Comparison of radiolabeled somatostatin analogs (DOTATATE, DOTANOC, and DOTATOC) in somatostatin receptor (SSTR) imaging for gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs): a narrative literature review

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) present a diagnostic challenge due to their heterogeneous nature and varying somatostatin receptor (SSTR) expressions. Although rare, their incidence has increased with earlier detection, which can improve overall survival. Functional SSTR imaging, especially with radiolabeled somatostatin analogs like DOTATATE, DOTANOC, and DOTATOC, offers greater sensitivity and specificity than anatomic imaging. However, differences in pharmacokinetics and binding affinities among these radiotracers lead to variability in diagnostic performance and clinical utility. As theranostics becomes central to GEP-NEN management, standardizing radiotracer selection is essential for diagnostic consistency and personalized therapy. This review summarizes current literature on the comparative performance of the three most commonly used radiotracers in GEP-NEN imaging, covering their SSTR subtype affinities, diagnostic accuracy, biodistribution, dosimetry, and clinical impact. Among the radiotracers, DOTATOC is considered the most superior for functional imaging due to its broad affinity for SSTR2 and SSTR5, yielding the highest tumor-to-background ratio (TBR). In comparison, DOTANOC is less effective because its lower tumor uptake and slower clearance result in a reduced TBR. Although it binds to SSTR2, SSTR3, and SSTR5, the low expression of SSTR3 in GEP-NENs limits the advantage of DOTANOC broader receptor affinity. DOTATATE exhibits the highest tumor uptake but also shows higher normal tissue uptake, potentially reducing diagnostic performance. However, its better tumor-to-bone uptake ratio makes it effective for detecting bone lesions, and it is also suitable for peptide receptor radionuclide therapy (PRRT) due to its prolonged intracellular retention. The sensitivity and specificity of these radiotracers vary across studies, with comparable clinical impact and dosimetry, suggesting they may be used interchangeably. However, DOTATATE combines high SSTR2 affinity, strong cellular retention, and rapid clearance, making it effective for both imaging and therapy. Its widespread use simplifies tracer inventory and supports harmonization in radiotheranostics, particularly in light of recent FDA approvals and the evolving landscape of theranostic practices. PET/CT scans are recommended over SPECT/CT for GEP-NEN diagnosis due to their higher accuracy. Enhancements in diagnostic performance may be achieved by combining SSTR tracers with radionuclides like ⁶⁴Cu and ¹⁸F, using somatostatin antagonists as tracers, or employing dual-tracer protocols with ¹⁸F-FDG.