PT  - JOURNAL ARTICLE
AU  - Ray Banerjee, Sangeeta
AU  - Minn, IL
AU  - Kumar, Vivek
AU  - Josefsson, Anders
AU  - Lisok, Ala
AU  - Brummet, Mary
AU  - Chen, Jian
AU  - Kiess, Ana
AU  - Baidoo, Kwamena
AU  - Brayton, Cory
AU  - Mease, Ronnie C
AU  - Brechbiel, Martin
AU  - Sgouros, George
AU  - Hobbs, Robert F
AU  - Pomper, Martin G.
TI  - Preclinical evaluation of <sup>203/212</sup>Pb-labeled low-molecular-weight compounds for targeted radiopharmaceutical therapy of prostate cancer
AID  - 10.2967/jnumed.119.229393
DP  - 2019 Jun 01
TA  - Journal of Nuclear Medicine
PG  - jnumed.119.229393
4099  - http://jnm.snmjournals.org/content/early/2019/06/27/jnumed.119.229393.short
4100  - http://jnm.snmjournals.org/content/early/2019/06/27/jnumed.119.229393.full
AB  - 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.