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Actinium-225 (²²⁵Ac) is one of the most promising radionuclides for targeted alpha therapy (TAT). With a half-life of 9.92 days and a decay chain that emits four high-energy α particles, ²²⁵Ac is well-suited for TAT when conjugated to macromolecular targeting vectors that exhibit extended in vivo circulation times. The implementation of ²²⁵Ac in these targeted constructs, however, requires a suitable chelator that can bind and retain this radionuclide in vivo. Previous work has demonstrated the suitability of a diaza-18-crown-6 macrocyclic chelator H₂macropa for this application. Building upon these prior efforts, in this study, two rigid variants of H₂macropa, which containmore » either one (H₂BZmacropa) or two (H₂BZ₂macropa) benzene rings within the macrocyclic core, were synthesized and investigated for their potential use for ²²⁵Ac TAT. The coordination chemistry of these ligands with La³⁺, used as a nonradioactive model for Ac³⁺, was carried out. Both NMR spectroscopic and X-ray crystallographic studies of the La³⁺ complexes of these ligands revealed similar structural features to those found for the related complex of H₂macropa. Thermodynamic stability constants of the La³⁺ complexes, however, were found to be 1 and 2 orders of magnitude lower than those of H₂macropa for H₂BZmacropa and H₂BZ₂macropa, respectively. The decrease in thermodynamic stability was rationalized via the use of density functional theory calculations. ²²⁵Ac radiolabeling and serum stability studies with H₂BZmacropa showed that this chelator compares favorably with H₂macropa. Based on these promising results, a bifunctional version of this chelator, H₂BZmacropa-NCS, was synthesized and conjugated to the antibody codrituzumab (GC33), which targets the liver cancer biomarker glypican-3 (GPC3). The resulting GC33-BZmacropa conjugate and an analogous GC33-macropa conjugate were evaluated for their ²²⁵Ac radiolabeling efficiencies, antigen-binding affinities, and in vivo biodistribution in HepG2 liver cancer tumor-bearing mice. Although both conjugates were comparably effective in their radiolabeling efficiencies, [²²⁵Ac]Ac-GC33-BZmacropa showed slightly poorer serum stability and biodistribution than [²²⁵Ac]Ac-GC33-macropa. Altogether, these results establish H2BZmacropa-NCS as a new bifunctional chelator for the preparation of ²²⁵Ac radiopharmaceuticals.« less

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–resistantmore » 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.« less