Efficient one-pot radiosynthesis of the 11C-labeled aquaporin-4 inhibitor TGN-020

Abstract

Background

[¹¹C]TGN-020 has been developed as a positron emission tomography (PET) tracer for imaging aquaporin-4 (AQP4) in the brain and used in clinical studies. Previously, [¹¹C]TGN-020 was synthesized through the acylation of [¹¹C]nicotinic acid, produced by the reaction of 3-bromopyridine and n-butyllithium with [¹¹C]CO₂, with 2-amino-1,3,4-thiadiazole. In this study, to enhance the automated radiosynthesis efficiency of [¹¹C]TGN-020, we optimized its radiosynthesis procedure using our in-house developed ¹¹C-labeling synthesizer.

Results

[¹¹C]TGN-020 was synthesized via direct [¹¹C]CO₂ fixation using n-butyllithium and 3-bromopyridine in tetrahydrofuran, followed by treatment of lithium [¹¹C]nicotinic acetate with isobutyl chloroformate and subsequent acylation with 2-amino-1,3,4-thiadiazole in the presence of N,N-diisopropylethylamine. The optimized process significantly improved the radiosynthesis efficiency of [¹¹C]TGN-020, achieving a high radiochemical yield based on [¹¹C]CO₂ (610‒1700 MBq, 2.8 ± 0.7%) at the end of synthesis (n = 12) and molar activity (A_m) of 160–360 GBq/μmol at the end of synthesis (n = 5). The radiosynthesis time and radiochemical purity were approximately 60 min and > 95% (n = 12), respectively. PET studies based on [¹¹C]TGN-020 with different A_m values were performed using healthy rats. The radioactive uptake of [¹¹C]TGN-020 with high A_m in the cerebral cortex was slightly higher than that with low A_m.

Conclusions

[¹¹C]TGN-020 with high A_m was obtained in reproducible radiochemical yield. Overall, the proposed optimization process for the radiosynthesis of [¹¹C]TGN-020 can facilitate its application as a PET radiopharmaceutical for clinical use.