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J Nucl Med. 2019 Jun 28. pii: jnumed.119.229393. doi: 10.2967/jnumed.119.229393. [Epub ahead of print]

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

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Jonhs Hopkins University School of Medicine, United States.
Johns Hopkins University, United States.
Johns Hopkins University School of Medicine, United States.
John Hopkins University, United States.
Johns Hopkins Medical Institute, United States.
National Institutes of Health, United States.
NCI, United States.
Johns Hopkins Medical Institutions, United States.


Targeted radiopharmaceutical therapy (TRT) employing 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 (LMW) agents for 212Pb-based TRT of patients with prostate cancer (PC) by evaluating the matching γ-emitting surrogate, 203Pb. Methods: Five rationally designed LMW ligands (L1-L5) were synthesized using the lysine-urea-glutamate (Lys-urea-Glu) scaffold and PSMA inhibition constants (Ki) were determined. Tissue biodistribution and SPECT/CT imaging of 203Pb-L1-203Pb-L5 were performed in mice bearing PSMA(+) PC3 PIP and PSMA(-) PC3 flu flank xenografts. Radiation absorbed 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 0.1-17 nM. 203Pb-L1-203Pb-L5 were synthesized in high radiochemical yield and specific activity. Whole-body clearances of 203Pb-L1-203Pb-L5 were 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) compared to the other agents, however, with lower tumor-to-blood ratios. PSMA(+) tumor lesions were visualized through SPECT/CT as early as 0.5 h post-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 to 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. Antitumor efficacy of 212Pb-L2 supports the corresponding 203Pb/212Pb theranostic pair for PSMA-based α-particle TRT in advanced PC.


α-particle radiopharmaceutical therapy; Animal Imaging; Prostate-specific membrane antigen; Radionuclide Therapy; Radiopharmaceuticals; SPECT/CT; murine pharmacokinetics; prostate cancer; surrogate imaging


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