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

• Published in: Journal of cerebral blood flow and metabolism p. 271678X251353140
• Main Authors: Ibrahimy, Alaaddin, Kim, Su Jin, Schmidt, Mark E, Slifstein, Mark, Mannaert, Erik, Andrews, Randolph D, Matthews, Dawn C, Constantinescu, Cristian C, Searle, Graham E, Gunn, Roger N, Rabiner, Eugenii A, Morris, Evan D
• Format: Journal Article
• Language: English
• Published: 25.06.2025
• ISSN: 1559-7016; 1559-7016
• DOI: 10.1177/0271678X251353140

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 Emax 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.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 Emax 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.