Comparison of [68Ga]Ga-HBED-CC-PEG6-Exendin-4 and [68Ga]Ga-HBED-CC-Exendin-4 PET/CT for Insulinoma Localization

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.