177Lu-labeled low-molecular-weight agents for PSMA-targeted radiopharmaceutical therapy

Sangeeta Ray Banerjee, Vivek Kumar, Ala Lisok, Jian Chen, Il Minn, Mary Brummet, Srikanth Boinapally, Michael Cole, Ethel Ngen, Bryan Wharram, Cory Brayton, Robert F. Hobbs, Martin G. Pomper

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Purpose: To develop a prostate-specific membrane antigen (PSMA)-targeted radiotherapeutic for metastatic castration-resistant prostate cancer (mCRPC) with optimized efficacy and minimized toxicity employing the β-particle radiation of 177Lu. Methods: We synthesized 14 new PSMA-targeted, 177Lu-labeled radioligands (177Lu-L1–177Lu-L14) using different chelating agents and linkers. We evaluated them in vitro using human prostate cancer PSMA(+) PC3 PIP and PSMA(−) PC3 flu cells and in corresponding flank tumor models. Efficacy and toxicity after 8 weeks were evaluated at a single administration of 111 MBq for 177Lu-L1, 177Lu-L3, 177Lu-L5 and 177Lu-PSMA-617. Efficacy of 177Lu-L1 was further investigated using different doses, and long-term toxicity was determined in healthy immunocompetent mice. Results: Radioligands were produced in high radiochemical yield and purity. Cell uptake and internalization indicated specific uptake only in PSMA(+) PC3 cells. 177Lu-L1, 177Lu-L3 and 177Lu-L5 demonstrated comparable uptake to 177Lu-PSMA-617 and 177Lu-PSMA-I&T in PSMA-expressing tumors up to 72 h post-injection. 177Lu-L1, 177Lu-L3 and 177Lu-L5 also demonstrated efficient tumor regression at 8 weeks. 177Lu-L1 enabled the highest survival rate. Necropsy studies of the treated group at 8 weeks revealed subacute damage to lacrimal glands and testes. No radiation nephropathy was observed 1 year post-treatment in healthy mice receiving 111 MBq of 177Lu-L1, most likely related to the fast renal clearance of this agent. Conclusions: 177Lu-L1 is a viable clinical candidate for radionuclide therapy of PSMA-expressing malignancies because of its high tumor-targeting ability and low off-target radiotoxic effects.

Original languageEnglish (US)
Pages (from-to)2545-2557
Number of pages13
JournalEuropean Journal of Nuclear Medicine and Molecular Imaging
Issue number12
StatePublished - Nov 1 2019


  • Lutetium
  • Metastatic
  • Prostate cancer
  • Prostate-specific membrane antigen
  • β-Particle

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging


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