Development and Preclinical Evaluation of 211AtPSAt-3-Ga: An Inhibitor for Targeted α-Therapy of Prostate Cancer

The application of prostate-specific membrane antigen (PSMA)- targeted α-therapy is a promising alternative to β¯-particle-based treatments. 211At is among the potential α-emitters that are favorable for this concept. Herein, 211At-based PSMA radiopharmaceuticals were designed, developed, and evaluated. Methods: To identify a 211At-labeled lead, a surrogate strategy was applied. Because astatine does not exist as a stable nuclide, it is commonly replaced with iodine to mimic the pharmacokinetic behavior of the corresponding 211At-labeled compounds. To facilitate the process of structural design, iodine-based candidates were radiolabeled with the PET radionuclide 68Ga to study their preliminary in vitro and in vivo properties before the desired 211At-labeled lead compound was formed. The most promising candidate from this evaluation was chosen to be 211At-labeled and tested in biodistribution studies. Results: All 68Ga-labeled surrogates displayed affinities in the nanomolar range and specific internalization in PSMA-positive LNCaP cells. PET imaging of these compounds identified 68GaPSGa- 3 as the lead compound. Subsequently, 211AtPSAt- 3 -Ga was synthesized in a radiochemical yield of 35% and showed tumor uptake of 19±8 percentage injected dose per gram of tissue (%ID/g) at 1 h after injection and 7.6±2.9 %ID/g after 24 h. Uptake in off-target tissues such as the thyroid (2.0±1.1 %ID/g), spleen (3.0±0.6 %ID/g), or stomach (2.0±0.4 %ID/g) was low, indicating low in vivo deastatination of 211AtPSAt- 3 -Ga. Conclusion: The reported findings support the use of iodine-based and 68Ga-labeled variants as a convenient strategy for developing astatinated compounds and confirm 211AtPSAt- 3 as a promising radiopharmaceutical for targeted α-therapy.