225 Ac-Macropatate: A Novel Alpha Particle Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors.

Neuroendocrine tumors (NETs) express Somatostatin Receptor-2 (SSTR2) and Somatostatin Receptor-5 (SSTR5). Modified variants of somatostatin, the cognate ligand for SSTR2/5, are used in treatment for metastatic and locoregional disease. Peptide receptor radionuclide therapy (PRRT) with Lu-Dotatate (DOTA-Octreotate), a beta particle-emitting somatostatin derivative, has demonstrated survival benefit in patients with SSTR+ NETs. Despite excellent results, a subset of patients has tumors that are resistant to treatment, and alternative agents are needed. Targeted alpha particle therapy (TAT) has been shown to kill tumors that are resistant to targeted beta-particle therapy, suggesting that TAT may offer a promising treatment option for patients with Lu -Dotatate resistant disease. While Dotatate can chelate the clinically relevant alpha particle-emitting radionuclide Ac, the labeling reaction requires high temperatures, and the resulting radioconjugate has suboptimal stability. Here, we design and synthesize Macropatate (Macropa-octreotate), a novel radioconjugate capable of chelating Ac at room temperature, and assess its in vitro and in vivo performance. Macropatate demonstrated comparable affinity to Dotatate (KD = 21 nM) in U2-OS-SSTR2, a SSTR2+ transfected cell line. Ac-Macropatate demonstrated superior serum stability at 37 °C over time compared to Ac-Dotatate. Biodistribution studies demonstrated higher tumor uptake of Ac-Macropatate relative to Ac-Dotatate in mice engrafted with subcutaneous H69 neuroendocrine tumors. Therapy studies showed that Ac-Macropatate exhibits significant antitumor and survival benefit compared to saline control in mice engrafted with SSTR+ tumors. However, the increased accumulation of Ac-Macropatate in liver and kidneys and subsequent toxicity to these organs decreased its therapeutic index compared to Ac-Dotatate. Ac-Macropatate and Ac-Dotatate exhibit favorable therapeutic efficacy in animal models. Because of elevated liver and kidney accumulation and lower administered activity for dose limiting toxicity of Ac-Macropatate, Ac-Dotatate was deemed the superior agent for TAT PRRT.