In vivo measurement of PDE10A enzyme occupancy by positron emission tomography (PET) following single oral dose administration of PF-02545920 in healthy male subjects

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 occupan...

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Published in:	Neuropharmacology Vol. 117; pp. 171 - 181
Main Authors:	Delnomdedieu, Marielle, Forsberg, Anton, Ogden, Adam, Fazio, Patrik, Yu, Ching-Ray, Stenkrona, Per, Duvvuri, Sridhar, David, William, Al-Tawil, Nabil, Vitolo, Ottavio V., Amini, Nahid, Nag, Sangram, Halldin, Christer, Varrone, Andrea
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01.05.2017
Subjects:	Adult Corpus Striatum - metabolism Enzyme occupancy Fluorine Radioisotopes - metabolism Healthy volunteer Humans Male Middle Aged Models, Biological PDE10 inhibitor PF-02545920 Phosphoric Diester Hydrolases - metabolism Phthalimides - blood Phthalimides - metabolism Positron emission tomography Pyrazoles - adverse effects Pyrazoles - pharmacokinetics Pyrazoles - pharmacology Quinazolinones - blood Quinazolinones - metabolism Quinolines - adverse effects Quinolines - pharmacokinetics Quinolines - pharmacology Radioligand [18F]MNI-659 Radioligand Assay - methods Single dose Enzyme occupancy PDE10 inhibitor Radioligand [18F]MNI-659 PF-02545920 Healthy volunteer Single dose Positron emission tomography Radioligand [F]MNI-659
ISSN:	0028-3908, 1873-7064
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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]. •Single oral doses (10 mg, 20 mg) of PF-02545920 were safe and well tolerated in healthy male volunteers.•Enzyme occupancy of PF-02545920 obtained using [18F]MNI-659 PET was in the expected range.•Striatal PDE10A occupancy increased with increasing PF-02545920 dose and exposure, reaching ∼50% following the 20 mg single dose.•A 20 mg oral dose of PF-02545920 provides sufficient target brain occupancy for evaluation in future PDE10 clinical trials.
AbstractList	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]. 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]. •Single oral doses (10 mg, 20 mg) of PF-02545920 were safe and well tolerated in healthy male volunteers.•Enzyme occupancy of PF-02545920 obtained using [18F]MNI-659 PET was in the expected range.•Striatal PDE10A occupancy increased with increasing PF-02545920 dose and exposure, reaching ∼50% following the 20 mg single dose.•A 20 mg oral dose of PF-02545920 provides sufficient target brain occupancy for evaluation in future PDE10 clinical trials. 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 [ F]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 [ F]MNI-659 binding to PDE10A. The occupancy of PF-02545920 was calculated with two different methods: In Method 1, [ F]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].
Author	Vitolo, Ottavio V. Stenkrona, Per Amini, Nahid Yu, Ching-Ray Al-Tawil, Nabil Nag, Sangram Varrone, Andrea Halldin, Christer Duvvuri, Sridhar Delnomdedieu, Marielle Forsberg, Anton Ogden, Adam Fazio, Patrik David, William
Author_xml	– sequence: 1 givenname: Marielle surname: Delnomdedieu fullname: Delnomdedieu, Marielle email: Marielle.Delnomdedieu@pfizer.com organization: Pfizer Neuroscience & Pain Research Unit, Cambridge, MA, USA – sequence: 2 givenname: Anton surname: Forsberg fullname: Forsberg, Anton email: Anton.Forsberg@ki.se organization: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden – sequence: 3 givenname: Adam orcidid: 0000-0001-9703-1644 surname: Ogden fullname: Ogden, Adam email: Adam.Ogden@pfizer.com organization: Pfizer Neuroscience & Pain Research Unit, Cambridge, MA, USA – sequence: 4 givenname: Patrik surname: Fazio fullname: Fazio, Patrik email: patrik.fazio@ki.se organization: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden – sequence: 5 givenname: Ching-Ray surname: Yu fullname: Yu, Ching-Ray email: Ching-Ray.Yu@pfizer.com organization: Pfizer Global Innovative Pharma, New York, NY, USA – sequence: 6 givenname: Per surname: Stenkrona fullname: Stenkrona, Per email: Per.Stenkrona@ki.se organization: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden – sequence: 7 givenname: Sridhar surname: Duvvuri fullname: Duvvuri, Sridhar email: sridhar.duvvuri@pfizer.com organization: Pfizer Neuroscience & Pain Research Unit, Cambridge, MA, USA – sequence: 8 givenname: William surname: David fullname: David, William email: William.David@pfizer.com organization: Mass General Hospital, Boston, MA, USA – sequence: 9 givenname: Nabil surname: Al-Tawil fullname: Al-Tawil, Nabil email: nabil.al-tawil@karolinska.se organization: Karolinska Trial Alliance, Stokholm, Sweden – sequence: 10 givenname: Ottavio V. surname: Vitolo fullname: Vitolo, Ottavio V. email: Ottavio.Vitolo@pfizer.com organization: Pfizer Neuroscience & Pain Research Unit, Cambridge, MA, USA – sequence: 11 givenname: Nahid surname: Amini fullname: Amini, Nahid email: Nahid.Amini@oriflame.com organization: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden – sequence: 12 givenname: Sangram surname: Nag fullname: Nag, Sangram email: Sangram.Nag@ki.se organization: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden – sequence: 13 givenname: Christer surname: Halldin fullname: Halldin, Christer email: Christer.Halldin@ki.se organization: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden – sequence: 14 givenname: Andrea surname: Varrone fullname: Varrone, Andrea email: andrea.varrone@ki.se organization: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden
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Keywords	Enzyme occupancy PDE10 inhibitor Radioligand [18F]MNI-659 PF-02545920 Healthy volunteer Single dose Positron emission tomography Radioligand [F]MNI-659
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Snippet	Phosphodiesterase 10A (PDE10A) is an enzyme highly enriched in the striatal medium spiny neurons. It is involved in the regulation of cytoplasmic levels of...
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SubjectTerms	Adult Corpus Striatum - metabolism Enzyme occupancy Fluorine Radioisotopes - metabolism Healthy volunteer Humans Male Middle Aged Models, Biological PDE10 inhibitor PF-02545920 Phosphoric Diester Hydrolases - metabolism Phthalimides - blood Phthalimides - metabolism Positron emission tomography Pyrazoles - adverse effects Pyrazoles - pharmacokinetics Pyrazoles - pharmacology Quinazolinones - blood Quinazolinones - metabolism Quinolines - adverse effects Quinolines - pharmacokinetics Quinolines - pharmacology Radioligand [18F]MNI-659 Radioligand Assay - methods Single dose
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
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