An interventional study of [68Ga]Ga-HBED-CC-PEG6-exendin-4 PET/CT and [68Ga]Ga-HBED-CC-exendin-4 PET/CT in Insulinoma, sponsored by Peking Union Medical College Hospital. Recruiting at 1 site in China. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2026-09-09.
Sponsored by Peking Union Medical College Hospital · Not applicable, Interventional, and Diagnostic
This clinical research evaluates a new PET/CT imaging agent, [68Ga]Ga-HBED-CC-PEG6-exendin-4, for localizing insulinoma, a rare pancreatic tumor that causes severe low blood sugar. Insulinomas are often small and hard to detect with regular CT, ultrasound or standard PET scans. This new tracer targets GLP1R, a protein highly expressed on insulinoma cells, with polyethylene glycol (PEG6) modification to improve tumor uptake and image contrast compared with the earlier similar agent [68Ga]Ga-HBED-CC-exendin-4.
The investigators plan to enroll 20 adult patients suspected of or confirmed to have insulinoma. All participants will receive two free PET/CT scans within one week: one with the new PEG6-modified tracer and one with the original tracer. The first 3 participants will also get dynamic PET scanning to analyze drug distribution and radiation dose in the human body. Within one month after imaging, patients will undergo surgery or biopsy to get pathological results, which serve as the gold standard to calculate and compare the diagnostic accuracy of the two tracers.
All imaging procedures follow standard clinical protocols with safe, low radiation doses within national diagnostic limits. Minor possible risks include slight pain or mild allergic reaction at the injection site; rare side effects related to exendin-4 may occur at a rate below 5%, and the research team has full emergency management measures ready. Participants can withdraw from the study at any time without penalty. All scan fees are covered by the research project, and each subject will receive a formal imaging report for clinical reference. The findings of this trial will help develop a more accurate imaging tool to precisely locate insulinoma and guide surgical treatment.
Insulinoma is the most common cause of endogenous hyperinsulinemic hypoglycemia in adults. Most lesions are benign but typically small (1-2 cm), leading to poor detection sensitivity for conventional cross-sectional imaging including abdominal ultrasound and routine CT, which frequently fails to pinpoint tiny tumor foci. Incomplete resection results in persistent hypoglycemic symptoms and poor quality of life, creating an urgent clinical demand for sensitive, noninvasive localization modalities.
Glucagon-like peptide-1 receptor (GLP-1R) is abundantly overexpressed on benign insulinoma cells at levels approximately five times higher than normal pancreatic beta cells, making it an ideal molecular target for positron emission tomography. Earlier GLP-1R-targeted radiotracers such as [68Ga]Ga-NOTA-exendin-4 require high-temperature heating and post-labeling purification, limiting routine clinical deployment. The precursor probe [68Ga]Ga-HBED-CC-exendin-4 can be synthesized under mild conditions without purification but still presents relatively high physiological renal uptake that may obscure lesions adjacent to the kidney.
To further optimize pharmacokinetic behavior, a PEG6 linker was conjugated to the HBED-CC-exendin-4 scaffold to generate the novel radiotracer [68Ga]Ga-HBED-CC-PEG6-exendin-4. Preclinical mouse biodistribution and microPET experiments demonstrated significantly higher pancreatic and insulinoma tumor uptake, longer intralesional tracer retention, and an improved pancreas-to-kidney ratio relative to the non-PEGylated counterpart, which is expected to enhance lesion conspicuity on clinical PET/CT. Competitive blocking assays verified that tumor signal originates from specific GLP-1R binding. This novel radiopharmaceutical meets compendial standards for sterility and bacterial endotoxin and maintains high radiochemical purity for two physical half-lives after formulation.
This single-center prospective comparative trial will recruit 20 subjects aged 18-70 years with suspected or pathologically verifiable insulinoma. Eligible participants complete two radiotracer PET/CT examinations within a 7-day window at no personal cost: one using the PEG6-modified investigational agent and one using the original [68Ga]Ga-HBED-CC-exendin-4 reference tracer. The initial three enrolled subjects additionally undergo dynamic PET acquisition to generate human pharmacokinetic parameters and internal radiation dosimetry estimates. Baseline laboratory tests, clinical history, and prior imaging data are collected before radiotracer injection. All participants receive surgical resection or biopsy within 30 days of scanning to obtain histopathological confirmation, the reference standard for diagnostic performance calculation.
Two independent experienced nuclear medicine physicians conduct blinded visual and semi-quantitative image analysis, measuring SUV values and tumor-to-background ratios for each tracer. Primary endpoints include comparative diagnostic sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the two PET agents for insulinoma localization. Secondary endpoints encompass human in vivo biodistribution, radiation dosimetry, and qualitative differences in tumor visualization and background interference.
All radiotracer administrations and PET/CT acquisitions adhere to standardized institutional operating procedures with radiation exposure within permissible diagnostic limits. Study staff monitor participants throughout imaging for adverse events related to intravenous injection or exendin-4-mediated effects, with standardized supportive protocols available for symptom management. Participants retain full voluntary withdrawal rights at any stage without impact on routine clinical care. All identifiable personal data are de-identified for analysis and long-term secure storage. Outcomes will be disseminated via peer-reviewed scientific publications to establish the clinical utility of PEG6-modified GLP-1R PET as an improved localization tool for insulinoma and guide surgical planning for hypoglycemic patients.
Exclusion Criteria:
All enrolled subjects receive two PET/CT scans within a 7-day interval at no cost. The first scan uses the investigational radiotracer \[68Ga\]Ga-HBED-CC-PEG6-exendin-4, and the second scan uses the reference tracer \[68Ga\]Ga-HBED-CC-exendin-4, or vice versa. The first 3 participants will additionally undergo dynamic PET/CT acquisition to calculate human pharmacokinetic parameters and internal radiation dosimetry. Baseline clinical history, laboratory tests and prior imaging data are collected before tracer injection. All subjects will receive surgical resection or biopsy within 30 days after imaging to obtain histopathological results as the reference standard. Two independent nuclear medicine physicians perform blinded visual and semi-quantitative analysis of all PET/CT images to compare the diagnostic performance of the two GLP-1R-targeted radiotracers for insulinoma localization.
Diagnostic Test: [68Ga]Ga-HBED-CC-PEG6-exendin-4 PET/CT · Diagnostic Test: [68Ga]Ga-HBED-CC-exendin-4 PET/CT
Investigational GLP-1R-targeted radiopharmaceutical modified with a PEG6 linker. Synthesized under mild 50 °C, 5 min one-step radiolabeling without purification, with radiochemical purity \>95% for up to two half-lives. Intravenous dose 1-4 mCi for whole-body PET/CT. The first 3 enrolled subjects receive dynamic PET acquisition to calculate human pharmacokinetic profiles and internal organ radiation dosimetry. Preclinical data confirmed elevated pancreatic and insulinoma uptake and improved pancreas-to-kidney ratio compared with non-PEGylated reference tracer.
Also known as: 68Ga-HBED-CC-PEG6-exendin-4
Reference GLP-1R-targeted radiopharmaceutical without PEG6 modification, serving as the control agent for head-to-head comparison. Prepared via one-step mild radiolabeling with no purification needed. Intravenous injection of 1-4 mCi followed by standard static PET/CT, completed within 7 days before or after the investigational tracer scan in each subject. Exhibits relatively higher renal background uptake that may interfere with visualization of left peri-renal insulinoma lesions. No dynamic PET acquisition is performed for this reference tracer.
Also known as: 68Ga-HBED-CC-exendin-4
Diagnostic performance comparison between two GLP-1R PET tracers for insulinoma localization
sensitivity of \[68Ga\]Ga-HBED-CC-PEG6-exendin-4 and \[68Ga\]Ga-HBED-CC-exendin-4 PET/CT.
Time frame: Up to 2 months after subjects complete both PET/CT scans and obtain pathological biopsy/surgical results
Diagnostic performance comparison between two GLP-1R PET tracers for insulinoma localization
specificity of \[68Ga\]Ga-HBED-CC-PEG6-exendin-4 and \[68Ga\]Ga-HBED-CC-exendin-4 PET/CT.
Time frame: Up to 2 months after subjects complete both PET/CT scans and obtain pathological biopsy/surgical results
Diagnostic performance comparison between two GLP-1R PET tracers for insulinoma localization
accuracy of \[68Ga\]Ga-HBED-CC-PEG6-exendin-4 and \[68Ga\]Ga-HBED-CC-exendin-4 PET/CT.
Time frame: Up to 2 months after subjects complete both PET/CT scans and obtain pathological biopsy/surgical results
Diagnostic performance comparison between two GLP-1R PET tracers for insulinoma localization
PPV of \[68Ga\]Ga-HBED-CC-PEG6-exendin-4 and \[68Ga\]Ga-HBED-CC-exendin-4 PET/CT.
Time frame: Up to 2 months after subjects complete both PET/CT scans and obtain pathological biopsy/surgical results
Diagnostic performance comparison between two GLP-1R PET tracers for insulinoma localization
NPV of \[68Ga\]Ga-HBED-CC-PEG6-exendin-4 and \[68Ga\]Ga-HBED-CC-exendin-4 PET/CT.
Time frame: Up to 2 months after subjects complete both PET/CT scans and obtain pathological biopsy/surgical results
Comparison of tumor-to-background ratios of the two GLP-1R radiotracers
Measure lesion SUV, tumor-to-background ratio (TBR) on PET/CT images of \[68Ga\]Ga-HBED-CC-PEG6-exendin-4 and reference tracer to compare image contrast and background interference.
Time frame: Within 2 months after completion of two PET/CT scans and pathological confirmation
Comparison of renal uptake of the two GLP-1R radiotracers
Measure renal semi-quantitative uptake on PET/CT images of \[68Ga\]Ga-HBED-CC-PEG6-exendin-4 and reference tracer to compare image contrast and background interference.
Time frame: Within 2 months after completion of two PET/CT scans and pathological confirmation
Area under plasma radioactivity concentration-time curve (AUC0-t)
Dynamic PET data from the first 3 participants are used to calculate in vivo biodistribution parameters and organ radiation absorbed dose of the PEG6-modified investigational tracer.
Time frame: Within 2 months after dynamic PET acquisition of the first three subjects
Internal radiation dosimetry of [68Ga]Ga-HBED-CC-PEG6-exendin-4
Dynamic PET data from the first 3 participants are used to calculate in vivo biodistribution parameters and organ radiation absorbed dose of the PEG6-modified investigational tracer.
Time frame: Within 2 months after dynamic PET acquisition of the first three subjects
Plan to share: No — Individual participant data (IPD) will not be shared publicly. This study involves sensitive clinical imaging data, laboratory test results and personal medical information of patients, which is protected by institutional privacy management regulations and relevant medical data confidentiality requirements. In addition, the investigational radiotracer is still under exploratory clinical evaluation, and complete raw IPD contains unvalidated proprietary research data not suitable for external open dissemination. Study-related aggregate summary results will be published in peer-reviewed academic journals upon trial completion to realize public scientific disclosure.
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Peking Union Medical College Hospital