Synthesis and preclinical evaluation of [11C]sotagliflozin: the first carbon-11 labelled dual SGLT1/2 inhibitor for PET imaging
Abstract
Abstract Background Sotagliflozin, a potent dual inhibitor of sodium-glucose co-transporters 1 and 2 (SGLT1/2), is the first FDA-approved SGLT inhibitor for the comprehensive management of heart failure. To elucidate its systemic pharmacokinetics and target engagement, we developed [ 11 C]sotagliflozin, the carbon-11 labeled isotopologue able to serve as a direct translational tool to map the in vivo biodistribution and molecular interactions of the parent drug using positron emission tomography/computed tomography (PET/CT). Results [ 11 C]sotagliflozin was efficiently synthesized via 11 C-methylation, yielding a decay-corrected radiochemical yield (RCY) of (66 ± 5)% within 30 minutes. The tracer exhibited high radiochemical purity (RCP) (99 ± 1)% and molar activity (MA) of 62 ± 5 GBq/µmol. HPLC analysis confirmed its robust in vitro stability in both saline and plasma for up to 120 minutes. Dynamic microPET/CT imaging in mice demonstrated high-contrast tracer accumulation in the renal cortex, liver, and gastrointestinal tract, reflecting the primary expression sites of SGLT1/2. Radio-metabolite profiling confirmed the presence of parent compound in the target organs alongside other metabolites derived from glucuronidation or oxidation reactions. Conclusion The radiosynthesis of [ 11 C]sotagliflozin is efficient, yielding high RCY, RCP, and moderate MA. The tracer exhibits excellent in vitro stability in both saline and plasma. In vivo evaluation confirmed a biodistribution…
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