The Second Nitrogen Fits: Development of Diazine-BasedMacrocyclic Chelators to Stably Bind Radionuclides Used in Targeted Alpha Therapy
8 affiliations
- 1Helmholtz-Zentrum Dresden-Rossendorf , Institute of Radiopharmaceutical Cancer Research, Bautzner Landstr. 400, D-01328Dresden, Germany.
- 2TU Dresden, School of Science, Faculty of Chemistry and Food Chemistry, D-01062Dresden, Germany.
- 3Helmholtz-Zentrum Dresden-Rossendorf, Institute of Resource Ecology, Bautzner Landstr. 400, D-0132Dresden, Germany.
- 4CERN, The European Organization for Nuclear Research , CH-1211Geneva, Switzerland.
- 5GIP ARRONAX, 1 Rue Aronnax, 44800Saint-Herblain, France.
- 6Subatech, UMR 6457, IMT Atlantique, CNRS/IN2P3, Nantes Université, 44307Nantes, France.
- 7National Center for Tumor Diseases (NCT), NCT/UCC Dresden, a partnership between DKFZ, University Hospital Carl Gustav Carus and Faculty of Medicine at TU Dresden, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), D-01307Dresden, Germany.
- 8German Cancer Consortium (DKTK), Partner Site Dresden, Fetscherstr. 74, D-01307Dresden, Germany.
Abstract
Identifying suitable chelators for 212Pb, 223Ra, and 225Ac and their diagnostic counterparts 131Ba, 133La, and 203Pb remains one of the major challenges in the development of radiopharmaceuticals for targeted alpha therapy. Four novel macrocyclic chelators containing the 2,4- and 2,6-pyrimidine moieties (pym-2,4 and pym-2,6), along with a combination thereof (pym-mix), as well as the pyrazine moiety (pazi), were synthesized and fully characterized. Protonation constants (pKa) were determined using 1H NMR spectroscopy. Stability constants (log K) for the complexes with La3+ (11.8-12.6), Ba2+ (10.1-10.3), and Pb2+ (15.3-15.5) are lower compared to macropa. However, pH-dependent binding affinities (pKd,M) with the novel chelators are higher for Ba2+ (8.7-8.9) and comparable or slightly lower for La3+ and Pb2+ at pH 6. DFT calculations enabled comprehensive elucidation of the molecular structures, facilitating in-depth analyses of the coordination environment. The determined 15N NMR chemical shifts of free chelators and complexes help to explain distinct complexation behavior. Finally, the novel chelators were radiolabeled with 131Ba, 223Ra, 133La, 225Ac, 203Pb, and 212Pb, and the radiochemical conversions were compared to results with macropa. All 223Ra complexes were incubated in human serum, pointing out an increased kinetic inertness and stability.
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BibTeX
@article{blei2026second,
title = {{The Second Nitrogen Fits: Development of Diazine-BasedMacrocyclic Chelators to Stably Bind Radionuclides Used in Targeted Alpha Therapy}},
author = {Magdalena K Blei and Lukas Waurick and Björn Drobot and Santiago A Brühlmann and Charlotte Duchemin and Edgars Mamis and Muhammad Inzamam and Thierry Stora and Nadia Audouin and Thomas Sounalet and Klaus Kopka and Thorsten Stumpf and Sven Stadlbauer and Jerome Kretzschmar and Constantin Mamat},
journal = {Inorg.Chem.},
year = {2026},
month = sep,
doi = {10.1021/acs.inorgchem.6c01646},
url = {https://hal.science/hal-05762844v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - The Second Nitrogen Fits: Development of Diazine-BasedMacrocyclic Chelators to Stably Bind Radionuclides Used in Targeted Alpha Therapy
AU - Magdalena K Blei
AU - Lukas Waurick
AU - Björn Drobot
AU - Santiago A Brühlmann
AU - Charlotte Duchemin
AU - Edgars Mamis
AU - Muhammad Inzamam
AU - Thierry Stora
AU - Nadia Audouin
AU - Thomas Sounalet
AU - Klaus Kopka
AU - Thorsten Stumpf
AU - Sven Stadlbauer
AU - Jerome Kretzschmar
AU - Constantin Mamat
PY - 2026
DA - 2026/09/01
JO - Inorg.Chem.
DO - 10.1021/acs.inorgchem.6c01646
UR - https://hal.science/hal-05762844v1
AB - Identifying suitable chelators for 212Pb, 223Ra, and 225Ac and their diagnostic counterparts 131Ba, 133La, and 203Pb remains one of the major challenges in the development of radiopharmaceuticals for targeted alpha therapy. Four novel macrocyclic chelators containing the 2,4- and 2,6-pyrimidine moieties (pym-2,4 and pym-2,6), along with a combination thereof (pym-mix), as well as the pyrazine moiety (pazi), were synthesized and fully characterized. Protonation constants (pKa) were determined using 1H NMR spectroscopy. Stability constants (log K) for the complexes with La3+ (11.8-12.6), Ba2+ (10.1-10.3), and Pb2+ (15.3-15.5) are lower compared to macropa. However, pH-dependent binding affinities (pKd,M) with the novel chelators are higher for Ba2+ (8.7-8.9) and comparable or slightly lower for La3+ and Pb2+ at pH 6. DFT calculations enabled comprehensive elucidation of the molecular structures, facilitating in-depth analyses of the coordination environment. The determined 15N NMR chemical shifts of free chelators and complexes help to explain distinct complexation behavior. Finally, the novel chelators were radiolabeled with 131Ba, 223Ra, 133La, 225Ac, 203Pb, and 212Pb, and the radiochemical conversions were compared to results with macropa. All 223Ra complexes were incubated in human serum, pointing out an increased kinetic inertness and stability.
SN - 0020-1669
SN - 1520-510X
ER -