²²⁷Th is a promising radioisotope for targeted α-particle therapy. It produces 5 α-particles through its decay, with the clinically approved ²²³Ra as its first daughter. There is an ample supply of ²²⁷Th, allowing for clinical use; however, the chemical challenges of chelating this large tetravalent f-block cation are considerable. Using the CD20-targeting antibody ofatumumab, we evaluated chelation of ²²⁷Th⁴⁺ for α-particle-emitting and radiotheranostic applications. Methods: We compared 4 bifunctional chelators for thorium radiopharmaceutical preparation: S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA), 2-(4-isothicyanatobenzyl)-1,2,7,10,13-hexaazacyclooctadecane-1,4,7,10,13,16-hexaacetic acid (p-SCN-Bn-HEHA), p-isothiacyanatophenyl-1-hydroxy-2-oxopiperidine-desferrioxamine (DFOcyclo*-p-Phe-NCS), and macrocyclic 1,2-HOPO N-hydroxysuccinimide (L804-NHS). Immunoconstructs were evaluated for yield, purity, and stability in vitro and in vivo. Tumor targeting of the lead ²²⁷Th-labeled compound in vivo was performed in CD20-expressing models and compared with a companion ⁸⁹Zr-labeled PET agent. Results: ²²⁷Th-labeled ofatumumab-chelator constructs were synthesized to a radiochemical purity of more than 95%, excepting HEHA. ²²⁷Th-HEHA-ofatumumab showed moderate in vitro stability. ²²⁷Th-DFOcyclo*-ofatumumab presented excellent ²²⁷Th labeling efficiency; however, high liver and spleen uptake was revealed in vivo, indicative of aggregation. ²²⁷Th-DOTA-ofatumumab labeled poorly, yielding no more than 5%, with low specific activity (0.08 GBq/g) and modest long-term in vitro stability (<80%). ²²⁷Th-L804-ofatumumab coordinated ²²⁷Th rapidly and efficiently at high yields, purity, and specific activity (8 GBq/g) and demonstrated extended stability. In vivo tumor targeting confirmed the utility of this chelator, and the diagnostic analog, ⁸⁹Zr-L804-ofatumumab, showed organ distribution matching that of ²²⁷Th to delineate SU-DHL-6 tumors. Conclusion: Commercially available and novel chelators for ²²⁷Th showed a range of performances. The L804 chelator can be used with potent radiotheranostic capabilities for ⁸⁹Zr/²²⁷Th quantitative imaging and α-particle therapy.

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