title: In vivo measurement of PDE10A enzyme occupancy by positron emission tomography (PET) following single oral dose administration of PF-02545920 in healthy male subjects.
abstract: Phosphodiesterase 10A (PDE10A) is an enzyme highly enriched in the striatal medium spiny neurons. It is involved in the regulation of cytoplasmic levels of cAMP and cGMP and signaling within the basal ganglia. This study with PDE10A radioligand [18F]MNI-659 was designed to measure the enzyme occupancy of PF-02545920 in 8 healthy male volunteers (48 ± 4 years) after a single oral dose (10 mg or 20 mg) and to evaluate safety and tolerability. Arterial blood sampling was performed to obtain a metabolite-corrected plasma input function for the quantification of [18F]MNI-659 binding to PDE10A. The occupancy of PF-02545920 was calculated with two different methods: In Method 1, [18F]MNI-659 enzyme occupancy was calculated from the estimates of binding potential, using the cerebellum as a reference region; in Method 2, occupancy was estimated from the slope of the revised Lassen's plot. Serum concentrations of PF-02545920 were measured to determine the relationship between concentration and occupancy. Based on Method 1, striatal PDE10A occupancy increased with increasing PF-02545920 dose: 14-27% at 10 mg dose (N = 4) and 45-63% at 20 mg dose (N = 3). Comparable occupancies were observed using Lassen's plot Method 2: 10 mg: 14-37%; 20 mg: 46-55%. The relationship between exposure and occupancy was best described using an Emax model. The serum concentration associated with 50% occupancy was estimated to be 93.2 ng/mL. Single oral doses of 10 mg or 20 mg of PF-02545920 were safe and well tolerated in healthy male volunteers [NCT# 01918202].
authors.affiliation: Pfizer Neuroscience & Pain Research Unit, Cambridge, MA, USA. Electronic address: Marielle.Delnomdedieu@pfizer.com.
authors.forename: Marielle
authors.initials: M
authors.lastname: Delnomdedieu
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden. Electronic address: Anton.Forsberg@ki.se.
authors.forename: Anton
authors.initials: A
authors.lastname: Forsberg
authors.affiliation: Pfizer Neuroscience & Pain Research Unit, Cambridge, MA, USA. Electronic address: Adam.Ogden@pfizer.com.
authors.forename: Adam
authors.initials: A
authors.lastname: Ogden
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden. Electronic address: patrik.fazio@ki.se.
authors.forename: Patrik
authors.initials: P
authors.lastname: Fazio
authors.affiliation: Pfizer Global Innovative Pharma, New York, NY, USA. Electronic address: Ching-Ray.Yu@pfizer.com.
authors.forename: Ching-Ray
authors.initials: CR
authors.lastname: Yu
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden. Electronic address: Per.Stenkrona@ki.se.
authors.forename: Per
authors.initials: P
authors.lastname: Stenkrona
authors.affiliation: Pfizer Neuroscience & Pain Research Unit, Cambridge, MA, USA. Electronic address: sridhar.duvvuri@pfizer.com.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Duvvuri
authors.affiliation: Mass General Hospital, Boston, MA, USA. Electronic address: William.David@pfizer.com.
authors.forename: William
authors.initials: W
authors.lastname: David
authors.affiliation: Karolinska Trial Alliance, Stokholm, Sweden. Electronic address: nabil.al-tawil@karolinska.se.
authors.forename: Nabil
authors.initials: N
authors.lastname: Al-Tawil
authors.affiliation: Pfizer Neuroscience & Pain Research Unit, Cambridge, MA, USA. Electronic address: Ottavio.Vitolo@pfizer.com.
authors.forename: Ottavio V
authors.initials: OV
authors.lastname: Vitolo
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden. Electronic address: Nahid.Amini@oriflame.com.
authors.forename: Nahid
authors.initials: N
authors.lastname: Amini
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden. Electronic address: Sangram.Nag@ki.se.
authors.forename: Sangram
authors.initials: S
authors.lastname: Nag
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden. Electronic address: Christer.Halldin@ki.se.
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden. Electronic address: andrea.varrone@ki.se.
authors.forename: Andrea
authors.initials: A
authors.lastname: Varrone
mesh_terms: D000328:Adult; D003342:Corpus Striatum / Q000378:metabolism; D005462:Fluorine Radioisotopes / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010797:Phthalimides / Q000097:blood / Q000378:metabolism; D049268:Positron-Emission Tomography; D011720:Pyrazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D052999:Quinazolinones / Q000097:blood / Q000378:metabolism; D011804:Quinolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D011869:Radioligand Assay / Q000379:methods
chemical_list: C545121:2-((4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy)methyl)quinoline; C000599323:2-(2-(3-(4-(2-fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione; D005462:Fluorine Radioisotopes; D010797:Phthalimides; D011720:Pyrazoles; D052999:Quinazolinones; D011804:Quinolines; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases
keywords: Enzyme occupancy; Healthy volunteer; PDE10 inhibitor; PF-02545920; Positron emission tomography; Radioligand [(18)F]MNI-659; Single dose