PT  - JOURNAL ARTICLE
AU  - Ana P. Kiess
AU  - Il Minn
AU  - Ganesan Vaidyanathan
AU  - Robert F. Hobbs
AU  - Anders Josefsson
AU  - Colette Shen
AU  - Mary Brummet
AU  - Ying Chen
AU  - Jaeyeon Choi
AU  - Eftychia Koumarianou
AU  - Kwamena Baidoo
AU  - Martin W. Brechbiel
AU  - Ronnie C. Mease
AU  - George Sgouros
AU  - Michael R. Zalutsky
AU  - Martin G. Pomper
TI  - (2<em>S</em>)-2-(3-(1-Carboxy-5-(4-<sup>211</sup>At-Astatobenzamido)Pentyl)Ureido)-Pentanedioic Acid for PSMA-Targeted α-Particle Radiopharmaceutical Therapy
AID  - 10.2967/jnumed.116.174300
DP  - 2016 Oct 01
TA  - Journal of Nuclear Medicine
PG  - 1569--1575
VI  - 57
IP  - 10
4099  - http://jnm.snmjournals.org/content/57/10/1569.short
4100  - http://jnm.snmjournals.org/content/57/10/1569.full
SO  - J Nucl Med2016 Oct 01; 57
AB  - 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.