Reproducible batch synthesis of radioligands for imaging by positron emission tomography (PET) in a manner that maximizes ligand yield, purity, and molar activity, and minimizes cost and exposure to radiation, remains a challenge, as new and synthetically complex radioligands become available. Commercially available automated synthesis units (ASUs) solve many of these challenges but are costly to install and cannot always accommodate diverse chemistries. Through a reiterative design process, we exploit the proliferation of three-dimensional (3D) printing technologies to translate optimized reaction conditions into ASUs composed of 3D-printed, electronic, and robotic parts. Our units are portable and robust and reduce radiation exposure, shorten synthesis time, and improve the yield of the final radiopharmaceutical for a fraction of the cost of a commercial ASU. These 3D-printed ASUs highlight the gains that can be made by designing a fit-for-purpose ASU to accommodate a synthesis over accommodating a synthesis to an unfit ASU.