Guillou Amaury, Ouadi Ali, Holland Jason P
University of Zurich, Department of Chemistry Winterthurerstrasse 190 CH-8057 Zurich Switzerland
Université de Strasbourg, CNRS, IPHC UMR 7178 F-67000 Strasbourg France.
Inorg Chem Front. 2022 May 10;9(12):3071-3081. doi: 10.1039/d2qi00442a. eCollection 2022 Jun 14.
Herein, we report the synthesis of three new bifunctional heptadentate metal ion binding chelates derived from desferrioxamine B (DFO) linked to a tripeptide unit that comprises of a glutamic acid and two glycine residues. The three DFO derivatives were also functionalised with a photoactivatable aryl azide unit for light-triggered labelling of proteins. The chelates were obtained in 3 synthetic steps in good overall yields by using solid phase peptide synthesis (SPPS). Density Functional Theory (DFT) calculations were used to estimate thermodynamic formation constants (log ) of the corresponding Zr complexes. Quantitative zirconium-89 radiolabelling (>95%) was obtained in <5 min at room temperature, and the stability of the radioconjugates toward different competitors (human serum, EDTA and Fe) was assessed . One-pot Zr-photoradiosynthesis produced [Zr]Zr-2-onartuzumab directly from the formulated, clinical-grade sample MetMAb™, without pre-purifying the monoclonal antibody (mAb) component, with an isolated decay-corrected radiochemical yield of 36.4 ± 2.4%. PET imaging and biodistribution studies were performed in female athymic nude mice bearing subcutaneous xenografts derived from the MKN-45 human gastric cancer cell line to assess the pharmacokinetic profile and tumour binding of [Zr]Zr-2-onartuzumab. Specific tumour uptake of [Zr]Zr-2-onartuzumab was confirmed by using competitive inhibition (blocking) studies and bone uptake was significantly reduced compared to the parent DFO analogue.
在此，我们报告了三种新的双功能七齿金属离子结合螯合物的合成，这些螯合物由去铁胺B（DFO）衍生而来，与一个由谷氨酸和两个甘氨酸残基组成的三肽单元相连。这三种DFO衍生物还通过光可活化芳基叠氮单元进行功能化，用于光触发的蛋白质标记。通过使用固相肽合成（SPPS），经3步合成以良好的总收率获得了这些螯合物。使用密度泛函理论（DFT）计算来估计相应锆配合物的热力学形成常数（log ）。在室温下不到5分钟即可获得定量的锆-89放射性标记（>95%），并评估了放射性缀合物对不同竞争剂（人血清、EDTA和铁）的稳定性。一锅法锆光放射性合成直接从配方的临床级样品MetMAb™中产生[Zr]Zr-2-onartuzumab，无需预先纯化单克隆抗体（mAb）成分，分离的经衰变校正的放射化学产率为36.4±2.4%。在携带源自MKN-45人胃癌细胞系的皮下异种移植物的雌性无胸腺裸鼠中进行了PET成像和生物分布研究，以评估[Zr]Zr-2-onartuzumab的药代动力学特征和肿瘤结合情况。通过竞争性抑制（阻断）研究证实了[Zr]Zr-2-onartuzumab对肿瘤的特异性摄取，并且与母体DFO类似物相比，骨摄取显著降低。
