2025 DMDG | 51st Open Meeting: Shaping the future of DMPK

GLP-1 receptor agonists, including mono-, dual-, and triple-receptor analogs engineered through sequence and fatty acid chain modifications, have gained significant momentum in treating type 2 diabetes and obesity. Understanding the absorption, distribution, metabolism, and excretion (ADME) of these large peptides (3,000~6,000 Da) necessitates radiolabeling techniques.

14C is the preferred isotope for GLP-1 analogs, consistent with clinical requirements. However, their low administered doses (0.15~3 mg/kg) demand high specific activity (~200 mCi/mmol). Prolonged half-lives further complicate ADME studies: excretion profiling and quantitative whole-body autoradiography (QWBA) often require >30 days of urine, feces, and carcass collection. Metabolite identification in excreta, bile, and plasma is particularly challenging due to catabolic pathways (e.g., β-oxidation of fatty acid moieties) beyond amide hydrolysis.

This presentation will detail:

1. Radiolabelling synthesis strategies for linear and cyclic GLP-1 peptides.

2. Complete excretion recovery methodologies in rodents and non-human primates.

3. Key metabolite profiling/identification of modified amino acids and fatty acid chains, supported by case studies.