A third generation PSMA-targeted agent [ 211 At]YF2: Synthesis and in vivo evaluation.

Introduction: Targeted α-particle therapy agents have shown promising responses in patients who have developed resistance to β ^- -particle emitting radionuclides, albeit off-target toxicity remains a concern. Astatine-211 emits only one α-particle per decay and may alleviate the toxicity from α-emitting daughter radionuclides. Previously, we developed the low-molecular-weight PSMA-targeted agent [ ²¹¹ At]L3-Lu that showed suitable therapeutic efficacy and was well tolerated in mice. Although [ ²¹¹ At]L3-Lu had good characteristics, we now have evaluated a closely related analogue, [ ²¹¹ At]YF2, to determine the better molecule for clinical translation.
Methods: The tin precursors and unlabeled iodo standards for [ ²¹¹ At]YF2 and [ ²¹¹ At]L3-Lu each were synthesized and a new one-step labeling method was developed to produce [ ²¹¹ At]YF2 and [ ²¹¹ At]L3-Lu from the respective tin precursor. RCY and RCP were determined using RP-HPLC. Cell uptake, internalization and in vitro cell-killing (MTT) assays were performed on PSMA ⁺ PC-3 PIP cells in parallel experiments to compare [ ²¹¹ At]YF2 and [ ²¹¹ At]L3-Lu directly. A paired-label biodistribution study was performed in athymic mice with subcutaneous PSMA-positive PC-3 PIP xenografts as a head-to-head comparison of [ ¹³¹ I]YF2 and [ ¹²⁵ I]L3-Lu. The tissue distribution of [ ²¹¹ At]YF2 and [ ²¹¹ At]L3-Lu were determined individually in the same animal model.
Results: The syntheses of tin precursors and unlabeled iodo standards were accomplished in reasonable yields. A streamlined and scalable radiolabeling method (1 h total synthesis time) was developed for the radiosynthesis of both [ ²¹¹ At]YF2 and [ ²¹¹ At]L3-Lu with 86 ± 7 % (n = 10) and 87 ± 5 % (n = 7) RCY, respectively, and > 95 % RCP for both. The maximum activity of [ ²¹¹ At]YF2 produced to date was 666 MBq. An alternative method that did not involve HPLC purification was developed that provided similar RCY and RCP. Significantly higher cell uptake, internalization and cytotoxicity was seen for [ ²¹¹ At]YF2 compared with [ ²¹¹ At]L3-Lu. Significantly higher uptake and longer retention in tumor was seen for [ ¹³¹ I]YF2 than for co-administered [ ¹²⁵ I]L3-Lu, while considerably higher renal uptake was seen for [ ¹³¹ I]YF2. The biodistribution of [ ²¹¹ At]YF2 was consistent with that of [ ¹³¹ I]YF2.
Conclusion: [ ²¹¹ At]YF2 exhibited higher cellular uptake, internalization and cytotoxicity than [ ²¹¹ At]L3-Lu on PSMA-positive PC3 PIP cells. Likewise, higher uptake and longer retention in tumor was seen for [ ²¹¹ At]YF2. Experiments to evaluate the dosimetry and therapeutic efficacy of [ ²¹¹ At]YF2 are under way.
Competing Interests: Declaration of competing interest Ganesan Vaidyanathan, Martin Pomper and Michael Zalutsky are co-inventors on a patent related to the labeled PSMA inhibitors described in this study and discussed in this publication. They are entitled to royalty distributions related to this technology, which was originally licensed by Precision Molecular, Inc. and now transferred to z-alpha, Inc. Martin Pomper and Michael Zalutsky are co-founders and paid consultants of z-alpha and are minority shareholders via stock options. No other potential competing interests related to this work are reported.
(Copyright © 2024 Elsevier Inc. All rights reserved.)