Molecular imaging of neuroendocrine tumors: Current applications and future trends

The prevalence of neuroendocrine neoplasms (NEN), which include neuroendocrine tumors (NET) and neuroendocrine carcinomas (NEC), has increasing during recent years. The approval of diagnostic single-photon emission computed tomography and positron emission tomography imaging agents for NEN is an important factor in pushing the development of additional agents using new targets to develop patient-specific, targeted, radiopharmaceuticals. Numerous NEN-specific targets exist, including somatostatin receptors, norepinephrine transport substrates, amino acid transport substrates, and glucagon-like peptide-1 receptor analogues, as well as non-specific targets, such as glucose metabolism. Additionally, there are targets that can be used in combination with current agents to further personalize NEN imaging. In well-differentiated gastroenteropancreatic NET, [⁶⁸Ga]DOTATATE is the first line agent. In pheochromocytoma, paraganglioma, and neuroblastomas [¹³¹I]MIBG can also be considered for imaging. [¹⁸F]FDOPA is mainly used for midgut NETs but is second line if access to [⁶⁸Ga]DOTATATE is difficult. In insulinomas, glucagon like peptide-1 receptor agents can be considered with [⁶⁸Ga]DOTATATE. In medullary thyroid carcinomas, [¹⁸F]FDOPA is preferred with or without [⁶⁸Ga]DOTATATE imaging. In poorly-differentiated NEN/NEC, non-specific agents such as [¹⁸F]Fluoro-2-deoxy-d-glucose and [⁶⁸Ga]fibroblast activation protein inhibitor-04 can be used if somatostatin imaging is insufficient. Urokinase plasminogen activator receptor targeting has been used as a method for risk stratification and can be used in combination with [⁶⁸Ga]DOTATATE. The use of somatostatin receptor antagonists, bombesin receptor 2, C-X-C motif chemokine receptor-4, and glucose-dependent insulinotropic polypeptide receptor agents are currently in development - with all of them requiring further studies to determine their potential utility. This review analyzes the current landscape of NEN imaging and discusses the emerging agents that can potentially contribute to NEN imaging in the future.