Derivatization of the putative neuroleptic 1-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-4-(4-fluorobenzyl)piperazine (3a) led to a series of new dopamine receptor D4 ligands displaying high affinity (Ki=1.1-15 nM) and D2/D4 subtype selectivities of about 800-6700. These ligands were labeled with the short-lived positron emitter fluorine-18 and analyzed for their potential application for imaging studies by positron emission tomography (PET). In vitro autoradiography was used to determine their nonspecific binding behavior as a result of their structural and thus physicochemical properties. The biodistribution, in vivo stability, and brain uptake of the most promising D4 radioligand candidate were determined. This proved to be 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-((6-fluoropyridin-3-yl)methyl)piperazine ([18F]3d), which revealed an excellent binding pattern with a high selectivity and limited nonspecific binding in vitro. This analogue also exhibited a high stability and an extremely high brain uptake in vivo with specific binding in hippocampus, cortex, colliculus, and cerebellum as determined by ex vivo autoradiography. Thus, [18F]3d appears as a suitable D4 radioligand for in vivo imaging, encouraging continued evaluation by PET studies.