Ramogida Caterina F, Murphy Lisa, Cawthray Jacqueline F, Ross James D, Adam Michael J, Orvig Chris
Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada; TRIUMF, 4004 Wesbrook Mall, Vancouver, British Columbia V6T 2A3, Canada.
Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
J Inorg Biochem. 2016 Sep;162:253-262. doi: 10.1016/j.jinorgbio.2015.11.021. Epub 2015 Nov 19.
A novel pyridyl functionalized analog of the promising hexadentate Ga chelate Hdedpa (NO, 1,2-[[6-carboxy-pyridin-2-yl]-methylamine]ethane) was successfully synthesized and characterized. This new bifunctional chelate (BFC) was used to prepare the first proof-of-principle bi-modal Hdedpa derivative for fluorescence and nuclear imaging. Two bi-modal Hdedpa derivatives were prepared: Hdedpa-propyl-FITC and Hdedpa-propyl-FITC-(N,N'-propyl-2-NI) (FITC=fluorescein, pyr=pyridyl functionalized, NI=nitroimidazole). The ligands possess the strong gallium-coordinating atoms contained within dedpa that are ideal for radiolabeling with Ga for positron-emission tomography (PET) imaging, and two fluorophores for optical imaging. In addition, one analog contains two NI moieties for specific entrapment of the tracer in hypoxic cells. These new bi-modal analogs were compared to the native unfunctionalized Hdedpa scaffold to determine the extent to which the addition of pyridyl functionalization would affect metal coordination, and complex stability. The non-radioactive gallium complexes were tested in a 3D tumor spheroid model. The novel pyridyl bis-functionalized Hdedpa ligand, Hdedpa-propyl-NH, was quantitatively radiolabeled with Ga (RCY>99%) under reaction conditions commensurate with unfunctionalized Hdedpa (10min at room temperature) at ligand concentrations as low as 10M. The resultant Ga-complex withstood transchelation to the in vivo metal-binding competitor apo-transferrin (2h at 37°C, 93% intact), signifying that [Ga(dedpa-propyl-NH)] is a kinetically inert complex suitable for in vivo use, but exhibited slightly reduced stability compared to the native [Ga(dedpa)] scaffold (>99% intact). Finally, bi-model fluorescent Ga-dedpa compounds were successfully imaged in a 3D tumor spheroid model. The Ga-dedpa-FITC-NI derivative was specifically localized in the central hypoxic core of the spheroid.
成功合成并表征了一种有前景的六齿镓螯合物Hdedpa（NO，1,2-[[6-羧基吡啶-2-基]甲胺]乙烷）的新型吡啶基官能化类似物。这种新型双功能螯合物（BFC）用于制备首个用于荧光和核成像的原理验证双模态Hdedpa衍生物。制备了两种双模态Hdedpa衍生物：Hdedpa-丙基-FITC和Hdedpa-丙基-FITC-(N,N'-丙基-2-NI)（FITC=荧光素，pyr=吡啶基官能化，NI=硝基咪唑）。这些配体具有dedpa中所含的强镓配位原子，非常适合用镓进行放射性标记以用于正电子发射断层扫描（PET）成像，并且含有两个用于光学成像的荧光团。此外，一种类似物含有两个NI部分，用于将示踪剂特异性捕获在缺氧细胞中。将这些新型双模态类似物与未官能化的天然Hdedpa支架进行比较，以确定吡啶基官能化的添加对金属配位和配合物稳定性的影响程度。在3D肿瘤球体模型中测试了非放射性镓配合物。新型吡啶基双官能化Hdedpa配体Hdedpa-丙基-NH在与未官能化Hdedpa相当的反应条件下（室温下10分钟），在低至10M的配体浓度下用Ga进行定量放射性标记（放射性化学产率>99%）。所得的Ga配合物能够抵抗向体内金属结合竞争剂脱铁转铁蛋白的转螯合作用（37°C下2小时，93%完整），这表明[Ga(dedpa-丙基-NH)]是一种动力学惰性配合物，适合体内使用，但与天然[Ga(dedpa)]支架相比稳定性略有降低（>99%完整）。最后，双模态荧光Ga-dedpa化合物在3D肿瘤球体模型中成功成像。Ga-dedpa-FITC-NI衍生物特异性定位于球体的中央缺氧核心。
