Alternative chelator for 89Zr-immuno-PET studies shows superior in vitro stability and in vivo performance

At present, 89Zr-immuno-PET procedures make use of the chelator desferrioxamine (DFO) to provide the zirconium molecule with a hexadentate coordination, thus leaving two sites available for coordination with other molecules, such as water, a relatively labile ligand. This unsaturated coordination of DFO in relation to zirconium possibly impairs the stability of the complex in vivo, resulting in undesired bone uptake of 89Zr.

Considering this, recent research [1] has introduced a bifunctional isothiocyanate variant of the octadentate chelator DFO* as an alternative for DFO in 89Zr-immuno-PET. The effects of both molecules, when conjugated with the monoclonal antibody trastuzumab, were compared in vitro (stability tests) and in vivo (biodistribution in N87 tumor-bearing mice and PET imaging).

More stable
The in vitro results showed that 89Zr-DFO*-trastuzumab in saline buffer was more stable than 89Zr-DFO-trastuzumab; respectively, 95% and 58% of intact tracer were left after 72 h of incubation at 2-8°C. On the other hand, no difference was observed between the complexes in histidine/sucrose buffer, with both products being ≥ 92% intact after the same period.

In the in vivo experiments, uptake at 144 h post injection (p.i.) was similar for both conjugates in tumors, blood and most normal organs, except for skin, liver, spleen, ileum and bone. Mean tumor uptake was 29.06% ID/g for 89Zr-DFO-trastuzumab and 32.59% ID/g for 89Zr-DFO*-trastuzumab. However, bone uptake was significantly lower for the alternative 89Zr-DFO*-trastuzumab compared to the traditional 89Zr-DFO-trastuzumab (at 144 h p.i., respectively: in sternum 0.92% and 3.33% ID/g; in femur 0.78% and 3.85% ID/g; in knee 1.38% and 8.20% ID/g). Further, bone uptake decreased about two-fold for the DFO* conjugate from 24 h to 144 h p.i., while increasing about two-fold for the DFO conjugate.

Superior performance
In conclusion, 89Zr-DFO*-trastuzumab proved to be superior to 89Zr-DFO-trastuzumab with regards to in vitro stability and in vivo performance. Therefore, the DFO* chelator constitutes a promising substitute for DFO in future clinical applications of 89Zr-immuno-PET.

*References:*
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[1] Vugts DJ, Klaver C, Sewing C, Poot AJ, Adamzek K, Huegli S, Mari C, Visser GW, Valverde IE, Gasser G, Mindt TL, van Dongen GA. Comparison of the octadentate bifunctional chelator DFO*-pPhe-NCS and the clinically used hexadentate bifunctional chelator DFO-pPhe-NCS for 89Zr-immuno-PET. Eur J Nucl Med Mol Imaging. 2016 Aug 30 [Epub ahead of print]. PMID: 27573793.