Development and Preclinical Evaluation of [At]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. At is among the potential α-emitters that are favorable for this concept. Herein, At-based PSMA radiopharmaceuticals were designed, developed, and evaluated. To identify a At-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 At-labeled compounds. To facilitate the process of structural design, iodine-based candidates were radiolabeled with the PET radionuclide Ga to study their preliminary in vitro and in vivo properties before the desired At-labeled lead compound was formed. The most promising candidate from this evaluation was chosen to be At-labeled and tested in biodistribution studies. All Ga-labeled surrogates displayed affinities in the nanomolar range and specific internalization in PSMA-positive LNCaP cells. PET imaging of these compounds identified [Ga]PSGa- as the lead compound. Subsequently, [At]PSAt--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 [At]PSAt--Ga. The reported findings support the use of iodine-based and Ga-labeled variants as a convenient strategy for developing astatinated compounds and confirm [At]PSAt- as a promising radiopharmaceutical for targeted α-therapy.