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To enhance targeting efficacy in the radioimmunotherapy of disseminated cancer, several pretargeting strategies have been developed. In pretargeted radioimmunotherapy, the tumor is pretargeted with a modified monoclonal antibody that has an affinity for both tumor antigens and radiolabeled carriers. In this work, we aimed to synthesize and evaluate poly-L-lysine-based effector molecules for pretargeting applications based on the tetrazine and trans-cyclooctene reaction using 211At for targeted alpha therapy and 125I as a surrogate for the imaging radionuclides 123, 124I. Poly-L-lysine in two sizes was functionalized with a prosthetic group, for the attachment of both radiohalogens, and tetrazine, to allow binding to the trans-cyclooctene-modified pretargeting agent, maintaining the structural integrity of the polymer. Radiolabeling resulted in a radiochemical yield of over 80% for astatinated poly-L-lysines and a range of 66–91% for iodinated poly-L-lysines. High specific astatine activity was achieved without affecting the stability of the radiopharmaceutical or the binding between tetrazine and transcyclooctene. Two sizes of poly-L-lysine were evaluated, which displayed similar blood clearance profiles in a pilot in vivo study. This work is a first step toward creating a pretargeting system optimized for targeted alpha therapy with 211At. [ABSTRACT FROM AUTHOR]