A series of conjugates based on prostate-specific membrane antigen ligands with the chelating agent DOTA: synthesis, radiolabeling, and biological activity.

Prostate-specific membrane antigen (PSMA) is a crucial zinc-containing metalloprotease that belongs to the type II transmembrane protein family, also known as glutamate carboxypeptidase II (GCPII). PSMA stands out as a highly promising target for the diagnosis and treatment of prostate cancer. In this study, we present the design and synthesis of 12 PSMA-targeted DOTA-conjugates, along with comprehensive assessments of their physicochemical properties, in vitro investigations, and in vivo biodistribution evaluations of four leading conjugates. The synthesized conjugates demonstrate remarkable stability in biological fluids. Our findings reveal that the four [Ga]-radioconjugates exhibit superior or comparable affinity and internalization parameters toward the PSMA-expressing LNCaP cell line in comparison to the conjugate [Ga]Ga-PSMA-617. Notably, we observed no significant cytotoxicity in any of the [Ga]-labelled conjugates. Furthermore, these labelled conjugates consistently show high affinity and internalization values with the LNCaP cell line in vitro. Importantly, the conjugate [Ga]Ga-13.1c demonstrates a good accumulation in the tumor tissues, and achieves the most optimal kidney-to-tumor accumulation ratio in vivo, surpassing the performance of the FDA-approved conjugate [68Ga]Ga-PSMA-11. This establishes [Ga]Ga-13.1c as a leading candidate in the pursuit of effective prostate cancer treatment.