Macrocyclic Diamide Ligand Systems: Potential Chelators for 64Cu- and 68Ga-Based Positron Emission Tomography Imaging Agents

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• 作者：Peter J. Barnard ; Jason P. Holland ; Simon R. Bayly ; Thaddeus J. Wadas ; Carolyn J. Anderson ; Jonathan R. Dilworth
• 刊名：Inorganic Chemistry
• 出版年：2009
• 出版时间：August 3, 2009
• 年：2009
• 卷：48
• 期：15
• 页码：7117-7126
• 全文大小：875K
• 年卷期：v.48,no.15(August 3, 2009)
• ISSN：1520-510X

文摘

The N₄-macrocyclic ligand 2,10-dioxo-1,4,8,11-tetraazabicyclo[11.4.0]1,12-heptadeca-1(12),14,16-triene H₂L has been synthesized by the [1 + 1] condensation reaction between N,N′-bis(chloroacetyl)-1,2-phenylenediamine and 1,3-propylenediamine. The coordination chemistry of this ligand has been investigated with the metal ions Cu(II), Ni(II), Zn(II), and Ga(III) (complexes 1, 2, 3 and 4, respectively). H₂L and its metal complexes have been fully characterized by the use of NMR, UV/vis, electron paramagnetic resonance, and elemental analysis where appropriate. The four metal complexes 1−4 have been structurally characterized by X-ray crystallography which confirmed that in all cases the amide nitrogen atoms are deprotonated and coordinated to the metal center. Complexes 3 and 4 are five-coordinate with a water molecule and chloride ion occupying the apical site, respectively. Cyclic voltammetric measurements on complex 1 show that this complex is oxidized reversibly with a half-wave potential, E_1/2 = 0.47 V, and reduced irreversibly at E_P = −1.84 V. Density functional theory calculations reproduce the geometries of the four complexes. The one-electron reduction and oxidation potentials for 1 were calculated by using two solvent models, DMF and H₂O. The calculations indicated that the one electron oxidation of 1 may involve removal of an electron from the ligand as opposed to the metal center, producing a diradical. The diamide macrocyle is of interest for the development of new positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging agents, and a radiolabeled complex has been synthesized with the positron emitting isotope ⁶⁴Cu. In vivo biodistribution studies for the ⁶⁴Cu labeled complex, ⁶⁴Cu-1, in male Lewis rats, showed that the activity is cleared rapidly from the blood within 1−2 h post-administration.