Macropa scaffold expansion for actinium-225 chelation: a synthetic strategy, labeling kinetics, and theoretical calculations
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+ chela...
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| Autori principali: | , , , , , , , , , , |
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| Natura: | Article (Journal) |
| Lingua: | inglese |
| Pubblicazione: |
April 29, 2026
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| In: |
Inorganic chemistry
Year: 2026, Pages: A-R |
| ISSN: | 1520-510X |
| DOI: | 10.1021/acs.inorgchem.5c05424 |
| Accesso online: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1021/acs.inorgchem.5c05424
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| Note sull'autore: | Nils F. Baier, Patrick Cieslik, Henning Rudolf, Marc Pretze, Björn Wängler, Ralf Schirrmacher, Lutz Greb, Gert Fricker, Zoltán Varga, Attila Kovács, and Carmen Wängler |
| Riassunto: | 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. |
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| Descrizione del documento: | Gesehen am 07.05.2026 |
| Descrizione fisica: | Online Resource |
| ISSN: | 1520-510X |
| DOI: | 10.1021/acs.inorgchem.5c05424 |