Investigation of the complexation of natZr(IV) and 89Zr(IV) by hydroxypyridinones for the development of chelators for PET imaging applications
Investigation of the complexation of natZr(IV) and 89Zr(IV) by hydroxypyridinones for the development of chelators for PET imaging applications
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DOI：
10.1039/c6dt04625h
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发表时间：
2017-04-14
影响因子：
4
通讯作者：
Brechbiel, M. W.
中科院分区：
文献类型：
--
作者：
Guerard, F.;Beyler, M.;Brechbiel, M. W.
研究了3种羟基吡啶酮（HOPO）的位置异构体- 1,2-HOPO （(LH)- h -1）及其水溶性类似物（(LH)- h -1′）、3,2-HOPO （(LH)- h -2）和3,4-HOPO （(LH)- h -3）与Zr（IV）的络合作用。电位和紫外可见光谱研究表明，与Zr(L-2)(4)和Zr(L-3)(4)相比，Zr（L-1’）(4)的形成具有更高的热力学稳定性，并且在与放射性示踪剂浓度为Zr-89的EDTA或Fe3+的竞争研究中具有更高的动力学惰性。除了与(LH)-H-2和(LH)-H-3 （pK(a)分别= 8.83和9.55）相比，H-L1或(LH)-H-1′（pK(a) = 5.01）具有较低的pK(a)外，Zr（L-1′）(4)具有较高的稳定性，部分原因是在螯合氧旁边存在酰胺基团，诱导了分子内氢键和酰胺/ π相互作用，这是通过x射线晶体学观察和量子化学计算证实的。结果表明，1,2- hopo L-1′具有最佳的Zr（IV）络合性能。然而，如果适当调整3,2- hopo和3,4- hopo模式，例如在1,2- hopo配体中添加酰胺基团，也可能成为设计具有改进特性的Zr（IV）螯合剂的有趣选择，用于Zr-89的核成像应用。
Three hydroxypyridinone (HOPO) positional isomers - 1,2-HOPO ((LH)-H-1) and its water soluble analogue ((LH)-H-1'), 3,2-HOPO ((LH)-H-2) and 3,4-HOPO ((LH)-H-3) have been investigated for the complexation of Zr(IV). Potentiometric and UV-Vis spectrometric studies show a higher thermodynamic stability for the formation of Zr(L-1')(4) in comparison with Zr(L-2)(4) and Zr(L-3)(4) as well as a higher kinetic inertness in competition studies with EDTA or Fe3+ at a radiotracer concentration with Zr-89. Besides the low pK(a) of H-L1 or (LH)-H-1' (pK(a) = 5.01) in comparison with (LH)-H-2 and (LH)-H-3 (pK(a) = 8.83 and 9.55, respectively), the higher stability of Zr(L-1')(4) can be attributed in part to the presence of the amide group next to the chelating oxygen that induces intramolecular H-bond and amide/pi interactions that were observed by X-ray crystallography and confirmed by quantum chemical calculations. The data presented here indicate that the 1,2-HOPO L-1' exhibits the best characteristics for Zr(IV) complexation. However, 3,2-HOPO and 3,4-HOPO patterns, if appropriately tuned, for instance with the addition of an amide group as in the 1,2-HOPO ligand, may also become interesting alternatives for the design of Zr(IV) chelators with improved characteristics for applications in nuclear imaging with Zr-89.