Radiochemistry of cyclen-derived chelators comprising five-membered azaheterocyclic arms with 212Pb2+, 213Bi3+, and 225Ac3+☆,☆☆

Abstract

In this work, we introduce the cyclen-based metal chelator DOTThia comprising four methylthiazole arms for metal complexation. Together with the recently described congener DOTI-Me bearing four methylimidazole arms, the radiochemistry of these two compounds with 212Pb, 213Bi, and 225Ac was investigated thoroughly. Radiolabeling experiments were performed at various pH values and temperatures to determine the optimal conditions for quantitative radiochemical conversions. Experiments revealed excellent complexation properties of DOTThia for 212Pb at room temperature, comparable to those of the current gold standard for Pb complexation, TCMC, while it was not well suited for 213Bi. Contrarily, DOTI-Me exhibited quantitative radiochemical conversions for 213Bi at pH 5.5 and room temperature, outperforming the metal chelator macropa, but was not able to quantitatively complex 212Pb under any conditions investigated. Of note, both novel chelators were not able to bind 225Ac. In preliminary experiments, we could also show that a functionalized DOTI-Me derivative is capable of complexing 213Bi selectively from 225Ac solutions. This feature may allow the preparation of 213Bi-labeled radiotracers directly from 225Ac solutions without the need for an 225Ac/213Bi generator. However, more detailed studies are needed to fully explore this potential application. Altogether, our results support the future development of 212Pb-labeled radiopharmaceuticals using bifunctional derivatives of DOTThia as well as of 213Bi-labeled radiotracers based on the DOTI-Me scaffold.