EC50 images reveal reproducible spatial variation in drug affinity across single- and repeat-dose occupancy studies.

Abstract

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 EC₅₀ 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 EC₅₀ 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. EC₅₀ images demonstrated reproducible spatial variation in drug affinity across striatal subregions; caudate and ventral striatum showed lower EC₅₀ values than putamen. Additionally, left-right asymmetries in EC₅₀ were detected, once the effects of upregulation were addressed. Our findings validate EC₅₀ 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.