title: 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 (A(2A)) receptors facilitates dopamine D(2) receptor function. In phase 2 clinical trials, A(2A) antagonists (istradefylline, preladenant, and tozadenant) improved motor function in PD. We developed a new A(2A) PET radiotracer, (18)F-MNI-444, and used it to investigate the relationship between plasma levels and A(2A) occupancy by preladenant and tozadenant in nonhuman primates (NHP).
  
  
  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 A(2A) occupancy in humans, based on median effective concentration (EC(50)) values estimated from the NHP PET measurements.
  
  
  RESULTS
  (18)F-MNI-444 regional uptake was consistent with A(2A) 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 A(2A) PET radiotracers. Pharmacokinetic modeling predicted that tozadenant and preladenant may have different profiles of A(2A) receptor occupancy in humans.
  
  
  CONCLUSIONS
  (18)F-MNI-444 appears to be a better PET radiotracer for A(2A) imaging than currently available radiotracers. Assuming that EC(50) in humans is similar to that in NHP, it appears that tozadenant will provide a more sustained A(2A) receptor occupancy than preladenant in humans at clinically tested doses.
authors.affiliation: Molecular NeuroImaging, LLC, New Haven, Connecticut obarret@mnimaging.com.
authors.forename: Olivier
authors.initials: O
authors.lastname: Barret
authors.affiliation: UCB Pharma, Braine-l'Alleud, Belgium; and.
authors.forename: Jonas
authors.initials: J
authors.lastname: Hannestad
authors.affiliation: Molecular NeuroImaging, LLC, New Haven, Connecticut.
authors.forename: David
authors.initials: D
authors.lastname: Alagille
authors.affiliation: Molecular NeuroImaging, LLC, New Haven, Connecticut.
authors.forename: Christine
authors.initials: C
authors.lastname: Vala
authors.affiliation: Molecular NeuroImaging, LLC, New Haven, Connecticut.
authors.forename: Adriana
authors.initials: A
authors.lastname: Tavares
authors.affiliation: Molecular NeuroImaging, LLC, New Haven, Connecticut.
authors.forename: Caroline
authors.initials: C
authors.lastname: Papin
authors.affiliation: Molecular NeuroImaging, LLC, New Haven, Connecticut.
authors.forename: Thomas
authors.initials: T
authors.lastname: Morley
authors.affiliation: Yale PET Center, New Haven, Connecticut.
authors.forename: Krista
authors.initials: K
authors.lastname: Fowles
authors.affiliation: Molecular NeuroImaging, LLC, New Haven, Connecticut.
authors.forename: Hsiaoju
authors.initials: H
authors.lastname: Lee
authors.affiliation: Molecular NeuroImaging, LLC, New Haven, Connecticut.
authors.forename: John
authors.initials: J
authors.lastname: Seibyl
authors.affiliation: UCB Pharma, Braine-l'Alleud, Belgium; and.
authors.forename: Dominique
authors.initials: D
authors.lastname: Tytgat
authors.affiliation: UCB Pharma, Braine-l'Alleud, Belgium; and.
authors.forename: Marc
authors.initials: M
authors.lastname: Laruelle
authors.affiliation: Molecular NeuroImaging, LLC, New Haven, Connecticut.
authors.forename: Gilles
authors.initials: G
authors.lastname: Tamagnan
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000737:chemistry*; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry*; D006801:Humans; D008253:Macaca mulatta; D010300:Parkinson Disease / Q000000981:diagnostic imaging* / Q000473:pathology; D049268:Positron-Emission Tomography / Q000379:methods*; D011743:Pyrimidines / Q000737:chemistry*; D011874:Radiometry / Q000379:methods; D043705:Receptor, Adenosine A2A / Q000737:chemistry*; D013997:Time Factors; D014230:Triazoles / Q000737:chemistry*; D051598:Whole Body Imaging
chemical_list: D052160:Benzothiazoles; D006575:Heterocyclic Compounds, 3-Ring; C000598565:MNI-444; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D014230:Triazoles; C539997:2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidine-5-amine; C000593256:tozadenant
keywords: A2A receptors PET imaging; Parkinson’s disease; preladenant; receptor occupancy; tozadenant