Developing 68Ga-Labeled Exendin(9-39) Derivatives for PET Imaging of Insulinomas.
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Glucagon-like peptide-1 receptor (GLP-1R) is overexpressed in >90% of insulinomas, making it an optimal target for imaging. However, current GLP-1R agonist tracers may induce side effects including hypoglycemia and nausea, particularly in pediatric patients. In this study, we employed a rational design approach combining molecular dynamics (MD) simulations with experimental validation to develop three 68Ga-labeled NOTA-conjugated exendin(9-39) derivatives featuring antagonist activity for safer imaging. MD simulations predicted differential binding affinities based on conjugation sites at Asp09 (E09), Lys12 (E12), and Lys27 (E27), with MM/GBSA calculations ranking E09 (-216.06 kcal/mol) > E12 (-200.01 kcal/mol) > E27 (-117.08 kcal/mol). Experimental validation through surface plasmon resonance confirmed these computational predictions, showing binding affinities consistent with the computational predictions. All radiotracers achieved radiochemical yields (>95%) and plasma stability (>91% intact after 120 min). In vivo PET imaging validated the computational hierarchy, with [68Ga]Ga-E09 demonstrating superior tumor uptake (SUVmax: 3.99 at 60 min) compared with E12 (SUVmax: 0.75 at 60 min) or E27 (undetectable). These findings highlight the power of combining computational screening with systematic experimental validation. In conclusion, [68Ga]Ga-E09 demonstrates superior binding affinity, cellular uptake, and imaging performance, suggesting its potential as a promising agent warranting further studies.