Aliphatic nucleophilic substitution (SN2) with [18F]fluoride is the most widely applied method to prepare 18F-labeled positron emission tomography (PET) tracers. Strongly basic conditions commonly used during 18F-labeling procedures inherently limit or prohibit labeling of base-sensitive scaffolds. The high basicity stems from the tradition to trap [18F]fluoride on anion exchange cartridges and elute it afterwards with basic anions. This sequence is used to facilitate the transfer of [18F]fluoride from an aqueous to an aprotic organic, polar reaction medium, which is beneficial for SN2 reactions. Furthermore, this sequence also removes cationic radioactive contaminations from cyclotron-irradiated [18O]water from which [18F]fluoride is produced. In this study, we developed an efficient elution procedure resulting in low basicity that permits SN2 18F-labeling of base-sensitive scaffolds. Extensive screening of trapping and elution conditions (>1000 experiments) and studying their influence on the radiochemical yield (RCY) allowed us to identify a suitable procedure for this. Four PET tracers and three synthons could be radiolabeled in substantially higher RCYs (up to 2.5-fold), even from lower precursor amounts, using this procedure. Encouraged by these results, we applied our low basicity method to the radiolabeling of highly base-sensitive tetrazines, which cannot be labeled using state-of-art direct aliphatic 18F-labeling procedures. Labeling succeeded in RCYs of up to 20%. We believe that our findings facilitate PET tracer development by opening the path towards simple and direct SN2 18F-fluorination of base-sensitive substrates.