Radiolabeled macrocyclic zinc complexes are more stable in serum than analogous copper compounds; an azacrown-derived cycle with five heteroatoms coordinates zinc, providing fast complexation and high in vivo stability.

Triacetate of 15-benzoazacrown-5 compound (H 3 BA3A) is a new ligand that has shown advantages towards chelation of some cations. In this paper H 3 BA3A was consequently studied for binding of lead cation. With respect to nuclear properties of 212 Pb radioisotope it can be used for therapy of various oncological diseases mainly due to alpha-emitting daughter radionuclide 212 Bi. Complexes of such radionuclides are considered as parts of targeted radiopharmaceuticals that can be conjugated with biomolecules to provide address delivery to cancerous tissues. Medical radionuclides are commonly short-lived and biomolecules are often heat-sensitive. That is why fast and stable complexation of trace amounts of lead cations in biologically relevant media without additional heating higher than 37 °C is important and challenging task. At the beginning we determined complexation constants in wide pH range including different protonated and hydrolyzed complex species via potentiometric titration technique. The obtained values are high enough for lead chelates logβ(BA3APb -) = 17.2 (1). Structural features of complex in aqueous solution were established due to 1 H and 13 C NMR spectroscopy. High resolution of obtained spectra and comparison with spectrum of deprotonated ligand shows presence of one rigid conformer of complexed form in the aqueous solution with C s symmetry. In order to study labelled compounds we used longer lived isotope of lead 210 Pb isolated from solution of 226 Ra. Using thin layer chromatography and gamma-spectrometry it was found that 100 μM of ligand is enough to completely chelate 210 Pb in the tracer concentration related to radiopharmaceutical concentration of 212 Pb. According to pH speciation obtained in complexation constant determination, pH 5.5-6 was selected for labelling experiments. Noteworthy, the labeled compound was obtained within 1-5 minutes at room temperature as well as upon heating at 90 o C. Macrocyclic H 3 BA3A demonstrates fast complexation apparently due to larger crown cavity compared to cyclen cavity in H 4 DOTA. This was indirectly shown in potentiometric titration where waiting time for curve's points was no longer than 5 minutes indicating that equilibrium was achieved within 5 minutes. In order to evaluate possible trans-chelation and transmetallation of complex in living organism we performed challenging experiments in static conditions: in presence of nine-fold excess of serum proteins, biologically relevant cations 5 mM Ca 2+ , 5 mM Mg 2+ , 0.1 mM Zn 2+ , 0.1 mM Cu 2+ , 0.1 mM Fe 3+ and isotonic solution of 0.15 M NaCl. It was shown that the 100 % intactness of complex can be kept for up to two days of incubation in competing media. Summarizing, the H 3 BA3A forms highly stable complex with lead cation not only in model solution, but also in presence of challenging agents. This stability is provided by high stability constants and rigid structure in solution.

A synthetic procedure for the synthesis of azacrown ethers with a combination of pendant arms has been developed and the synthesized ligand, characterized by various techniques, was studied. The prepared benzoazacrown ether with hybrid pendant arms and its complexes with copper and lead cations were studied in terms of biomedical applications. Similarly to a fully acetate analog, the new one binds both cations with close stability constants, despite the decrease in both constants. The calculated geometry of the complexes correlate with the data from X-ray absorption and NMR spectroscopy. Coordination of both cations differs due to the difference between the ionic radii. However, these chelation modes provide effective shielding of cations in both cases, that was shown by the stability of their complexes in the biologically relevant media towards transchelation and transmetallation.

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