Non-activated (electron-rich and/or sterically hindered) arenes are prevalent chemical scaffolds in pharmaceuticals and positron emission tomography (PET) diagnostics. Despite substantial efforts to develop a general method to introduce 18F into these moieties for molecular imaging by PET, there is an urgent and unmet need for novel radiofluorination strategies that result in sufficiently labeled tracers to enable human imaging. Herein, we describe an efficient method that relies on spirocyclic iodonium ylide (SCIDY) precursors for one-step and regioselective radiofluorination, as well as proof-of-concept translation to the radiosynthesis of a clinically useful PET tracer, 3-[18F]fluoro-5-[(pyridin-3-yl)ethynyl] benzonitrile ([18F]FPEB). The protocol begins with the preparation of a SCIDY precursor for FPEB, followed by radiosynthesis of [18F]FPEB, by either manual operation or an automated synthesis module. [18F]FPEB can be obtained in quantities >7.4 GBq (200 mCi), ready for injection (20 ± 5%, non-decay corrected), and has excellent chemical and radiochemical purity (>98%) as well as high molar activity (666 ± 51.8 GBq/μmol; 18 ± 1.4 Ci/μmol). The total time for the synthesis and purification of the corresponding labeling SCIDY precursor is 10 h. The subsequent radionuclide production, experimental setup, 18F labeling, and formulation of a product that is ready for injection require 2 h.