Abstract

In recent years, clinical imaging with zirconium-89 (⁸⁹Zr)-labelled monoclonal antibodies (Ab) by positron emission tomography (immunoPET) has been gaining significant importance in nuclear medicine for the diagnosis of different types of cancer. For complexation of the radiometal ⁸⁹Zr and its attachment to the Ab, chelating agents are required. To date, only the hexadentate chelator desferrioxamine (DFO) is applied in the clinic for this purpose. However, there is increasing preclinical evidence that the [⁸⁹Zr]Zr-DFO complex is not sufficiently stable and partly releases the radiometal in vivo due to the incomplete coordination sphere of the metal. This leads to unfavourable unspecific uptake of the osteophilic radiometal in bones, hence decreasing the signal-to-noise-ratio and leading to an increased dose to the patient. In the past, several new chelators with denticities > 6 have been published, notably the octadentate DFO derivative DFO*. DFO*, however, shows limited water solubility, wherefore an oxygen containing analogue, termed oxoDFO*, was developed in 2017. However, no data on the suitability of oxoDFO* for radiolabelling with ⁸⁹Zr has yet been reported. In this proof-of-concept study, we present the first radiolabelling results of the octadentate, water-soluble chelator oxoDFO*, as well as the in vitro stability of the resulting complex [⁸⁹Zr]Zr-oxoDFO* in comparison to the analogous octadentate, but less water-soluble derivative DFO* and the current “standard” chelator DFO. In addition, the suitability of DFO* and oxoDFO* for radiolabeling with the short-lived PET metal gallium-68 is discussed.

Graphic abstract

The water-soluble, octadentate chelator oxoDFO* provides stable complexes with the positron emitter Zirconium-89. The radiolabelling can be performed at room temperature and neutral pH and thus, oxoDFO* represents a promising chelator for applications in immunoPET.

中文翻译：

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用锆89和镓68对八齿螯合剂DFO *和oxoDFO *进行放射性标记。

摘要

近年来，通过正电子发射断层扫描（immunoPET）用锆89（⁸⁹ Zr）标记的单克隆抗体（Ab）进行临床成像在核医学中诊断不同类型的癌症中已变得越来越重要。为了使放射性金属⁸⁹ Zr络合及其与Ab的结合，需要螯合剂。迄今为止，在临床中仅为此目的使用六齿螯合剂去铁胺（DFO）。但是，越来越多的临床前证据表明[ ⁸⁹Zr] Zr-DFO络合物不够稳定，并且由于金属的不完全配位域而部分地在体内释放了放射性金属。这导致骨骼中嗜骨放射性金属的非特异性非特异性摄取，从而降低了信噪比并导致增加了对患者的剂量。过去，已经发布了几种密度> 6的新螯合剂，特别是八齿DFO衍生物DFO *。然而，DFO *的水溶性有限，因此于2017年开发了一种含氧类似物oxoDFO *。但是，没有关于oxoDFO *适于⁸⁹放射性标记的数据。Zr尚未被报道。在此概念验证研究中，我们提供了八齿水溶性螯合剂oxoDFO *的第一个放射性标记结果，以及与类似物相比，所得复合物[ ⁸⁹ Zr] Zr-oxoDFO *的体外稳定性。八齿，但水溶性衍生物DFO *和目前的“标准”螯合剂DFO较少。此外，还讨论了DFO *和oxoDFO *对于使用短寿命PET金属镓68进行放射性标记的适用性。

图形摘要

水溶性八齿螯合剂oxoDFO *可与正电子发射体Zirconium-89形成稳定的络合物。放射性标记可以在室温和中性pH下进行，因此oxoDFO *代表了在免疫PET中应用的有前途的螯合剂。