The Second Nitrogen Fits: Development of Diazine-Based Macrocyclic Chelators to Stably Bind Radionuclides Used in Targeted Alpha Therapy

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.