Abstract
1094
Objectives: Nucleophilic aliphatic 18F-fluorination is a widely applied labeling method in PET radiochemistry due to the reliability, generally high yields and high molar activity.1 Unfortunately, the reaction sometimes entails precursors that are susceptible to hydrolysis, elimination or other side product formation under the basic conditions required for the substitution reaction.2 As such, several PET tracers can only be produced in unsatisfactory radiochemical yield (RCY).3,4 This study aimed to investigate how base-sensitive precursors and radiotracers can be produced using standard labeling procedures.
Methods: A systematic screening of anion exchange cartridge elution conditions was performed, exploring the following parameters: type of cartridge, preconditioning anion, type and concentration of the eluting anion and solvent composition of the elution solution. The amount of base present in the eluates was determined using pH measurements and qNMR. The most promising conditions with respect to elution power and base content were then tested with a simple model reaction to see how the elution conditions influence 18F-fluorination (Figure 1 and 2 A.). To ensure that the findings can be converted into actual clinically relevant yields, emphasis was directed towards the possibility to resolubilize the dried [18F]fluoride. Finally, the best conditions were screened in respect to solvent, temperature, reaction time, precursor concentration and leaving group influence.
Results: Initial screening of elution conditions revealed the pKa dependency of not only the eluting anion but also the preconditioning anion. Both anions heavily affect the elution efficiency together. Labeling reactions using different preconditioned QMAs showed that the preconditioning anion elutes with the [18F]-fluoride is a major contributor to the basicity of the reaction mixture when using low-base conditions. Further, the non-basic tetrabutylammonium salt Bu4NOMs proved to have very good resolubilization capabilities when using anions from the preconditioning cartridge as the only source of basicity. Consequently, we explored how preconditioning of the QMA cartridge with different phosphate or carbonate salts can be combined with various tetraalkylammonium salt solutions (consisting of basic, acidic and neutral properties) as eluates to achieve minimal basicity and maximal pseudo radiochemical yields (pRCY, defined in Figure 1). Commonly used solvents for aliphatic substitutions with different hydrogen bond accepting (HBA) and hydrogen bond donating (HBD) properties were also included to identify optimal labeling conditions (Figure 2, Table 1). Gained results helped us figure out improved labeling conditions for a set of clinically relevant tracers as well as synthons for research and routine productions. For example, we were able to derive conditions for the synthesis of [18F]FE-PE2I, a currently popular tracer used in PD, which resulted in a threefold increase of the isolated yield (Figure 2 B., RCY defined in Figure 1) compared to standard conditions of routine production with a pRCY of 74±12%.
Conclusions: Through systematic screening, we have successfully identified optimal conditions for aliphatic 18F-fluorination of base-sensitive precursors, which in respect to base content and precursor stability. With this knowledge, we have been able to drastically increase the RCY of many base sensitive tracers and synthons currently used.Figure 1. Overview of how reactions were performed and analyzed as well as important terms for describing the results. Table 1. Pseudo radiochemical yields (pRCY) of the model compound (A. Figure 2) using different Tetraalkylammonium-salts with various preconditioning anions in MeCN, DMSO or tBuOH/MeCN. Gives as mean values with standard deviation, n = 3. * n = 1 due to low (<10%) elution efficiency. ǂ n=1 due to low conversion. Figure 2. [18F]-fluorination reactions of model compound (A.) and [18F]FE-PE2I (B.)
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