Synthesis of C-14 labeled Rac-(3R,2S)-glycopyrronium bromide

Area of Science:

• Medicinal Chemistry
• Radiochemistry
• Pharmacokinetics

Background:

• Glycopyrronium bromide is a muscarinic acetylcholine receptor antagonist.
• Understanding its drug metabolism and pharmacokinetics (DMPK) is crucial for clinical applications.
• A radiolabeled isotopologue is necessary for detailed DMPK studies.

Purpose of the Study:

• To synthesize a C-14 labeled isotopologue of glycopyrronium bromide.
• To investigate the DMPK properties of glycopyrronium bromide.
• To obtain the specific enantiomers of the radiolabeled compound.

Main Methods:

• A five-step synthetic route was employed starting from Cu¹⁴ CN.
• Radiolabeling was achieved using C-14.
• Chiral chromatography was used for enantiomeric separation and purification.

Main Results:

• The synthesis yielded an overall radiochemical yield of 5%.
• An unexpected decarboxylation of phenylglyoxylate occurred during synthesis, impacting yield.
• The desired pair of enantiomers of [¹⁴ C]-glycopyrronium bromide were successfully isolated.

Conclusions:

• A feasible synthetic route for C-14 labeled glycopyrronium bromide was established.
• The study highlights synthetic challenges, such as decarboxylation, in radiolabeling.
• Chiral chromatography proved effective for isolating enantiomerically pure radiolabeled glycopyrronium bromide for DMPK studies.