Behavioral and cellular studies indicate that serotonin interacting with the 5-HT2a receptor (5-HT2aR) is involved in cognitive processes supporting working memory (WM). However, 5-HT receptor neuroimaging studies directly relating WM-induced neuronal activations to concomitant changes in the availability of 5-HT receptors as a functional measure for serotonin release are lacking. This controlled cross-over PET study aimed to identify brain regions with WM-induced changes in the binding potential (BP nd ) of the 5-HT2aR antagonist [ 18 F]altanserin. Ten young males underwent a delayed match-to-sample task using photographs of faces and a control task. The BP nd s for both conditions were calculated by applying Ichise's noninvasive plot. Statistics were performed with the SPM toolbox statistical nonparametric mapping (SnPM3) particularly suited for analyzing whole-brain PET data in an exploratory way.A higher BP nd for [ 18 F]altanserin during WM versus control was found in the orbitofrontal cortex (OFC) pointing towards an increased [ 18 F]altanserin/5-HT2aR interaction in OFC while BP nd decreases during WM were not found. Furthermore, no BP nd changes in regions known from functional neuroimaging studies to be more specifically involved in WM were identified. These findings may suggest that the increased [ 18 F]altanserin BP nd under WM challenge and hence the increased availability of 5-HT2aR reflects a decrease in local OFC serotonin. As the OFC plays a prominent role in decision-making and supports cognitive processes related to the central executive functions of WM it might be modulated by the serotoninergic system via the 5-HT2aR in order to support and optimize basic cognitive functions.