Ⅰ. HIGHLIGHTS OF THE YEARRIKEN Accel. Prog. Rep. 56 (2023)
RIKEN
Accel. Prog. Rep. 56 (2023)

Innovative targeted alpha therapy for prostate cancer: preclinicalevaluation of [211 At]PSMA5†
T. Watabe,∗1,∗2 K. Kaneda-Nakashima,∗2,∗3 Y. Shirakami,∗2 Y. Kadonaga,∗1,∗2 K. Ooe,∗2 Y. Wang,∗4 H. Haba,∗4A. Toyoshima,∗2 J. Cardinale,∗5 F. Giesel,∗5 N. Tomiyama,∗2 and K. Fukase∗2,∗3Prostate cancer is currently the most prevalent cancer among men (92,021 new cases/year in Japan). After surgery and radiation therapy, hormone therapy is
performed for recurrent lesions. However, the prognosis
is poor if the hormone therapy becomes resistant withmultiple metastases.
In recent years, prostate-speciﬁc membrane antigen (PSMA), which is a membrane marker expressedin prostate cancer, has received signiﬁcant attention.
PSMA is expressed in more than 90% of prostatecancers.1) Targeted α-therapy (TAT) for PSMA is apromising treatment for metastatic castration-resistant
prostate cancer (CRPC).2) Astatine is an α-emitter(half-life T 1/2 = 7.2 h) that can be produced by a30 MeV cyclotron. In this study, we evaluated the treatment eﬀect of 211 At-labeled PSMA compounds in mouse
xenograft models.
211At was procured from RIKEN via the short-lived
RI supply platform. Upon procurement, dry distillation
was used to separate and purify 211 At. 211 At-labeled
PSMA1, PSMA5, and PSMA6 were synthesized by thesubstitution reaction of 211 At with the dihydroxyboryl
groups.3)
Tumor xenograft models were established by subcutaneous transplantation of human prostate cancercells (LNCaP) in NOD/SCID mice.4) [211 At]PSMA1,[211 At]PSMA5, or [211 At]PSMA6 was administered toLNCaP xenograft mice to evaluate biodistribution at
3 and 24 h. The treatment eﬀect was evaluatedby administering [211 At]PSMA1 (0.40 ± 0.07 MBq),[211 At]PSMA5 (0.39 ± 0.03 MBq), or saline. Histopathological evaluation was performed for the at-risk organs
at three and six weeks after administration.
All the animal experiments were performed in compliance with the guidelines of the Institute of Experimental
Animal Sciences. The protocol was approved by the Animal Care and Use Committee of the Osaka University
Graduate School of Medicine.
[211 At]PSMA5 resulted in higher tumor retention
compared to [211 At]PSMA1 and [211 At]PSMA6 (30.6 ±17.8, 12.4±4.8, and 19.1±4.5%ID/g at 3 h versus 40.7±2.6, 8.7±3.5, and 18.1±2.2%ID/g at 24 h, respectively),
whereas kidney excretion was superior in [211 At]PSMA1
compared to [211 At]PSMA5 and [211 At]PSMA6. The
administration of [211 At]PSMA5 had an excellent treat†
∗1
∗2
∗3
∗4
∗5Condensed from the article in Eur. J. Nucl. Med. Mol. Imaging. 50, 849 (2023)
Graduate School of Medicine, Osaka University
Institute for Radiation Sciences, Osaka University
Graduate School of Science, Osaka University
RIKEN Nishina Center
University Hospital Dusseldorf

Fig. 1. (a) Planar images of [211 At]PSMA5 in LNCaP
xenograft mice.
High uptake was observed in thexenografts (arrows). (b) Change in the tumor size after administering [211 At]PSMA1 (0.4 MBq, n = 5),[211 At]PSMA5 (0.4 MBq, n = 12), or control (saline,n = 10).

ment eﬀect on tumor growth. [211 At]PSMA1 also
showed a substantial treatment eﬀect; however, the tumor size was relatively more prominent than in the caseof [211 At]PSMA5. In the histopathological evaluation,
regenerated tubules were detected in the kidneys at threeand six weeks after administering [211 At]PSMA5. No
abnormality was found in the histology of the thyroid.
TAT using [211 At]PSMA5 resulted in excellent tumor growth suppression with minimal side eﬀects inthe normal organs. [211 At]PSMA5 should be considered as a new possible TAT for metastatic CRPC. An
investigator-initiated clinical trial will start at the OsakaUniversity after tox studies.
References
1) T. Watabe et al., Ann. Nucl. Med. 35, 523 (2021).
2) C. Kratochwil et al., J. Nucl. Med. 57, 1941 (2016).
3) Y. Shirakami et al., Sci. Rep. 11, 12982 (2021).
4) F. Soeda et al., J. Nucl. Med. 60, 1594 (2019).

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