Overview of Upcoming PET Tracers and Radiotracers for Treatment in Neuroendocrine Tumors

Introduction: 1.) Review the current positron emission tomography (PET) radiotracers used to diagnose and treat neuroendocrine tumors (NETs) 2.) Identify the future directions for PET radiotracers used to visualize or treat NETs.

Methods: A comprehensive search using PubMed, Google Scholar, and Scopus search engines was conducted to identify relevant studies on the diagnosis and treatment of neuroendocrine tumors (NETs). This search included terms such as "neuroendocrine tumors," "peptide receptor radionuclide therapy," "PET/CT," and "α particle emitters." Studies were included if they were primary research articles that focused on the diagnosis or treatment of NETs, and the data was analyzed to identify trends in the use of various modalities for the diagnosis and treatment of NETs.

Results: NETs are a heterogenous group of neoplasms that most commonly originate in the small bowel, stomach, pancreas, or bronchopulmonary tree, and they often upregulate the somatostatin receptor (SSTR) on their surface. This receptor is used as a target for peptide receptor radionuclide therapy (PRRT), in which a somatostatin analog like Tyr³-octreotate (TATE) is chelated to a positron-emitting radiotracer, and the complex binds to the SSTR. The uptake of the decaying radiotracer can be visualized using PET. Radionuclide-labeled SSTR agonists such as ⁶⁸Ga-DOTA-TATE are the most commonly used tracers for visualizing tumors, while β^- particle emitting radiotracers such as ¹⁷⁷Lu-DOTA-TATE are used for treatment. To improve the diagnostic capability of PET in NETs, scientists are exploring options such as using SSTR antagonists and hybrid agonists, or using a different radionuclide altogether. Some studies have replaced the SSTR agonist ⁶⁸Ga-DOTA-TATE with antagonists such as ⁶⁸Ga-NODAGA-LM3 to improve NET detection by reducing the uptake in normal tissues. A prospective randomized, double-blind study found that the antagonist identified more lesions in 61% of patients compared to the agonist, especially when comparing liver lesions, which is a common location for metastases. Previous research has found similar results when comparing the antagonist ⁶⁸Ga-NODAGA-JR11 to the agonist ⁶⁸Ga-DOTA-TOC. Other studies have compared the uptake of ⁶⁸Ga-DOTA-TATE to that of ⁶⁸Ga-NOTA-3P-TATE-RGD, a dual SSTR and integrin ανβ₃-targeting tracer, and to ⁶⁴Cu-SAR-TATE, which uses a different radioactive particle. Both radiotracers showed a higher tumor-to-background ratio compared to ⁶⁸Ga-DOTA-TATE. When treating NETs, studies are looking to replace β^- particle emitters with α particle emitters like ²¹²Pb-DOTAM-TATE, which has been well tolerated in patients in a recent phase 1 study. α particles have a higher linear energy transfer to induce more DNA damage in tumor cells, and a shorter path length to reduce scattering and adverse side effects. Additionally, the α-emitter ²¹³Bi-DOTA-TOC has been shown to overcome resistance to β-emitters in patients with NETs that are refractory to ¹⁷⁷Lu-DOTA-TOC, with reduced hematological toxicity and long-lasting anti-tumor responses. α particles should continue to be studied in larger, randomized clinical trials to hopefully improve outcomes for patients with inoperable or metastatic NETs.

Conclusions: Neuroendocrine tumors (NETs) are commonly visualized and treated using peptide receptor radionuclide therapy (PRRT) with a somatostatin analog like Tyr³-octreotate (TATE) chelated to a positron-emitting radiotracer. While ⁶⁸Ga-DOTA-TATE is currently the preferred imaging modality, there is ongoing research to improve the visualization of NETs on PET scans, including the use of SSTR antagonists, hybrid agonists, and alternative radionuclides. β^- particle emitters like ¹⁷⁷Lu-DOTA-TATE are commonly used for treatment, but there is increasing interest in the use of α particle emitters, which seem to have improved targeting of NETs. Despite these advances, more research is needed to fully understand the potential of these techniques for diagnosis and treatment of NETs.