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Background <p>[<sup>11</sup>C]Acetate and [<sup>11</sup>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. [<sup>11</sup>C]Acetate was synthesized via Grignard carboxylation using [<sup>11</sup>C]CO<sub>2</sub> and purified with a cartridge-based system. [<sup>11</sup>C]Acetoacetate was produced via in-loop [<sup>11</sup>C]CO<sub>2</sub> 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 [<sup>11</sup>C]acetoacetate.</p> Results <p>Omission of helium flow during [<sup>11</sup>C]CO<sub>2</sub> trap bake-out significantly improved activity recovery from the [<sup>11</sup>C]CO<sub>2</sub> trap (from 63 to 89%) and reduced release time (from 4.8 to 3.1&#xa0;min). [<sup>11</sup>C]Acetate and [<sup>11</sup>C]acetoacetate were synthesized with mean isolated activities of 30.2&#xa0;GBq and 3.24&#xa0;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 [<sup>11</sup>C]acetate from [<sup>11</sup>C]acetoacetate, the newly-developed RP-HPLC method enabled unambiguous separation. Literature analysis revealed that most published studies on [<sup>11</sup>C]acetoacetate likely overlooked [<sup>11</sup>C]acetate as a radiochemical impurity due to insufficient analytical separation.</p> Conclusions <p>Reliable synthesis protocols for [<sup>11</sup>C]acetate and [<sup>11</sup>C]acetoacetate were established on the GE TRACERlab FX2 C, with significant improvements in [<sup>11</sup>C]CO<sub>2</sub> 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 [<sup>11</sup>C]acetoacetate.</p>

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Unambiguous analytical separation and improved syntheses of [11C]acetate and [11C]acetoacetate

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月26日

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  • Karsten Bamminger,
  • Lukas Nics,
  • Marcus Hacker,
  • Cécile Philippe,
  • Marius Ozenil

摘要

Background

[11C]Acetate and [11C]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. [11C]Acetate was synthesized via Grignard carboxylation using [11C]CO2 and purified with a cartridge-based system. [11C]Acetoacetate was produced via in-loop [11C]CO2 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 [11C]acetoacetate.

Results

Omission of helium flow during [11C]CO2 trap bake-out significantly improved activity recovery from the [11C]CO2 trap (from 63 to 89%) and reduced release time (from 4.8 to 3.1 min). [11C]Acetate and [11C]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 [11C]acetate from [11C]acetoacetate, the newly-developed RP-HPLC method enabled unambiguous separation. Literature analysis revealed that most published studies on [11C]acetoacetate likely overlooked [11C]acetate as a radiochemical impurity due to insufficient analytical separation.

Conclusions

Reliable synthesis protocols for [11C]acetate and [11C]acetoacetate were established on the GE TRACERlab FX2 C, with significant improvements in [11C]CO2 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 [11C]acetoacetate.