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

Yutian Feng1, Rebecca L Meshaw1, Sean W Finch2

  • 1Department of Radiology, Duke University Medical Center, Durham, NC 27710, USA.

Nuclear Medicine and Biology
|May 4, 2024
PubMed
Summary

Astatine-211 (At-211) targeted alpha therapy shows promise. The new [At-211]YF2 agent demonstrated superior cell uptake, internalization, and cytotoxicity compared to [At-211]L3-Lu, suggesting better potential for clinical translation.

Keywords:
(211)AstatineProstate cancerProstate-specific membrane antigenRadionuclide therapyTargeted alpha-particle therapy

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Area of Science:

  • Nuclear medicine
  • Radiopharmaceutical therapy
  • Oncology

Background:

  • Targeted alpha therapy using alpha-particle emitting radionuclides is a promising approach for cancer treatment, particularly for patients resistant to beta-particle therapies.
  • Astatine-211 (At-211) is an attractive alpha-emitter due to its single alpha emission per decay, potentially reducing off-target toxicity from daughter radionuclides.
  • Previous development of [At-211]L3-Lu showed therapeutic efficacy, but a closely related analog, [At-211]YF2, was evaluated for improved clinical translation.

Purpose of the Study:

  • To compare the efficacy and characteristics of [At-211]YF2 and [At-211]L3-Lu for targeted alpha therapy.
  • To evaluate [At-211]YF2 as a potential candidate for clinical translation in prostate-specific membrane antigen (PSMA)-positive cancers.

Main Methods:

  • Synthesis of tin precursors and unlabeled iodo standards for both [At-211]YF2 and [At-211]L3-Lu.
  • Development of a one-step radiolabeling method for producing [At-211]YF2 and [At-211]L3-Lu with high radiochemical yield (RCY) and purity (RCP).
  • In vitro assays including cell uptake, internalization, and cytotoxicity (MTT) on PSMA-positive PC-3 PIP cells.
  • Paired-label biodistribution studies in mice bearing PSMA-positive xenografts to compare [At-211]YF2 with [At-211]L3-Lu.

Main Results:

  • A streamlined, scalable one-step radiolabeling method yielded high RCY (>86%) and RCP (>95%) for both [At-211]YF2 and [At-211]L3-Lu.
  • [At-211]YF2 demonstrated significantly higher cell uptake, internalization, and in vitro cytotoxicity compared to [At-211]L3-Lu.
  • Biodistribution studies showed higher tumor uptake and longer retention for [At-211]YF2 compared to [At-211]L3-Lu, although with higher renal uptake.

Conclusions:

  • [At-211]YF2 exhibits superior cellular uptake, internalization, and cytotoxicity against PSMA-positive cells compared to [At-211]L3-Lu.
  • The enhanced tumor targeting and retention of [At-211]YF2 suggest its potential as a superior candidate for clinical translation in targeted alpha therapy.
  • Further studies on dosimetry and therapeutic efficacy of [At-211]YF2 are ongoing.