Abstract View

Objectives: (R)-[¹⁸F]MeFAMP is a clinically significant non-natural amino acid PET imaging agent targeting system A transport. While its automated radiosynthesis was originally established on a legacy GE TracerLab FXFN module, expanding its clinical accessibility requires migration to modern automation systems and overcoming upstream synthetic bottlenecks. This study reports process optimizations for both the MeFAMP cyclic sulfamidate precursor and its reference standard to address historical reproducibility issues, alongside the successful transfer of the fully automated, GMP-compliant radiosynthesis onto a Synthra RN Plus platform.

Methods: The automated synthesis sequence was reconfigured and programmed for the Synthra RN Plus module. To resolve reproducibility failures, the multi-step organic synthesis of the cyclic sulfamidate precursor (TH-I-17) and cold reference standard (TH-I-45) were systematically overhauled. For precursor synthesis, the work-up of the intermediate (TH-I-4) was modified to ensure complete acidification at pH ≤ 2, eliminating upstream acid–base carryover that previously hindered the esterification Step to TH-I-6. Additionally, a NaHCO₃ wash was introduced post N-methylation step to quench and fully remove residual dimethyl sulfate (Me₂SO₄). For the reference standard synthesis, a column chromatography purification step was introduced after the ring-opening/fluorination step to isolate TH-I-43 as a clean solid rather than an oily material, thereby preventing the physical coating of NaH and ensuring efficient methylation step to TH-I-44, which also successfully eliminated DMF carryover into the final product (TH-I-45).

Results: Automated radiosynthesis sequences on the Synthra RN Plus module were successfully established and operational. Upstream process controls led to marked improvements in batch-to-batch reproducibility: the yield of the key intermediate TH-I-6 was stabilized, significantly reducing the batch variability and trace impurities; the 4.0 ppm NMR impurity (Me₂SO₄) in the final precursor (TH-I-17) was successfully removed. For the standard, robust conversion was achieved during methylation, and the final reference standard (TH-I-45) was delivered at a high yield (95%) completely free of DMF contamination. On the new Synthra module, (R)-[¹⁸F]MeFAMP was successfully produced in 10–12% decay-corrected radiochemical yield with a radiochemical purity of >99% within a total radiosynthesis time of 80 min (including semi-preparative HPLC purification). The production framework has been designed to meet current Good Manufacturing Practice (GMP) standards. Currently, the system is undergoing late-stage technical evaluation; stabilizing the analytical HPLC column equilibration to resolve time-dependent retention time drift remains under ongoing optimization prior to full GMP validation.

Conclusions: Critical synthetic and process-related issues affecting the MeFAMP precursor and reference standard were resolved, enabling improved batch-to-batch reproducibility and successful implementation of the automated radiosynthesis on the Synthra RN Plus platform. Remaining optimization efforts are currently focused on improving analytical HPLC retention time consistency prior to final GMP validation.