An Improved 211 At-Labeled Agent for PSMA-Targeted α-Therapy

The Journal of Nuclear Medicine

article

Ronnie C. Mease¹  Choong Mo Kang²  Vivek Kumar¹  Sangeeta Ray Banerjee¹  Il Minn¹  Mary Brummet¹  Kathleen L. Gabrielson³  Yutian Feng²  Andrew Park¹  Ana P. Kiess⁴  George Sgouros¹  Ganesan Vaidyanathan²  Michael R. Zalutsky²  Martin G. Pomper¹ 

[1] Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine;Department of Radiology, Duke University Medical Center;Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine;Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine

关键词: prostate cancer;    α-emitter;    radiopharmaceutical therapy;    211At;    PSMA;    murine models;   

DOI  :  10.2967/jnumed.121.262098

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

α-Particle emitters targeting the prostate-specific membrane antigen (PSMA) proved effective in treating patients with prostate cancer who were unresponsive to the corresponding β-particle therapy. 211At is an α-emitter that may engender less toxicity than other α-emitting agents. We synthesized a new 211At-labeled radiotracer targeting PSMA that resulted from the search for a pharmacokinetically optimized agent. Methods: A small series of 125I-labeled compounds was synthesized from tin precursors to evaluate the effect of the location of the radiohalogen within the molecule and the presence of lutetium in the chelate on biodistribution. On that basis, 211At-3-Lu was selected and evaluated in cell uptake and internalization studies, and biodistribution and PSMA-expressing (PSMA+) PC3 PIP tumor growth control were evaluated in experimental flank and metastatic (PC3-ML-Luc) models. A long-term (13-mo) toxicity study was performed for 211At-3-Lu, including tissue chemistries and histopathology. Results: The radiochemical yield of 211At-3-Lu was 17.8% ± 8.2%. Lead compound 211At-3-Lu demonstrated total uptake within PSMA+ PC3 PIP cells of 13.4 ± 0.5% of the input dose after 4 h of incubation, with little uptake in control cells. In SCID mice, 211At-31.48 MBq) in both flank and metastatic models. There was little off-target toxicity, as demonstrated by hematopoietic stability, unchanged tissue chemistries, weight gain rather than loss throughout treatment, and favorable histopathologic findings. Conclusion: Compound 211At-3-Lu or close analogs may provide limited and acceptable toxicity while retaining efficacy in management of prostate cancer.

【 授权许可】

CC BY