Preclinical evaluation of 203/212Pb-labeled low-molecular-weight compounds for targeted radiopharmaceutical therapy of prostate cancer

Sangeeta Ray Banerjee, Il Minn, Vivek Kumar, Anders Josefsson, Ala Lisok, Mary Brummet, Jian Chen, Ana P. Kiess, Kwamena Baidoo, Cory Brayton, Ronnie C. Mease, Martin Brechbiel, George Sgouros, Robert F. Hobbs, Martin G. Pomper

Research output: Contribution to journalArticle


Targeted radiopharmaceutical therapy (TRT) using α-particle radiation is a promising approach for treating both large and micrometastatic lesions. We developed prostate-specific membrane antigen (PSMA)–targeted low-molecular-weight agents for 212Pb-based TRT of patients with prostate cancer (PC) by evaluating the matching γ-emitting surrogate, 203Pb. Methods: Five rationally designed low-molecular-weight ligands (L1-L5) were synthesized using the lysine-urea-glutamate scaffold, and PSMA inhibition constants were determined. Tissue biodistribution and SPECT/CT imaging of 203Pb-L1–203Pb-L5 were performed on mice bearing PSMA(+) PC3 PIP and PSMA(−) PC3 flu flank xenografts. The absorbed radiation dose of the corresponding 212Pb-labeled analogs was determined using the biodistribution data. Antitumor efficacy of 212Pb-L2 was evaluated in PSMA(+) PC3 PIP and PSMA(−) PC3 flu tumor models and in the PSMA(+) luciferase-expressing micrometastatic model. 212Pb-L2 was also evaluated for dose-escalated, long-term toxicity. Results: All new ligands were obtained in high yield and purity. PSMA inhibitory activities ranged from 0.10 to 17 nM. 203Pb-L1–203Pb-L5 were synthesized in high radiochemical yield and specific activity. Whole-body clearance of 203Pb-L1–203Pb-L5 was fast. The absorbed dose coefficients (mGy/kBq) of the tumor and kidneys were highest for 203Pb-L5 (31.0, 15.2) and lowest for 203Pb-L2 (8.0, 4.2). The tumor-to-kidney absorbed dose ratio was higher for 203Pb-L3 (3.2) and 203Pb-L4 (3.6) than for the other agents, but with lower tumor-to-blood ratios. PSMA(+) tumor lesions were visualized through SPECT/CT as early as 0.5 h after injection. A proof-of-concept therapy study with a single administration of 212Pb-L2 demonstrated dose-dependent inhibition of tumor growth in the PSMA(+) flank tumor model. 212Pb-L2 also demonstrated an increased survival benefit in the micrometastatic model compared with 177Lu-PSMA-617. Long-term toxicity studies in healthy, immunocompetent CD-1 mice revealed kidney as the dose-limiting organ. Conclusion: 203Pb-L1–203Pb-L5 demonstrated favorable pharmacokinetics for 212Pb-based TRT. The antitumor efficacy of 212Pb-L2 supports the corresponding 203Pb/212Pb theranostic pair for PSMA-based α-particle TRT in advanced PC.

Original languageEnglish (US)
Pages (from-to)80-88
Number of pages9
JournalJournal of Nuclear Medicine
Issue number1
StatePublished - Jan 2020



  • Lead-212
  • Murine pharmacokinetics
  • Prostate-specific membrane antigen
  • Theranostic pair
  • α-particle

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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