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

Abstract

Aliphatic nucleophilic substitution (S N 2) with [ 18 F]fluoride is the most widely applied method to prepare 18 F-labeled positron emission tomography (PET) tracers. Strong basic conditions commonly used during 18 F-labeling procedures inherently limit or prohibit labeling of base-sensitive scaffolds. The high basicity stems from the tradition to trap [ 18 F]fluoride on anion exchange cartridges and elute it afterward with basic anions. This sequence is used to facilitate the transfer of [ 18 F]fluoride from an aqueous to an aprotic organic, polar reaction medium, which is beneficial for S N 2 reactions. Furthermore, this sequence also removes cationic radioactive contaminations from cyclotron-irradiated [ 18 O]water from which [ 18 F]fluoride is produced. In this study, we developed an efficient elution procedure resulting in low basicity that permits S N 2 18 F-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 18 F-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 N 2 18 F fluorination of base-sensitive substrates.

Development of 18F-Labeled Bispyridyl Tetrazines for In Vivo Pretargeted PET Imaging

“…We have previously reported that fluoroethyl moieties can be used to introduce 18 Ffluoride into H-Tz employing non-nucleophilic bases [33,34]. We believed that these conditions could also be suitable to label bispyridyl-based Tzs.…”

“…Compound 8 and its precursor 8a were synthesized as previously reported [33]. Compounds 3 and 4 and their corresponding precursor were obtained as reported in Scheme 1.…”

“…As we recently reported, nosyl leaving groups are optimally suited to aliphatically 18 F-label high-reactive Tzs. A mesylate or tosylate base precursor resulted in low radiochemical yields (RCY) [33,43]. Radiolabeling only succeeded using low basicity conditions, since H-Tzs are too sensitive for standard-rather, basic-aliphatic 18 F-fluorination approaches [29,33].…”

“…A mesylate or tosylate base precursor resulted in low radiochemical yields (RCY) [33,43]. Radiolabeling only succeeded using low basicity conditions, since H-Tzs are too sensitive for standard-rather, basic-aliphatic 18 F-fluorination approaches [29,33]. Within this study, we applied the same labeling conditions.…”

“…In a similar way, we were able to develop the first direct aliphatic 18 F-radiolabeled Tz (2) (Figure 2). This was possible using ultralow basic conditions [33,34]. Both compounds (1 and 2) showed high imaging contrast during in vivo experiments, and are currently subjects in further studies to evaluate their potential to be translated into the clinic.…”