H₂BZmacropa-NCS: A Bifunctional Chelator for Actinium-225 Targeted Alpha Therapy

Abstract

Ac) 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, 225 Ac is well-suited for TAT when conjugated to macromolecular targeting vectors that exhibit extended in vivo circulation times. The implementation of 225 Ac 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 H 2 macropa for this application. Building upon these prior efforts, in this study, two rigid variants of H 2 macropa, which contain either one (H 2 BZmacropa) or two (H 2 BZ 2 macropa) benzene rings within the macrocyclic core, were synthesized and investigated for their potential use for 225 Ac TAT. The coordination chemistry of these ligands with La 3+ , used as a nonradioactive model for Ac 3+ , was carried out. Both NMR spectroscopic and X-ray crystallographic studies of the La 3+ complexes of these ligands revealed similar structural features to those found for the related complex of H 2 macropa. Thermodynamic stability constants of the La 3+ complexes, however, were found to be 1 and 2 orders of magnitude lower than those of H 2 macropa for H 2 BZmacropa and H 2 BZ 2 macropa, respectively. The decrease in thermodynamic stability was rationalized via the use of density functional theory calculations. 225 Ac radiolabeling and serum stability studies with H 2 BZmacropa showed that this chelator compares favorably with H 2 macropa. Based on these promising results, a bifunctional version of this chelator, H 2 BZmacropa-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 225 Ac 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, [ 225 Ac]Ac-GC33-BZmacropa showed slightly poorer serum stability and biodistribution than [ 225 Ac]Ac-GC33-macropa. Together, these results establish H 2 BZmacropa-NCS as a new bifunctional chelator for the preparation of 225 Ac radiopharmaceuticals.

Insights into Actinium Complexes with Tetraacetates─AcBATA versus AcDOTA: Thermodynamic, Structural, and Labeling Properties

“…This explains the slight decrease in the difference between the ionic radii of actinium and lanthanum compared to those expected from the literature (0.06 Å vs 0.09 Å) . The chemical similarity ,, of La 3+ and Ac 3+ also proves the correctness of the results.…”

“…This explains the slight decrease in the difference between the ionic radii of actinium and lanthanum compared to those expected from the literature (0.06 Å vs 0.09 Å). 30 The chemical similarity 17,18,29 of La 3+ and Ac 3+ also proves the correctness of the results. The H 4 octapa ligand, like H 4 BATA, has four donor nitrogen atoms and four carboxyl oxygens coordinating lanthanum.…”

“…To test the applicability of the liquid extraction technique, first, we determined the stability constant of the complex of La 3+ with the H 4 BATA ligand. La 3+ is usually used in works where it is impossible to conduct an experiment with the trace amounts of Ac 3+ . ,,, The reason is that the Ac 3+ ion possesses chemical properties that are similar to that of the lanthanide and Ln 3+ ions. Specifically, lanthanum, La 3+ , is a suitable nonradioactive surrogate for the Ac 3+ ion .…”

“…La 3+ is usually used in works where it is impossible to conduct an experiment with the trace amounts of Ac 3+ . 17,18,23,29 The reason is that the Ac 3+ ion possesses chemical properties that are similar to that of the lanthanide and Ln 3+ ions. Specifically, lanthanum, La 3+ , is a suitable nonradioactive surrogate for the Ac 3+ ion.…”

Chelating Rare-Earth Metals (Ln3+) and 225Ac3+ with the Dual-Size-Selective Macrocyclic Ligand Py2-Macrodipa

“…The resistance to human serum for [ 225 Ac]Ac 3+ −macropa observed here is also consistent with prior studies. 15,30,53 Although the radiolabeling efficiency of py 2 -macrodipa is comparable to that of pymacrodipa, the kinetic stability of [ 225 Ac]Ac 3+ −py 2 -macrodipa is substantially enhanced relative to that of [ 225 Ac]Ac 3+ −pymacrodipa, which showed a ∼90% complex dissociation in human serum at 37 °C after 24 h. 15 This observation is also consistent with the DTPA transchelation challenge results (Table 2), which also revealed an overall higher Ln 3+ complex kinetic stability for py 2 -macrodipa. Collectively, py 2 -macrodipa shows promise for use with 225 Ac 3+ based on its efficient radiolabeling and high complex stability.…”