²²⁵Ac-MACROPATATE: A Novel α-Particle Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors

Neuroendocrine tumors (NETs) express somatostatin receptors (SSTRs) 2 and 5. Modified variants of somatostatin, the cognate ligand for SSTR2 and SSTR5, are used in treatment for metastatic and locoregional disease. Peptide receptor radionuclide therapy with ¹⁷⁷Lu-DOTATATE (DOTA-octreotate), a β-particle–emitting somatostatin derivative, has demonstrated survival benefit in patients with SSTR-positive NETs. Despite excellent results, a subset of patients has tumors that are resistant to treatment, and alternative agents are needed. Targeted α-particle therapy has been shown to kill tumors that are resistant to targeted β-particle therapy, suggesting that targeted α-particle therapy may offer a promising treatment option for patients with ¹⁷⁷Lu-DOTATATE–resistant disease. Although DOTATATE can chelate the clinically relevant α-particle–emitting radionuclide ²²⁵Ac, the labeling reaction requires high temperatures, and the resulting radioconjugate has suboptimal stability. Methods: We designed and synthesized MACROPATATE (MACROPA-octreotate), a novel radioconjugate capable of chelating ²²⁵Ac at room temperature, and assessed its in vitro and in vivo performance. Results: MACROPATATE demonstrated comparable affinity to DOTATATE (dissociation constant, 21 nM) in U2-OS-SSTR2, a SSTR2-positive transfected cell line. ²²⁵Ac-MACROPATATE demonstrated superior serum stability at 37°C over time compared with ²²⁵Ac-DOTATATE. Biodistribution studies demonstrated higher tumor uptake of ²²⁵Ac-MACROPATATE than of ²²⁵Ac-DOTATATE in mice engrafted with subcutaneous H69 NETs. Therapy studies showed that ²²⁵Ac-MACROPATATE exhibits significant antitumor and survival benefit compared with saline control in mice engrafted with SSTR-positive tumors. However, the increased accumulation of ²²⁵Ac-MACROPATATE in liver and kidneys and subsequent toxicity to these organs decreased its therapeutic index compared with ²²⁵Ac-DOTATATE. Conclusion:²²⁵Ac-MACROPATATE and ²²⁵Ac-DOTATATE exhibit favorable therapeutic efficacy in animal models. Because of elevated liver and kidney accumulation and lower administered activity for dose-limiting toxicity of ²²⁵Ac-MACROPATATE, ²²⁵Ac-DOTATATE was deemed the superior agent for targeted α-particle peptide receptor radionuclide therapy.