EC 50 images reveal reproducible spatial variation in drug affinity across single- and repeat-dose occupancy studies

We investigated spatial variation in the apparent affinity of the D2 antagonist drug, JNJ-37822681, for dopamine receptors across single-dose (SD) and repeat-dose (RD) PET occupancy studies. Traditional whole-brain EC 50 estimates overlook potential spatial variation in drug affinity. We reanalyzed PET occupancy data from two published studies in healthy male volunteers (SD: administering 1 dose between 2–20 mg; RD: administering 13 doses of 10 mg over 7 days). Voxel-level occupancy images were generated from binding potential maps using Lassen Plot Filter (LPF), clustered via SLIC-Occ, and fitted to one- and two-parameter E max models to generate EC 50 images, revealing regional variation in apparent affinity within the striatum. The two-parameter model incorporated receptor upregulation in a joint analysis of SD and RD data. EC 50 images demonstrated reproducible spatial variation in drug affinity across striatal subregions; caudate and ventral striatum showed lower EC 50 values than putamen. Additionally, left-right asymmetries in EC 50 were detected, once the effects of upregulation were addressed. Our findings validate EC 50 images for capturing spatial variation in drug affinity and highlights the importance of accurate modeling in chronic dosing studies. LPF and SLIC-Occ provide a robust framework for analyzing occupancy data, aiding dose optimization for drug trials.