sustained A2A receptor occupancy than preladenant in humans at clinically tested doses.