In vivo measurement of PDE10A enzyme occupancy by positron emission tomography (PET) following single oral dose administration of PF-02545920 in healthy male subjects.
2017
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
PDE10Aradioligand [ 18 F]MNI-659 was designed to measure the enzyme
occupancyof 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 samplingwas performed to obtain a metabolite-corrected plasma input function for the quantification of [ 18 F]MNI-659 binding to
PDE10A. The
occupancyof PF-02545920 was calculated with two different methods: In Method 1, [ 18 F]MNI-659 enzyme
occupancywas calculated from the estimates of
binding potential, using the cerebellum as a reference region; in Method 2,
occupancywas 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
occupancyincreased with increasing PF-02545920 dose: 14–27% at 10 mg dose (N = 4) and 45–63% at 20 mg dose (N = 3). Comparable
occupancieswere observed using Lassen's plot Method 2: 10 mg: 14–37%; 20 mg: 46–55%. The relationship between exposure and
occupancywas best described using an Emax model. The serum concentration associated with 50%
occupancywas 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].
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