Thiol-Reactive Bifunctional Chelators for the Creation of Site-Selectively Modified Radioimmunoconjugates with Improved Stability

Abstract

<p class="first" id="P1">Maleimide-bearing bifunctional chelators have been used extensively for the site-selective bioconjugation and radiolabeling of peptides and proteins. However, bioconjugates obtained using these constructs inevitably suffer from limited stability <i>in vivo</i>, a trait which translates into suboptimal activity concentrations in target tissue and higher uptake levels in healthy, non-target tissues. To circumvent this issue, phenyloxadiazolyl methylsulfones have previously been reported as alternatives to maleimides for thiol-based ligations, but these constructs have scarcely been used in the field of radiochemistry. In this report, we describe the synthesis of two thiol-reactive bifunctional chelators for ⁸⁹Zr and ¹⁷⁷Lu based on a new, easy-to-make phenyloxadiazolyl methylsulfone reagent: PODS. Radioimmunoconjugates created using these novel bifunctional chelators displayed higher <i>in vitro</i> stability than their maleimide-derived cousins. More importantly, PET imaging in murine models of cancer revealed that a ⁸⁹Zr-labeled radioimmunoconjugate created using a PODS-bearing bifunctional chelator produced significantly lower uptake in non-target tissues than its analogous maleimide-based counterpart. </p><p id="P2"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/536d53f9-24e5-400f-b12a-e3b37e0e6b4c/PubMedCentral/image/nihms-1012351-f0001.jpg"/> </div> </p>