Molecules of 3-hydroxypyridin-2-one (dhpyH2) coordinate in an O,O′-chelating fashion or in a monodentate binding mode. Heteroleptic complex species M(dhpyH2)4L2n+ (M = Mn, Co, Ni; L = Cl, ROH, n = 0, ...2) with four monodentate equatorially ligated molecules of dhpyH2 are stabilized by a strong intramolecular hydrogen-bonding of aromatic molecules into a macrocycle resembling 16-crown ethers.
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Reactions of MCl2·nH2O (M = Mn, Co, Ni) and 3-hydroxypyridin-2-one (dhpyH2 = C5H5NO2) afforded novel molecular complexes MCl2(dhpyH2)4 (M = Mn (1), Co (3)) and binuclear Co2Cl2(µ-Cl)2(dhpyH2)2(MeCN)2 (4), as well as ionic complexes M(dhpyH2)4(ROH)2Cl2·2ROH (R = Et, M = Co (6), Ni (8); R = Me, M = Ni (9)), and Ni(dhpyH2)4(MeOH)2Cl2 (10). In addition, two cocrystals, namely MCl2(dhpyH2)4M(dhpyH2)4L2Cl2·S, (M = Mn, L = H2O, S = 4THF (2), M = Co, L = MeOH, S = 2MeOH (5)) were prepared. Single crystal X-ray analyses reveal two modes of 3-hydroxypyridin-2-one ligation; a chelate coordination to central cobalt ion in binuclear complex 4 and a monodentate coordination in complexes 1–3, 5, 6, 8–10. The monodentate coordination of four 3-hydroxypyridin-2-one molecules to central ion is favored due to the stabilization by strong intramolecular hydrogen bonds and formation of a macrocycle resembling 16-membered crown ethers. Coordination modes of 3-hydroxypyridin-2-one, ancillary ligands and solvate molecules determine connectivity patterns in crystal structures. Various hydrogen-bonding motifs and off-center parallel stacking arrangements of coordinated 3-hydroxypyridin-2-one molecules result in layered (4, 6, 8, 9) and 3D structures (1–3, 5, 10). Coordinated or free chloride ions are in some complexes the only (and in other complexes, prevailing) acceptors of intermolecular hydrogen bonds. A variety of D–H⋯Cl (D = O, N) geometries of hydrogen bonds in complexes is investigated. Chloride ions are in the majority of these complexes concomitantly engaged as acceptors in two hydrogen bonds, if coordinated to metal ions, and in three hydrogen bonds, if not ligated.
A novel octadentate 3-hydroxypyridin-2-one (2,3-HOPO) based di-macrocyclic ligand was evaluated for chelation of (89)Zr; subsequently, it was used as a bi-functional chelator for preparation of ...(89)Zr-labeled antibodies. Quantitative chelation of (89)Zr(4+) with the octadentate ligand forming (89)ZrL complex was achieved under mild conditions within 15 minutes. The (89)Zr-complex was stable in vitro in presence of DTPA, but a slow degradation was observed in serum. In vivo, the hydrophilic (89)Zr-complex showed prevalently renal excretion; and an elevated bone uptake of radioactivity suggested a partial release of (89)Zr(4+) from the complex. The 2,3-HOPO based ligand was conjugated to the monoclonal antibodies, HER2-specific trastuzumab and an isotypic anti-gD antibody, using a p-phenylene bis-isothiocyanate linker to yield products with an average loading of less than 2 chelates per antibody. Conjugated antibodies were labeled with (89)Zr under mild conditions providing the PET tracers in 60-69% yield. Despite the limited stability in mouse serum; the PET tracers performed very well in vivo. The PET imaging in mouse model of HER2 positive ovarian carcinoma showed tumor uptake of (89)Zr-trastuzumab (29.2 ± 12.9 %ID/g) indistinguishable (p = 0.488) from the uptake of positive control (89)Zr-DFO-trastuzumab (26.1 ± 3.3 %ID/g). In conclusion, the newly developed 3-hydroxypyridin-2-one based di-macrocyclic chelator provides a viable alternative to DFO-based heterobifunctional ligands for preparation of (89)Zr-labeled monoclonal antibodies for immunoPET studies.
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