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(2S)-2-(3-(1-Carboxy-5-(4-211At-Astatobenzamido)Pentyl)Ureido)-Pentanedioic Acid for PSMA-Targeted α-Particle Radiopharmaceutical Therapy.

Publication ,  Journal Article
Kiess, AP; Minn, I; Vaidyanathan, G; Hobbs, RF; Josefsson, A; Shen, C; Brummet, M; Chen, Y; Choi, J; Koumarianou, E; Baidoo, K; Brechbiel, MW ...
Published in: J Nucl Med
October 2016

UNLABELLED: Alpha-particle emitters have a high linear energy transfer and short range, offering the potential for treating micrometastases while sparing normal tissues. We developed a urea-based, 211At-labeled small molecule targeting prostate-specific membrane antigen (PSMA) for the treatment of micrometastases due to prostate cancer (PC). METHODS: PSMA-targeted (2S)-2-(3-(1-carboxy-5-(4-211At-astatobenzamido)pentyl)ureido)-pentanedioic acid (211At- 6: ) was synthesized. Cellular uptake and clonogenic survival were tested in PSMA-positive (PSMA+) PC3 PIP and PSMA-negative (PSMA-) PC3 flu human PC cells after 211At- 6: treatment. The antitumor efficacy of 211At- 6: was evaluated in mice bearing PSMA+ PC3 PIP and PSMA- PC3 flu flank xenografts at a 740-kBq dose and in mice bearing PSMA+, luciferase-expressing PC3-ML micrometastases. Biodistribution was determined in mice bearing PSMA+ PC3 PIP and PSMA- PC3 flu flank xenografts. Suborgan distribution was evaluated using α-camera images, and microscale dosimetry was modeled. Long-term toxicity was assessed in mice for 12 mo. RESULTS: 211At- 6: treatment resulted in PSMA-specific cellular uptake and decreased clonogenic survival in PSMA+ PC3 PIP cells and caused significant tumor growth delay in PSMA+ PC3 PIP flank tumors. Significantly improved survival was achieved in the newly developed PSMA+ micrometastatic PC model. Biodistribution showed uptake of 211At- 6: in PSMA+ PC3 PIP tumors and in kidneys. Microscale kidney dosimetry based on α-camera images and a nephron model revealed hot spots in the proximal renal tubules. Long-term toxicity studies confirmed that the dose-limiting toxicity was late radiation nephropathy. CONCLUSION: PSMA-targeted 211At- 6: α-particle radiotherapy yielded significantly improved survival in mice bearing PC micrometastases after systemic administration. 211At- 6: also showed uptake in renal proximal tubules resulting in late nephrotoxicity, highlighting the importance of long-term toxicity studies and microscale dosimetry.

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Published In

J Nucl Med

DOI

EISSN

1535-5667

Publication Date

October 2016

Volume

57

Issue

10

Start / End Page

1569 / 1575

Location

United States

Related Subject Headings

  • Urea
  • Tissue Distribution
  • Radiopharmaceuticals
  • Radiochemistry
  • Organometallic Compounds
  • Nuclear Medicine & Medical Imaging
  • Mice
  • Maximum Tolerated Dose
  • Kidney
  • Humans
 

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Kiess, A. P., Minn, I., Vaidyanathan, G., Hobbs, R. F., Josefsson, A., Shen, C., … Pomper, M. G. (2016). (2S)-2-(3-(1-Carboxy-5-(4-211At-Astatobenzamido)Pentyl)Ureido)-Pentanedioic Acid for PSMA-Targeted α-Particle Radiopharmaceutical Therapy. J Nucl Med, 57(10), 1569–1575. https://doi.org/10.2967/jnumed.116.174300
Kiess, Ana P., Il Minn, Ganesan Vaidyanathan, Robert F. Hobbs, Anders Josefsson, Colette Shen, Mary Brummet, et al. “(2S)-2-(3-(1-Carboxy-5-(4-211At-Astatobenzamido)Pentyl)Ureido)-Pentanedioic Acid for PSMA-Targeted α-Particle Radiopharmaceutical Therapy.J Nucl Med 57, no. 10 (October 2016): 1569–75. https://doi.org/10.2967/jnumed.116.174300.
Kiess AP, Minn I, Vaidyanathan G, Hobbs RF, Josefsson A, Shen C, et al. (2S)-2-(3-(1-Carboxy-5-(4-211At-Astatobenzamido)Pentyl)Ureido)-Pentanedioic Acid for PSMA-Targeted α-Particle Radiopharmaceutical Therapy. J Nucl Med. 2016 Oct;57(10):1569–75.
Kiess, Ana P., et al. “(2S)-2-(3-(1-Carboxy-5-(4-211At-Astatobenzamido)Pentyl)Ureido)-Pentanedioic Acid for PSMA-Targeted α-Particle Radiopharmaceutical Therapy.J Nucl Med, vol. 57, no. 10, Oct. 2016, pp. 1569–75. Pubmed, doi:10.2967/jnumed.116.174300.
Kiess AP, Minn I, Vaidyanathan G, Hobbs RF, Josefsson A, Shen C, Brummet M, Chen Y, Choi J, Koumarianou E, Baidoo K, Brechbiel MW, Mease RC, Sgouros G, Zalutsky MR, Pomper MG. (2S)-2-(3-(1-Carboxy-5-(4-211At-Astatobenzamido)Pentyl)Ureido)-Pentanedioic Acid for PSMA-Targeted α-Particle Radiopharmaceutical Therapy. J Nucl Med. 2016 Oct;57(10):1569–1575.

Published In

J Nucl Med

DOI

EISSN

1535-5667

Publication Date

October 2016

Volume

57

Issue

10

Start / End Page

1569 / 1575

Location

United States

Related Subject Headings

  • Urea
  • Tissue Distribution
  • Radiopharmaceuticals
  • Radiochemistry
  • Organometallic Compounds
  • Nuclear Medicine & Medical Imaging
  • Mice
  • Maximum Tolerated Dose
  • Kidney
  • Humans