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 K_LaL 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.