Abstract
Zirconium-89 is an emerging radionuclide for positron emission tomography (PET) especially for biomolecules with slow pharmacokinetics as due to its longer half-life, in comparison to fluorine-18 and gallium-68, imaging at late time points is feasible. Desferrioxamine B (DFO), a linear bifunctional chelator (BFC) is mostly used for this radionuclide so far but shows limitations regarding stability. Our group recently reported on fusarinine C (FSC) with similar zirconium-89 complexing properties but potentially higher stability related to its cyclic structure. This study was designed to compare FSC and DFO head-to-head as bifunctional chelators for 89Zr-radiolabeled EGFR-targeting ZEGFR:2377 affibody bioconjugates. FSC-ZEGFR:2377 and DFO-ZEGFR:2377 were evaluated regarding radiolabeling, in vitro stability, specificity, cell uptake, receptor affinity, biodistribution, and microPET-CT imaging. Both conjugates were efficiently labeled with zirconium-89 at room temperature but radiochemical yields increased substantially at elevated temperature, 85 °C. Both 89Zr-FSC-ZEGFR:2377 and 89Zr-DFO-ZEGFR:2377 revealed remarkable specificity, affinity and slow cell-line dependent internalization. Radiolabeling at 85 °C showed comparable results in A431 tumor xenografted mice with minor differences regarding blood clearance, tumor and liver uptake. In comparison 89Zr-DFO-ZEGFR:2377, radiolabeled at room temperature, showed a significant difference regarding tumor-to-organ ratios. MicroPET-CT imaging studies of 89Zr-FSC-ZEGFR:2377 as well as 89Zr-DFO-ZEGFR:2377 confirmed these findings. In summary we were able to show that FSC is a suitable alternative to DFO for radiolabeling of biomolecules with zirconium-89. Furthermore, our findings indicate that 89Zr-radiolabeling of DFO conjugates at higher temperature reduces off-chelate binding leading to significantly improved tumor-to-organ ratios and therefore enhancing image contrast.
Highlights
The positron-emitting radiometal zirconium-89 has attracted great attention for targeted molecular imaging due to its long half-life of 78.4 h enabling high-resolution positron emission tomography (PET) imaging at late time points
DFOZEGFR:2377 and fusarinine C (FSC)-ZEGFR:2377, respectively, were obtained in good yield and high chemical purity (>95%) and ESI-MS analysis was in excellent agreement with theoretical calculations. 89Zr Radiolabeling and Stability
The radiochemical yield (RCY) was already >96% after 30 min when elevated temperature was used whereas the corresponding RCY was around 60% for 89Zr-FSCZEGFR:2377 and around 50% for 89Zr-desferrioxamine B (DFO)-ZEGFR:2377 at 28 °C
Summary
The positron-emitting radiometal zirconium-89 has attracted great attention for targeted molecular imaging due to its long half-life of 78.4 h enabling high-resolution positron emission tomography (PET) imaging at late time points. This is of particular interest for radiolabeling of biomolecules undergoing slow distribution in vivo. Even if that study has proven FSC to be an interesting alternative to DFO for radiolabeling with zirconium-89, the results obtained from a Received: September 11, 2017 Revised: November 6, 2017 Accepted: November 21, 2017 Published: November 21, 2017
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