Abstract

This comprehensive review describes the development of [²¹¹At]PSMA-5, a cyclotron-produced alpha-particle–emitting radiopharmaceutical for targeted therapy of metastatic castration-resistant prostate cancer (mCRPC). The article covers ²¹¹At production via the ²⁰⁹Bi(α,2n)²¹¹At reaction, radiosynthesis of [²¹¹At]PSMA-5 with radiochemical yields exceeding 60%, and comprehensive preclinical evaluation demonstrating superior cytotoxicity compared to [²²⁵Ac]PSMA-617. Biodistribution studies in mice and cynomolgus monkeys revealed high tumor uptake with favorable kinetics and excellent in vivo stability. Toxicology studies supported clinical translation with no severe toxicities identified up to 35 MBq/kg. The first-in-human Phase I trial (NCT06441994) at the University of Osaka Hospital, which began in May 2024, is enrolling 15 patients with mCRPC. To date, nine patients have been treated, with promising therapeutic effects observed at the third dose level. The development of [²¹¹At]PSMA-5 represents a significant advance in sustainable, cyclotron-based alpha therapy with potential to address patients refractory to current standard-of-care treatments.

Publication Information

Journal: Seminars in Nuclear Medicine

Volume: 55, Issue 6

Pages: 947-954

Publication Date: November 2025

DOI: 10.1053/j.semnuclmed.2025.09.005

Journal Link: https://www.sciencedirect.com/science/article/pii/S0001299825001205?via%3Dihub

Authors

Takahiro Watabe, Satoru Naka, Yuri Shirakami, Kazuki Kaneda, Masatoshi Murakami, Akira Toyoshima, Jörg Cardinale, Frederik L. Giesel

Institutional Affiliations: University of Osaka Hospital, Fukushima Medical University, RIKEN Nishina Center for Accelerator-Based Science, Research Center for Nuclear Physics (RCNP), University of Osaka, Japan; University of Heidelberg, Germany

Funding: AMED translational research grant (Seeds-F) (Grant Number: JP23ym0126091)

Associated Clinical Trial: NCT06441994 (15 patients with mCRPC, estimated completion March 2027)