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Published on: February 3, 2023
Developing 68Ga-Labeled Exendin(9-39) Derivatives for PET Imaging of Insulinomas
Tuo Li1, Linlin Li1, Yaping Luo1
1Department of Nuclear Medicine, State Key Laboratory of Common Mechanism Research for Major Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Hospital, Beijing 100730, China.
Abstract:
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.
Insights
Researchers developed a novel Gallium-68 labeled tracer, [68Ga]Ga-E09, for imaging glucagon-like peptide-1 receptor (GLP-1R) positive tumors. This safer antagonist tracer shows superior tumor uptake and binding affinity compared to previous agents.
Area of Science:
- Nuclear Medicine
- Radiopharmaceutical Chemistry
- Molecular Imaging
Background:
- Glucagon-like peptide-1 receptor (GLP-1R) is highly expressed in insulinomas, making it a key target for diagnostic imaging.
- Current GLP-1R agonist tracers can cause adverse effects like hypoglycemia, especially in pediatric patients.
Purpose of the Study:
- To design and develop novel, safer GLP-1R antagonist radiotracers for improved insulinoma imaging.
- To evaluate the performance of these new tracers using computational and experimental methods.
Main Methods:
- Utilized molecular dynamics (MD) simulations and MM/GBSA calculations to predict binding affinities of NOTA-conjugated exendin(9-39) derivatives.
- Synthesized and characterized three 68Ga-labeled derivatives (E09, E12, E27) with antagonist properties.
- Validated binding affinities using surface plasmon resonance (SPR) and assessed in vivo performance via PET imaging.
Main Results:
- MD simulations accurately predicted binding affinities, ranking E09 > E12 > E27.
- [68Ga]Ga-E09 exhibited significantly higher tumor uptake (SUVmax: 3.99) compared to E12 (SUVmax: 0.75) and E27 (undetectable) in PET imaging.
- All radiotracers demonstrated excellent radiochemical yields (>95%) and plasma stability (>91% intact).
Conclusions:
- The combination of computational screening and experimental validation is effective for developing novel radiotracers.
- [68Ga]Ga-E09 shows superior binding affinity, tumor uptake, and imaging characteristics, positioning it as a promising candidate for insulinoma imaging.
- This novel antagonist tracer offers a potentially safer alternative for patients, particularly children, undergoing GLP-1R targeted imaging.
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