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

BACKGROUND

[C]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, [C]TGN-020 was synthesized through the acylation of [C]nicotinic acid, produced by the reaction of 3-bromopyridine and n-butyllithium with [C]CO, with 2-amino-1,3,4-thiadiazole. In this study, to enhance the automated radiosynthesis efficiency of [C]TGN-020, we optimized its radiosynthesis procedure using our in-house developed C-labeling synthesizer.

RESULTS

[C]TGN-020 was synthesized via direct [C]CO fixation using n-butyllithium and 3-bromopyridine in tetrahydrofuran, followed by treatment of lithium [C]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 [C]TGN-020, achieving a high radiochemical yield based on [C]CO (610‒1700 MBq, 2.8 ± 0.7%) at the end of synthesis (n = 12) and molar activity (A) 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 [C]TGN-020 with different A values were performed using healthy rats. The radioactive uptake of [C]TGN-020 with high A in the cerebral cortex was slightly higher than that with low A.

CONCLUSIONS

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