Traditional radiosynthetic optimization faces the challenges of high radiation exposure, cost, and inability to perform serial reactions due to tracer decay. To accelerate tracer development, we have developed a strategy to simulate radioactive 18F‐syntheses by using tracer‐level (nanomolar) non‐radioactive 19F‐reagents and LC‐MS/MS analysis. The methodology was validated with fallypride synthesis under tracer‐level 19F‐conditions, which showed reproducible and comparable results with radiosynthesis, and proved the feasibility of this process. Using this approach, the synthesis of [18F]MDL100907 was optimized under 19F‐conditions with greatly improved yield. The best conditions were successfully transferred to radiosynthesis. A radiochemical yield of 19% to 22% was achieved with the radiochemical purity >99% and the molar activity 38.8 to 53.6 GBq/ μmol (n = 3). The tracer‐level 19F‐approach provides a high‐throughput and cost‐effective process to optimize radiosynthesis with reduced radiation exposure. This new method allows medicinal and synthetic chemists to optimize radiolabeling conditions without the need to use radioactivity.