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

Abstract

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

Aliphatic 18F‐Radiofluorination: Recent Advances in the Labeling of Base‐Sensitive Substrates**

“…[31][32][33][34][35][36] Recently, interest has been focused on the development of synthesis strategies that allow for 18 F-labeling of base-sensitive structures. [37,38] Standard aliphatic and aromatic labeling approaches can cause undesired side reactions and degradation of the synthesized tracer due to the presence of carbonate bases commonly used in these processes. [39] For aromatic labeling, the introduction of Cu-mediated 18 F-fluorinations has led to improved labelings of base-sensitive structures, [40] as recently demonstrated by García Vázquez et al [41] However, the efforts to address this challenge in aliphatic labeling have been less highlighted.…”

“…[70] Intrigued by these studies, our group has recently performed an investigation to determine the key parameters which influence the basicity in such approach, i. e. when only the preconditioning anion is used as base. [38] Various preconditioning anions and elution ions combined with several reaction solvents were tested for their ability to promote aliphatic S N 2 18 F-labeling of base-sensitive structures. For example, the concentrations of preconditioning anions eluted with non-basic anions such as mesylates were quantified by qNMR or pH measurements.…”

“…RCYs increased by 100-170 % compared to yields obtained with conventional preconditioning and elution conditions (Figure 6). [38]…”

“…[66] However, there have been reports of problems using this method due to high adsorption of [ 18 F]F À to the glass wall of the reaction vessel. [38] In this respect, it would be interesting to use preconditioning anions which are released from the AEC while eluting [ 18 F]F À with non-basic e. g. OMs À ions as the only source of basicity (Figure 6). These eluted anions could provide enough basicity to promote the nucleophilic fluorination, but not enough to initiate side reactions or decomposition processes.…”

“…[57] Interestingly, the best 18 Ffluorination RCYs for the extremely base-sensitive structures were obtained when using tert-butanol (tBuOH) with 16 % MeCN or DMSO (v/v) as reaction solvent, while for the less basesensitive structures, the best RCY values were obtained in neat MeCN or DMSO. [38] This may be due to the trade-off between the rates of [ 18 F]fluoride incorporation and precursor degradation. Both processes are faster in MeCN and DMSO compared to tBuOH, and more base-sensitive precursors degrade faster than less base-sensitive ones.…”