Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, British Columbia V6T 2A3, Canada.
Inorg Chem. 2020 Apr 20;59(8):5728-5741. doi: 10.1021/acs.inorgchem.0c00509. Epub 2020 Apr 3.
[Sc]Sc, [Ga]Ga, and [In]In are the three most attractive trivalent smaller radiometalnuclides, offering a wide range of distinct properties (emission energies and types) in the toolbox of nuclear medicine. In this study, all three of the metal ions are successfully chelated using a new oxine-based hexadentate ligand, Hglyox, which forms thermodynamically stable neutral complexes with exceptionally high pM values [pIn (34) > pSc (26) > pGa (24.9)]. X-ray diffraction single crystal structures with stable isotopes revealed that the ligand is highly preorganized and has a perfect fit to size cavity to form [Sc(glyox)(HO)] and [In(glyox)(HO)] complexes. Quantitative radiolabeling with gallium-68 (RCY > 95%, [L] = 10 M) and indium-111 (RCY > 99%, [L] = 10 M) was achieved under ambient conditions (RT, pH 7, and 15 min) with very high apparent molar activities of 750 MBq/μmol and 650 MBq/nmol, respectively. Preliminary quantitative radiolabeling of [Sc]ScCl (RCY > 99%, [L] = 10 M) was fast at room temperature (pH 7 and 10 min). experiments revealed exceptional stability of both [Ga]Ga(glyox) and [In]In(glyox) complexes against human serum (transchelation <2%) and its suitability for biological applications. Additionally, on chelation with metal ions, Hglyox exhibits enhanced fluorescence, which was employed to determine the stability constants for Sc(glyox) in addition to the in-batch UV-vis spectrophotometric titrations; as a proof-of-concept these complexes were used to obtain fluorescence images of live HeLa cells using Sc(glyox) and Ga(glyox), confirming the viability of the cells. These initial investigations suggest Hglyox to be a valuable chelator for radiometal-based diagnosis (nuclear and optical imaging) and therapy.
[Sc]Sc、[Ga]Ga 和 [In]In 是三种最具吸引力的三价较小放射性核素，它们在核医学工具包中提供了广泛的独特性质（发射能量和类型）。在这项研究中，使用一种新的基于邻菲啰啉的六齿配体 Hglyox 成功螯合了所有三种金属离子，该配体与异常高的 pM 值形成热力学稳定的中性配合物 [pIn (34) > pSc (26) > pGa (24.9)]。带有稳定同位素的 X 射线单晶结构表明，该配体高度预组织，并且与尺寸腔完美匹配，形成 [Sc(glyox)(HO)] 和 [In(glyox)(HO)] 配合物。在环境条件下（RT、pH7 和 15 分钟），通过定量标记镓-68（RCY > 95%，[L] = 10 M）和铟-111（RCY > 99%，[L] = 10 M），并分别实现了非常高的表观摩尔活性 750 MBq/μmol 和 650 MBq/nmol。[Sc]ScCl 的初步定量标记（RCY > 99%，[L] = 10 M）在室温下（pH7 和 10 分钟）快速进行。实验表明，[Ga]Ga(glyox) 和 [In]In(glyox) 配合物对人血清具有异常稳定性（转金属<2%），适用于生物应用。此外，在与金属离子螯合后，Hglyox 表现出增强的荧光，这被用于确定 Sc(glyox) 的稳定常数，除了批次内的 UV-vis 分光光度滴定法；作为概念验证，这些配合物被用于使用 Sc(glyox) 和 Ga(glyox) 获得活 HeLa 细胞的荧光图像，证实了细胞的活力。这些初步研究表明 Hglyox 是一种用于基于放射性金属的诊断（核和光学成像）和治疗的有价值的螯合剂。
