Insights into Elution of Anion Exchange Cartridges: Opening the Path toward Aliphatic ¹⁸ F-Radiolabeling of Base-Sensitive Tracers

Abstract

Aliphatic nucleophilic substitution (S_N2) with [¹⁸F]fluoride is the most widely applied method to prepare ¹⁸F-labeled positron emission tomography (PET) tracers. Strong 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 afterward 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 S_N2 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 S_N2 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. Using this procedure, four PET tracers and three synthons could be radiolabeled in substantially higher RCYs (up to 2.5-fold) compared to those of previously published procedures, even from lower precursor amounts. 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 toward simple and direct S_N2 ¹⁸F fluorination of base-sensitive substrates.