Enhanced radiosyntheses of [¹¹C]raclopride and [¹¹C]DASB using ethanolic loop chemistry.

INTRODUCTION: To improve the synthesis and quality control of carbon-11 labeled radiopharmaceuticals, we report the fully automated loop syntheses of [¹¹C]raclopride and [¹¹C]DASB using ethanol as the only organic solvent for synthesis module cleaning, carbon-11 methylation, HPLC purification, and reformulation. METHODS: Ethanolic loop chemistry is fully automated using a GE TRACERLab FX(C-Pro) synthesis module, and is readily adaptable to any other carbon-11 synthesis apparatus. Precursors (1 mg) were dissolved in ethanol (100 µL) and loaded into the HPLC loop. [¹¹C]MeOTf was passed through the HPLC loop and then the labeled products were purified by semi-preparative HPLC and reformulated into ethanolic saline. RESULTS: Both [¹¹C]raclopride (3.7% RCY; >95% RCP; SA=20831 Ci/mmol; n=64) and [¹¹C]DASB, both with (3.0% RCY; >95% RCP; SA=15152Ci/mmol; n=9) and without (3.0% RCY; >95% RCP; SA=10931 Ci/mmol; n=3) sodium ascorbate, have been successfully prepared using the described methodology. Doses are suitable for human use and the described methods are now employed for routine clinical production of both radiopharmaceuticals at the University of Michigan. CONCLUSIONS: Ethanolic loop chemistry is a powerful technique for preparing [¹¹C]raclopride and [¹¹C]DASB, and we are in the process of adapting it for other carbon-11 radiopharmaceuticals prepared in our laboratories ([¹¹C]PMP, [¹¹C]PBR28 etc.).

Fully automated preparation of [11C]choline and [18F]fluoromethylcholine using TracerLab synthesis modules and facilitated quality control using analytical HPLC.

Modifications of a GE TracerLab FX(C-Pro), which can be implemented for solid-phase [(11)C]methylation are described. The simplified procedure for synthesis of [(11)C]choline uses a single Sep-Pak CM-Light cation-exchange cartridge for both solid-supported reaction and purification. Compared with the commonly used two Sep-Pak method, the low back-pressure of this Sep-Pak enables efficient and reliable production of [(11)C]choline using a TracerLab FX(C-Pro) without requirement for any gas pressure adjustment. Typical radiochemical yields (RCY) are >60%, radiochemical purity (RCP) is 99.9% and levels of residual precursor in the final product, which may inhibit the uptake of [(11)C]choline, are reduced to 1 µg/mL. Similarly, modification of a GE TracerLab FX(FN) is reported which enables gas-phase production of [(18)F]fluoromethylcholine, suitable for pre-clinical use, (in 4-6% RCY and >99.7% RCP) using a related Sep-Pak method. These modifications can be utilized for solid-phase [(11)C]methylation and [(18)F]fluoromethylation of other radiotracers, and allow straightforward switching to other module configurations for solution-phase radiochemistry or loop chemistry. In addition, we report a convenient HPLC ion chromatography method, which can monitor residual precursor and the radiochemical purity of product at the same time, providing highly efficient quality control for routine clinical application. The reported HPLC method is appropriate for analysis of doses of both [(11)C]choline and [(18)F]fluoromethylcholine, and eliminates the need for a GC method to determine residual precursor levels.