EC 50 images, a novel endpoint from PET target occupancy studies, reveal spatial variation in apparent drug affinity

• Published in: European journal of nuclear medicine and molecular imaging 2022-03, Vol.49 (4), p.1232
• Main Authors: de Laat, Bart, Hoye, Jocelyn, Liu, Heather, Morris, Evan D
• Format: Article
• Language: English
• ISSN: 1619-7089
• DOI: 10.1007/s00259-021-05561-3

We recently introduced voxel-level images of drug occupancy from PET via our "Lassen plot filter." Occupancy images revealed clear dependence of C-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 EC values. We introduce an "EC image" from human data to evaluate this hypothesis. Five healthy subjects were scanned with the nonselective GABAa tracer, C-flumazenil, before and (twice) after administration of CVL-865. We created ten occupancy images and applied an E model locally to create one EC image. We also performed simulations to confirm our observations of regional variation in EC and to identify the main source of variability in EC . As expected, the EC image revealed spatial variation in apparent drug affinity. High EC 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 EC 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 EC throughout the brain. The EC 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.