Multifunctional Desferrichrome Analogues as Versatile (89)Zr(IV) Chelators for ImmunoPET Probe Development.
Multifunctional Desferrichrome Analogues as Versatile (89)Zr(IV) Chelators for ImmunoPET Probe Development.
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DOI：
10.1021/acs.molpharmaceut.7b00343
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发表时间：
2017-08-07
影响因子：
4.9
通讯作者：
Boros E
中科院分区：
文献类型：
--
作者：
Adams CJ;Wilson JJ;Boros E
新的双功能六齿和八齿类似物的异羟肟酸含铁载体去铁铬（DFC）已被合成和评价为89 Zr-螯合剂的免疫PET应用。将这些新配体Orn 3-hx（六齿）和Orn-4 hx衍生物（八齿）的体外和体内惰性与金标准六齿、含异羟肟酸盐的89 Zr去铁胺（DFO）螯合剂进行比较。采用密度泛函理论（DFT）对所得Zr（IV）配合物的几何构型进行了模拟，并预测了它们的相对稳定性：Zr（Orn 4-hx）> Zr（DFC）> Zr（Orn 3-hx）。相应的放射化学配合物与过量的乙二胺四乙酸盐（EDTA）的transschedule挑战实验表明，根据DFT计算的复杂的稳定性。这些配体与89 Zr的放射性标记是定量的（0.25 μmol配体，pH 7.4，室温，20 min）。对于抗体缀合，将异硫氰酸酯（NCS）官能团引入Orn 3-hx和Orn-4 hx的N末端。一个额外的三官能衍生物，承载硅罗丹明荧光团的C-末端和NCS的N-末端也提供。作为概念证明，所有NCS衍生物均与HER 2靶向抗体曲妥珠单抗偶联。用89 Zr对免疫缀合物进行放射性标记，放射化学产率为16 ± 2%至95 ± 2%。将这些构建体施用给未处理小鼠（雄性，C57 BL/6 J，n = 4）以评估96小时循环时间后的体内惰性，其与骨中89 Zr的摄取负相关。我们发现骨摄取范围为7.0 ± 2.2至10.7 ± 1.3%ID/g，该值与相应的DFO缀合物（7.1 ± 0.8%ID/g）相当。总之，我们已经合理地设计了线性，双功能和三功能的desferrichrome类似物适合于温和的和惰性的放射性同位素89锆的抗体的放射性标记。
New bifunctional hexa- and octadentate analogues of the hydroxamate-containing siderophore desferrichrome (DFC) have been synthesized and evaluated as 89Zr-chelating agents for immunoPET applications. The in vitro and in vivo inertness of these new ligands, Orn3-hx (hexadentate) and Orn-4hx derivatives (octadentate), was compared to the gold standard hexadentate, hydroxamate-containing chelator for 89Zr desferrioxamine (DFO). Density functional theory was employed to model the geometries of the resulting Zr(IV) complexes and to predict their relative stabilities as follows: Zr(Orn4-hx) > Zr(DFC) > Zr(Orn3-hx). Transchelation challenge experiments of the corresponding radiochemical complexes with excess ethylenediaminetetraacetate (EDTA) indicated complex stability in accordance with DFT calculations. Radiolabeling of these ligands with 89Zr was quantitative (0.25 μmol of ligand, pH 7.4, room temperature, 20 min). For antibody conjugation, the isothiocyanate (NCS) functional group was introduced to the N terminus of Orn3-hx and Orn-4hx. An additional trifunctional derivative that bears a silicon-rhodamine fluorophore on the C-terminus and NCS on the N terminus was also furnished. As proof of concept, all NCS derivatives were conjugated to the HER2-targeting antibody, trastuzumab. Radiolabeling of immunoconjugates with 89Zr was accomplished with radiochemical yields of 16 ± 2% to 95 ± 2%. These constructs were administered to naive mice (male, C57BL/6J, n = 4) to assess in vivo inertness, which is inversely correlated with uptake of 89Zr in bone, after 96 h circulation time. We found bone uptake to range from 7.0 ± 2.2 to 10.7 ± 1.3% ID/g, values that compare well to the corresponding DFO conjugate (7.1 ± 0.8% ID/g). In conclusion, we have rationally designed linear, bifunctional and trifunctional desferrichrome analogues suitable for the mild and inert radiolabeling of antibodies with the radionuclide 89Zr.
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