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

Publication ,  Journal Article
Mease, RC; Kang, CM; Kumar, V; Banerjee, SR; Minn, I; Brummet, M; Gabrielson, KL; Feng, Y; Park, A; Kiess, AP; Sgouros, G; Vaidyanathan, G ...
Published in: J Nucl Med
February 2022

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-3-Lu provided uptake that was 30.6 ± 4.8 percentage injected dose per gram (%ID/g) in PSMA+ PC3 PIP tumor at 1 h after injection, and this uptake decreased to 9.46 ± 0.96 %ID/g by 24 h. Tumor-to-salivary gland and tumor-to-kidney ratios were 129 ± 99 at 4 h and 130 ± 113 at 24 h, respectively. Deastatination was not significant (stomach, 0.34 ± 0.20 %ID/g at 4 h). Dose-dependent survival was demonstrated at higher doses (>1.48 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.

Duke Scholars

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Published In

J Nucl Med

DOI

EISSN

1535-5667

Publication Date

February 2022

Volume

63

Issue

2

Start / End Page

259 / 267

Location

United States

Related Subject Headings

  • Tissue Distribution
  • Radiopharmaceuticals
  • Prostatic Neoplasms
  • Nuclear Medicine & Medical Imaging
  • Mice, SCID
  • Mice
  • Male
  • Lutetium
  • Humans
  • Glutamate Carboxypeptidase II
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Mease, R. C., Kang, C. M., Kumar, V., Banerjee, S. R., Minn, I., Brummet, M., … Pomper, M. G. (2022). An Improved 211At-Labeled Agent for PSMA-Targeted α-Therapy. J Nucl Med, 63(2), 259–267. https://doi.org/10.2967/jnumed.121.262098
Mease, Ronnie C., Choong Mo Kang, Vivek Kumar, Sangeeta Ray Banerjee, Il Minn, Mary Brummet, Kathleen L. Gabrielson, et al. “An Improved 211At-Labeled Agent for PSMA-Targeted α-Therapy.J Nucl Med 63, no. 2 (February 2022): 259–67. https://doi.org/10.2967/jnumed.121.262098.
Mease RC, Kang CM, Kumar V, Banerjee SR, Minn I, Brummet M, et al. An Improved 211At-Labeled Agent for PSMA-Targeted α-Therapy. J Nucl Med. 2022 Feb;63(2):259–67.
Mease, Ronnie C., et al. “An Improved 211At-Labeled Agent for PSMA-Targeted α-Therapy.J Nucl Med, vol. 63, no. 2, Feb. 2022, pp. 259–67. Pubmed, doi:10.2967/jnumed.121.262098.
Mease RC, Kang CM, Kumar V, Banerjee SR, Minn I, Brummet M, Gabrielson KL, Feng Y, Park A, Kiess AP, Sgouros G, Vaidyanathan G, Zalutsky MR, Pomper MG. An Improved 211At-Labeled Agent for PSMA-Targeted α-Therapy. J Nucl Med. 2022 Feb;63(2):259–267.

Published In

J Nucl Med

DOI

EISSN

1535-5667

Publication Date

February 2022

Volume

63

Issue

2

Start / End Page

259 / 267

Location

United States

Related Subject Headings

  • Tissue Distribution
  • Radiopharmaceuticals
  • Prostatic Neoplasms
  • Nuclear Medicine & Medical Imaging
  • Mice, SCID
  • Mice
  • Male
  • Lutetium
  • Humans
  • Glutamate Carboxypeptidase II