title: Preclinical Evaluation of 18F-PF-05270430, a Novel PET Radioligand for the Phosphodiesterase 2A Enzyme.
abstract: The enzyme phosphodiesterase 2A (PF-05270430) is a potential target for development of novel therapeutic agents for the treatment of cognitive impairments. The goal of the present study was to evaluate the PDE2A ligand (18)F-PF-05270430, 4-(3-fluoroazetidin-1-yl)-7-methyl-5-(1-methyl-5-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)imidazo[1,5-f][1,2,4]triazine, in nonhuman primates.
  
  
  
  (18)F-PF-05270430 was radiolabeled by 2 methods via nucleophilic substitution of its tosylate precursor. Tissue metabolite analysis in rodents and PET imaging in nonhuman primates under baseline and blocking conditions were performed to determine the pharmacokinetic and binding characteristics of the new radioligand. Various kinetic modeling approaches were assessed to select the optimal method for analysis of imaging data.
  
  
  
  (18)F-PF-05270430 was synthesized in greater than 98% radiochemical purity and high specific activity. In the nonhuman primate brain, uptake of (18)F-PF-05270430 was fast, with peak concentration (SUVs of 1.5-1.8 in rhesus monkeys) achieved within 7 min after injection. The rank order of uptake was striatum > neocortical regions > cerebellum. Regional time-activity curves were well fitted by the 2-tissue-compartment model and the multilinear analysis-1 (MA1) method to arrive at reliable estimates of regional distribution volume (VT) and binding potential (BPND) with 120 min of scan data. Regional VT values (MA1) ranged from 1.28 mL/cm(3) in the cerebellum to 3.71 mL/cm(3) in the putamen, with a BPND of 0.25 in the temporal cortex and 1.92 in the putamen. Regional BPND values estimated by the simplified reference tissue model (SRTM) were similar to those from MA1. Test-retest variability in high-binding regions (striatum) was 4% ± 6% for MA1 VT, 13% ± 6% for MA1 BPND, and 13% ± 7% SRTM BPND, respectively. Pretreatment of animals with the PDE2A inhibitor PF-05180999 resulted in a dose-dependent reduction of (18)F-PF-05270430 specific binding, with a half maximal effective concentration of 69.4 ng/mL in plasma PF-05180999 concentration.
  
  
  
  (18)F-PF-05270430 displayed fast and reversible kinetics in nonhuman primates, as well as specific binding blockable by a PDE2A inhibitor. This is the first PET tracer with desirable imaging properties and demonstrated ability to image and quantify PDE2A in vivo.
authors.affiliation: Pfizer Worldwide Research and Development, Groton, Connecticut; and.
authors.forename: Laigao
authors.initials: L
authors.lastname: Chen
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Nabulsi
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut.
authors.forename: Mika
authors.initials: M
authors.lastname: Naganawa
authors.affiliation: Pfizer Worldwide Research and Development, Groton, Connecticut; and.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Zasadny
authors.affiliation: Pfizer Worldwide Research and Development, Groton, Connecticut; and.
authors.forename: Marc B
authors.initials: MB
authors.lastname: Skaddan
authors.affiliation: Pfizer Worldwide Research and Development, Groton, Connecticut; and.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut.
authors.forename: Soheila
authors.initials: S
authors.lastname: Najafzadeh
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut.
authors.forename: Shu-Fei
authors.initials: SF
authors.lastname: Lin
authors.affiliation: Pfizer Worldwide Research and Development, Groton, Connecticut; and.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Helal
authors.affiliation: Pfizer Worldwide Research and Development, Groton, Connecticut; and.
authors.forename: Tracey L
authors.initials: TL
authors.lastname: Boyden
authors.affiliation: Pfizer Worldwide Research and Development, Groton, Connecticut; and.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chang
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut.
authors.forename: Jim
authors.initials: J
authors.lastname: Ropchan
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Carson
authors.affiliation: Pfizer Worldwide Research and Development, Groton, Connecticut; and.
authors.forename: Anabella
authors.initials: A
authors.lastname: Villalobos
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut henry.huang@yale.edu.
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000818:Animals; D053961:Azabicyclo Compounds / Q000493:pharmacokinetics*; D001384:Azetidines / Q000493:pharmacokinetics*; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000378:metabolism*; D008253:Macaca mulatta; D008297:Male; D008657:Metabolic Clearance Rate; D057054:Molecular Imaging / Q000379:methods*; D009928:Organ Specificity; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013045:Species Specificity; D014018:Tissue Distribution
chemical_list: C582922:4-(3-fluoroazetidin-1-yl)-7-methyl-5-(1-methyl-5-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)imidazo(5,1-f)(1,2,4)triazine; D053961:Azabicyclo Compounds; D001384:Azetidines; D019275:Radiopharmaceuticals; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2
keywords: non-human primates; phosphodiesterase 2A; positron emission tomography; radioligand