Quantification of human brain PDE4 occupancy by GSK356278: A [11C](R)-rolipram PET study

Abstract

We characterized the relationship between the plasma concentration of the phospodiesterase (PDE)-4 inhibitor GSK356278 and occupancy of the PDE4 enzyme in the brain of healthy volunteers, using the positron emission tomography (PET) tracer [¹¹C](R)-rolipram. To this end, PET scans were acquired in eight male volunteers before and at 3 and 8 h after a single 14 mg oral dose of GSK356278. A metabolite-corrected arterial input function was used in conjunction with the dynamic PET emission data to estimate volumes of distribution (V_T) from a two-tissue compartment model. The administration of GSK356278 reduced [¹¹C](R)-rolipram whole brain V_T by 17% at 3 h post-dose (p = 0.01) and by 4% at 8 h post-dose. The mean plasma C_max was 42.3 ng/ml, leading to a PDE4 occupancy of 48% at T_max. The in vivo affinity of GSK356278 was estimated as EC₅₀ = 46 ± 3.6 ng/ml. We present the first report of a direct estimation of PDE4 blockade in the living human brain. In vivo affinity of GSK356278 for the PDE4, estimated in this early phase study, was combined with GSK356278 safety and tolerability data to decide on a therapeutic dose for future clinical development.

Keywords: GSK356278; PDE4; PET; [11C](R)-rolipram; quantitative imaging.

Figure 1.

(a) Anatomical MRI and PET-integrated activity from 30 to 90 min post [¹¹C](R)-rolipram injection at baseline, post-dose 1 (3 h) and post-dose 2 (8 h) for subject 2. Data for each scan have been normalized by the injected activity per liter (%ID/l). (b) Regional measured data (circles) and model fits (lines) for subject 2. For each region, the baseline (red), post-dose 1 (3 h, green) and post-dose 2 (8 h, blue) time activity curves are shown.

Figure 2.

Global brain volumes of distribution (V_T) for baseline, 3 and 8 h post-dose scans in all eight subjects. Subjects 5 and 6 completed one post-dose scan.

Figure 3.

Individual plasma GSK356278 concentration-time curves. The dotted lines show the average time of the post-dose scans.

Figure 4.

Model fits of the PET occupancy data and plasma GSK356278 concentration with estimated EC₅₀ in all subjects examined (top row) and for the dataset excluding subjects 3 and 7 (bottom row). Column 2 represents the most likely value of the non-displaceable binding potential (BP_ND) while the other two columns are intended to show the effect of a different estimate of BP_ND on the EC₅₀.