Ac-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 Lu-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 Lu-DOTATATE-resistant disease. Although DOTATATE can chelate the clinically relevant α-particle-emitting radionuclide Ac, the labeling reaction requires high temperatures, and the resulting radioconjugate has suboptimal stability. We designed and synthesized MACROPATATE (MACROPA-octreotate), a novel radioconjugate capable of chelating Ac at room temperature, and assessed its in vitro and in vivo performance. MACROPATATE demonstrated comparable affinity to DOTATATE (dissociation constant, 21 nM) in U2-OS-SSTR2, a SSTR2-positive transfected cell line. Ac-MACROPATATE demonstrated superior serum stability at 37°C over time compared with Ac-DOTATATE. Biodistribution studies demonstrated higher tumor uptake of Ac-MACROPATATE than of Ac-DOTATATE in mice engrafted with subcutaneous H69 NETs. Therapy studies showed that Ac-MACROPATATE exhibits significant antitumor and survival benefit compared with saline control in mice engrafted with SSTR-positive tumors. However, the increased accumulation of Ac-MACROPATATE in liver and kidneys and subsequent toxicity to these organs decreased its therapeutic index compared with 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 targeted α-particle peptide receptor radionuclide therapy.