Targeted radionuclide therapy and diagnostic imaging of SSTR positive neuroendocrine tumors: a clinical update in the new decade.

Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms characterized by their overexpression of somatostatin receptors (SSTRs), which can be utilized for peptide receptor radionuclide therapy. This review provides a comprehensive update on the clinical trials of radiolabeled SSTR-targeting radiopharmaceuticals since 2020, with a focus on somatostatin receptor agonists and antagonists radiolabeled with ⁶⁸Ga, ¹⁸F, ^99mTc, ¹⁷⁷Lu, ¹⁶¹Tb, ²¹²Pb, ⁶⁷Cu, and ²²⁵Ac. Head-to-head clinical trials demonstrate that radiolabeled SSTR antagonists such as [⁶⁸Ga]Ga-DOTA-JR11 and [⁶⁸Ga]Ga-DOTA-LM3 offer improved lesion detection and tumor-to-background ratios (particularly in liver metastases) compared to radiolabeled agonists like [⁶⁸Ga]Ga-DOTA-TOC and [⁶⁴Cu]Cu-DOTA-TATE. Additionally, ¹⁸F-labeled agents offer logistical and dosimetric advantages over ⁶⁸Ga, due to ¹⁸F's longer half-life and cyclotron production, allowing for delayed imaging and increased availability to a wider range of patients. Emerging targeted alpha therapy agents, including [²²⁵Ac]Ac-DOTA-TATE, show promising results in treating disease resistant to conventional therapies due to the high linear energy transfer of alpha particles, which leads to improved localized cytotoxicity. Collectively, these developments support a shift toward more precise, receptor-specific theragnostics, emphasizing the need for further head-to-head clinical trials and integration of dosimetry-driven, personalized treatment planning in the management of NETs.