Unambiguous analytical separation and improved syntheses of [11C]acetate and [11C]acetoacetate
Year: 2025
Type: article
Abstract: [ 11 C]Acetate and [ 11 C]acetoacetate are PET radiotracers widely used to assess oxidative metabolism and ketone body utilization, respectively. This study aimed to establish robust, high-yield syntheses of both tracers using a GE TRACERlab FX2 C module, with an emphasis on improving radiochemical purity (RCP), radiochemical yield (RCY), optimizing operational parameters, and developing accurate quality control methods. [ 11 C]Acetate was synthesized via Grignard carboxylation using [ 11 C]CO 2 and purified with a cartridge-based system. [ 11 C]Acetoacetate was produced via in-loop [ 11 C]CO 2 carboxylation of a lithium enolate precursor, followed by semi-preparative reversed-phase HPLC purification. Quality control was performed by reported ion-exchange chromatography (IEX-HPLC) and novel reversed-phase HPLC (RP-HPLC). A systematic literature review was conducted to evaluate prior quality control methods for [ 11 C]acetoacetate. Omission of helium flow during [ 11 C]CO 2 trap bake-out significantly improved activity recovery from the [ 11 C]CO 2 trap (from 63 to 89%) and reduced release time (from 4.8 to 3.1 min). [ 11 C]Acetate and [ 11 C]acetoacetate were synthesized with mean isolated activities of 30.2 GBq and 3.24 GBq and mean RCPs of 96.9% and 97.1%, respectively. The final formulations met all European Pharmacopoeia criteria. While the widely-used IEX-HPLC method failed to differentiate [ 11 C]acetate from [ 11 C]acetoacetate, the newly-developed RP-HPLC method enabled unambiguous separation. Literature analysis revealed that most published studies on [ 11 C]acetoacetate likely overlooked [ 11 C]acetate as a radiochemical impurity due to insufficient analytical separation. Reliable synthesis protocols for [ 11 C]acetate and [ 11 C]acetoacetate were established on the GE TRACERlab FX2 C, with significant improvements in [ 11 C]CO 2 handling and product purification. Inclusion of the proposed RP-HPLC method enables a more accurate and specific assessment of RCP compared to IEX-HPLC alone and should be considered for a valid quality control of [ 11 C]acetoacetate.
Institution: Medical University of Vienna
Language: English
Subfield: Radiology, Nuclear Medicine and Imaging
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,290
OpenAlex ID: W7117326829