Baier NF, Cieslik P, Rudolf H, Pretze M, Wängler B, Schirrmacher R, Greb L, Fricker G, Varga Z, Kovács A*, Wängler C* (2026) Macropa Scaffold Expansion for Actinium-225 Chelation: Synthetic Strategy, Labeling Kinetics, and Theoretical Calculations. Inorganic Chemistry, 65(18), 9769–9786.
DOI: 10.1021/acs.inorgchem.5c05424.
225Ac is a key α-emitter for targeted alpha therapy. Among available chelators, Macropa currently provides some of the most stable 225Ac complexes, yet the limited stability of [225Ac]Ac-Macropa indicates a further optimization potential. Here, we report the design and evaluation of a new Ac3+ chelator, coined Megapa, and assessed its suitability to produce stably labeled 225Ac-based radiopharmaceuticals using radiochemical and computational methods. Unexpectedly, Megapa showed poorer radiolabeling performance than Macropa, showing reduced 225Ac incorporation (80.2 ± 2.9% RCC vs quantitative labeling) across multiple conditions tested. In addition, [225Ac]Ac-Megapa displayed lower kinetic inertness than [225Ac]Ac-Macropa, with lower stability in human serum (45.8% intact after 7 days vs no detectable degradation) and substantially higher 225Ac release in La3+ challenge experiments (64.3% vs 0.7%). Thermodynamic stability studies supported these results, indicating a lower thermodynamic stability of La-Megapa compared to La-Macropa (log KLaL of 10.53 vs 13.90). To rationalize these findings, quantum chemical calculations were performed on the Ac3+ and La3+ complexes of Megapa and Macropa. The computed low-energy structures were closely analogous for both chelators, indicating that the differing radiochemical behavior is unlikely to arise from intrinsic metal-ligand bonding. Instead, solvation effects and solution-phase molecular interactions are the most probable contributors to the poorer performance of Megapa.
