title: In vivo assessment and dosimetry of 2 novel PDE10A PET radiotracers in humans: 18F-MNI-659 and 18F-MNI-654.
abstract: Phosphodiesterase (PDE) 10A is an enzyme involved in the regulation of cyclic adenosine monophosphate and cyclic guanosine monophosphate and is highly expressed in medium-sized spiny neurons of the striatum, making it an attractive target for novel therapies for a variety of neurologic and psychiatric disorders that involve striatal function. Potential ligands for PET imaging of PDE10A have been reported. Here, we report the first-in-human characterization of 2 new PDE10A radioligands, 2-(2-(3-(1-(2-fluoroethyl)-1H-indazol-6-yl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ((18)F-MNI-654) and 2-(2-(3-(4-(2-fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ((18)F-MNI-659), with the goal of selecting the best one for use in future studies interrogating pathophysiologic changes in neuropsychiatric disorders and aiding pharmaceutical development targeting PDE10A.
  
  
  METHODS
  Eleven healthy volunteers participated in this study ((18)F-MNI-654 test-retest, 2 men; (18)F-MNI-659 test-retest, 4 men and 1 woman; (18)F-MNI-659 dosimetry, 2 men and 2 women). Brain PET images were acquired over 5.5 h for (18)F-MNI-654 and over 3.5 h for (18)F-MNI-659, and pharmacokinetic modeling with plasma- and reference-region (cerebellar cortex)-based methods was performed. Whole-body PET images were acquired over 6 h for (18)F-MNI-659 and radiation dosimetry estimated with OLINDA.
  
  
  RESULTS
  Both radiotracers were similarly metabolized, with about 20% of intact parent remaining at 120 min after injection. PET time-activity data demonstrated that (18)F-MNI-654 kinetics were much slower than (18)F-MNI-659 kinetics. For (18)F-MNI-659, there was good agreement between the Logan and simplified reference tissue models for nondisplaceable binding potential (BPND), supporting noninvasive quantification, with test-retest variability less than 10% and intraclass correlation greater than 0.9. The (18)F-MNI-659 effective dose was estimated at 0.024 mSv/MBq.
  
  
  CONCLUSIONS
  PET imaging in the human brain with 2 novel PDE10A (18)F tracers is being reported. Noninvasive quantification of (18)F-MNI-659 with the simplified reference tissue model using the cerebellum as a reference is possible. In addition, (18)F-MNI-659 kinetics are fast enough for a good estimate of BPND with 90 min of data, with values around 3.0 in the basal ganglia. Finally, (18)F-MNI-659 dosimetry is favorable and consistent with values reported for other PET radiotracers currently used in humans.
authors.affiliation: Molecular NeuroImaging, LLC, New Haven, Connecticut; and obarret@mnimaging.com.
authors.forename: Olivier
authors.initials: O
authors.lastname: Barret
authors.affiliation: Molecular NeuroImaging, LLC, New Haven, Connecticut; and.
authors.forename: David
authors.initials: D
authors.lastname: Thomae
authors.affiliation: Molecular NeuroImaging, LLC, New Haven, Connecticut; and.
authors.forename: Adriana
authors.initials: A
authors.lastname: Tavares
authors.affiliation: Molecular NeuroImaging, LLC, New Haven, Connecticut; and.
authors.forename: David
authors.initials: D
authors.lastname: Alagille
authors.affiliation: Molecular NeuroImaging, LLC, New Haven, Connecticut; and.
authors.forename: Caroline
authors.initials: C
authors.lastname: Papin
authors.affiliation: Pfizer Global R&D, Groton, Connecticut.
authors.forename: Rikki
authors.initials: R
authors.lastname: Waterhouse
authors.affiliation: Pfizer Global R&D, Groton, Connecticut.
authors.forename: Timothy
authors.initials: T
authors.lastname: McCarthy
authors.affiliation: Molecular NeuroImaging, LLC, New Haven, Connecticut; and.
authors.forename: Danna
authors.initials: D
authors.lastname: Jennings
authors.affiliation: Molecular NeuroImaging, LLC, New Haven, Connecticut; and.
authors.forename: Ken
authors.initials: K
authors.lastname: Marek
authors.affiliation: Molecular NeuroImaging, LLC, New Haven, Connecticut; and.
authors.forename: David
authors.initials: D
authors.lastname: Russell
authors.affiliation: Molecular NeuroImaging, LLC, New Haven, Connecticut; and.
authors.forename: John
authors.initials: J
authors.lastname: Seibyl
authors.affiliation: Molecular NeuroImaging, LLC, New Haven, Connecticut; and.
authors.forename: Gilles
authors.initials: G
authors.lastname: Tamagnan
mesh_terms: D000328:Adult; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007211:Indoles / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008954:Models, Biological; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010797:Phthalimides / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods*; D052999:Quinazolinones / Q000378:metabolism; D011849:Radioactive Tracers; D011874:Radiometry; D051381:Rats; D051598:Whole Body Imaging
chemical_list: C000599324:2-(2-(3-(1-(2-fluoroethyl)-1H-indazol-6-yl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione; C000599323:2-(2-(3-(4-(2-fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione; D007211:Indoles; D010797:Phthalimides; D052999:Quinazolinones; D011849:Radioactive Tracers; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases
keywords: PDE10A; PET imaging; dosimetry; kinetic modeling; test–retest