Development and Preclinical Evaluation of [<sup>211</sup>At]PSAt-3-Ga: An Inhibitor for Targeted α-Therapy of Prostate Cancer
Mohamed El Fakiri, Nawal Ayada, Marius Müller, Lars Hvass, Teodor H. Gamzov, Anne Skovsbo Clausen, Nicolas M. Geis, Nils Steinacker, Ellinor Hansson, Sture Lindegren, Emma Aneheim, Holger Jensen, Ann-Christin Eder, Andreas I. Jensen, Christian B. M. Poulie, Andreas Kjær, Matthias Eder, Matthias M. Herth
Abstract
The application of prostate-specific membrane antigen (PSMA)–targeted α-therapy is a promising alternative to β<sup>−</sup>-particle–based treatments. <sup>211</sup>At is among the potential α-emitters that are favorable for this concept. Herein, <sup>211</sup>At-based PSMA radiopharmaceuticals were designed, developed, and evaluated. <b>Methods:</b> To identify a <sup>211</sup>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 <sup>211</sup>At-labeled compounds. To facilitate the process of structural design, iodine-based candidates were radiolabeled with the PET radionuclide <sup>68</sup>Ga to study their preliminary in vitro and in vivo properties before the desired <sup>211</sup>At-labeled lead compound was formed. The most promising candidate from this evaluation was chosen to be <sup>211</sup>At-labeled and tested in biodistribution studies. <b>Results:</b> All <sup>68</sup>Ga-labeled surrogates displayed affinities in the nanomolar range and specific internalization in PSMA-positive LNCaP cells. PET imaging of these compounds identified [<sup>68</sup>Ga]PSGa-<b>3</b> as the lead compound. Subsequently, [<sup>211</sup>At]PSAt-<b>3</b>-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 [<sup>211</sup>At]PSAt-<b>3</b>-Ga. <b>Conclusion:</b> The reported findings support the use of iodine-based and <sup>68</sup>Ga-labeled variants as a convenient strategy for developing astatinated compounds and confirm [<sup>211</sup>At]PSAt-<b>3</b> as a promising radiopharmaceutical for targeted α-therapy.