Development and Preclinical Evaluation of [²¹¹At]PSAt-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 [⁶⁸Ga]PSGa-3 as the lead compound. Subsequently, [²¹¹At]PSAt-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 [²¹¹At]PSAt-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 [²¹¹At]PSAt-3 as a promising radiopharmaceutical for targeted α-therapy.