Towards Molecular Specificity in Pharmacoimaging

Molecular-enriched fMRI promises to bridge the gap between neurotransmitter systems and macro-scale network dynamics, yet empirical validation has remained elusive. Commenting on van den Bosch and Cools (2025), we evaluate the first rigorous validation of Receptor-Enriched Analysis of functional Connectivity by Targets (REACT) against individual-level PET data. They found that the effects of methylphenidate on dopamine-enriched networks, but not noradrenaline-enriched networks, tracked individual differences in striatal dopamine synthesis capacity and reward prediction error signaling. While establishing the validity of molecular-enriched networks for this specific use case, the study also exposes critical methodological boundary conditions. We discuss the constraints imposed by spatial collinearity between molecular targets, the influence of state-dependent effects in task-based paradigms, and the necessity of pharmacological blocking studies for establishing causal specificity. Finally, we look to the future of molecular-informed functional imaging.