EC₅₀ images, a novel endpoint from PET target occupancy studies, reveal spatial variation in apparent drug affinity

We recently introduced voxel-level images of drug occupancy from PET via our "Lassen plot filter." Occupancy images revealed clear dependence of ¹¹C-flumazenil displacement on dose of GABAa inhibitor, CVL-865, but with different scales in different brain regions. We hypothesized that regions requiring higher drug concentrations to achieve desired occupancy would have higher EC₅₀ values. We introduce an "EC₅₀ image" from human data to evaluate this hypothesis.

Five healthy subjects were scanned with the nonselective GABAa tracer, ¹¹C-flumazenil, before and (twice) after administration of CVL-865. We created ten occupancy images and applied an E_max model locally to create one EC₅₀ image. We also performed simulations to confirm our observations of regional variation in EC₅₀ and to identify the main source of variability in EC₅₀.

As expected, the EC₅₀ image revealed spatial variation in apparent drug affinity. High EC₅₀ was found in areas of low occupancy for a given drug dose. Simulations demonstrated that sampling from an inadequate range of plasma drug concentrations could impair precision.

Our results argue for (a) confidence in the ability of the EC₅₀ images to identify regional differences and (b) a need to tailor the range of drug doses in an occupancy study to regularize the precision of the EC₅₀ throughout the brain. The EC₅₀ image could add value to early-phase drug development by identifying regional variation in affinity that might impact therapy or safety and by guiding dose selection for later-phase trials.