Copper Complexes of New Benzodioxotetraaza Macrocycles with Potential Applications in Nuclear Medicine

Two novel benzodioxotetraaza macrocycles [2,9-dioxo-1,4,7,10-tetraazabicyclo[10.4.0]1,11-hexadeca-1(11),13,15-triene (H2L1) and 2,10-dioxo-1,4,8,11-tetraazabicyclo[11.4.0]1,12-heptadeca-1(12),14,16-triene (H2L2)] were synthesized by a [1 + 1] crablike cyclization. The protonation constants of both ligands were determined by 1H NMR
titration and by potentiometry at 25.0 °C in 0.10 M ionic strength in KNO3. The latter method was also used to
ascertain the stability constants of their copper(II) complexes. These studies showed that the CuL1 complex has
a much lower thermodynamic stability than the CuL2, and the H2L2 displays an excellent affinity for copper(II), due
to the good fit of copper(II) into its cavity. The copper complexes of the novel ligands were characterized by
electronic spectroscopy in solution and by crystal X-ray diffraction. These studies indicated that the copper center
in the CuL1 complex adopts a square−pyramidal geometry with the four nitrogen atoms of the macrocycle forming
the equatorial plane and a water molecule at axial position, and the copper in the CuL2 complex is square−planar.
Several labeling conditions were tested, and only H2L2 could be labeled with 67Cu efficiently (>98%) in mild conditions
(39 °C, 15 min) to provide a slightly hydrophilic radioligand (log D = −0.19 ±0.03 at pH 7.4). The in vitro stability
was studied in the presence of different buffers or with an excess of diethylenetriamine-pentaethanoic acid. Very
high stability was shown under these conditions for over 5 days. The incubation of the radiocopper complex in
human serum showed 6% protein binding.

通过[1+1]蟹状环合反应，成功合成了两种新型苯并二氧四氮杂大环（benzodioxotetraaza macrocycles）配体：2,9-二氧代-1,4,7,10-四氮杂双环[10.4.0]1,11-十六碳-1(11),13,15-三烯（H₂L₁）与2,10-二氧代-1,4,8,11-四氮杂双环[11.4.0]1,12-十七碳-1(12),14,16-三烯（H₂L₂）。采用质子核磁共振（¹H NMR）滴定法与电位滴定法，于25.0℃、0.10 M硝酸钾（KNO₃）离子强度条件下，测定了两种配体的质子化常数；其中电位滴定法同时被用于确定其铜(II)配合物的稳定常数。研究表明，CuL₁配合物的热力学稳定性远低于CuL₂；H₂L₂对铜(II)展现出优异的配位亲和力，这归因于铜(II)与其空腔尺寸高度适配。通过溶液电子光谱与单晶X射线衍射，对该类新型配体的铜配合物进行了结构表征。结果显示，CuL₁配合物中的铜中心采取四方锥配位构型：大环的四个氮原子构成赤道配位平面，轴向位置结合一个水分子；而CuL₂配合物中的铜中心则为平面正方形配位构型。对多种放射性标记条件进行了筛选，仅H₂L₂可在温和条件（39℃、15 min）下以高于98%的标记效率与铜-67（⁶⁷Cu）结合，得到亲水性略强的放射性配体（pH 7.4时log D = -0.19 ±0.03）。在不同缓冲液或过量二乙三胺五乙酸存在的体系中开展了体外稳定性考察，该放射性铜配合物在上述条件下可保持极高稳定性长达5天以上。将该放射性铜配合物与人血清孵育后，结果显示其蛋白结合率为6%。