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 212 Pb-based TRT of patients with prostate cancer (PC) by evaluating the matching γ-emitting surrogate, 203 Pb. 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 203 Pb-L1-203 Pb-L5 were performed on mice bearing PSMA(1) PC3 PIP and PSMA(−) PC3 flu flank xenografts. The absorbed radiation dose of the corresponding 212 Pb-labeled analogs was determined using the biodistribution data. Antitumor efficacy of 212 Pb-L2 was evaluated in PSMA(1) PC3 PIP and PSMA(−) PC3 flu tumor models and in the PSMA(1) luciferase-expressing micrometastatic model. 212 Pb-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. 203 Pb-L1-203 Pb-L5 were synthesized in high radiochemical yield and specific activity. Whole-body clearance of 203 Pb-L1-203 Pb-L5 was fast. The absorbed dose coefficients (mGy/kBq) of the tumor and kidneys were highest for 203 Pb-L5 (31.0, 15.2) and lowest for 203 Pb-L2 (8.0, 4.2). The tumor-to-kidney absorbed dose ratio was higher for 203 Pb-L3 (3.2) and 203 Pb-L4 (3.6) than for the other agents, but with lower tumor-to-blood ratios. PSMA(1) 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 212 Pb-L2 demonstrated dose-dependent inhibition of tumor growth in the PSMA(1) flank tumor model. 212 Pb-L2 also demonstrated an increased survival benefit in the micrometastatic model compared with 177 Lu-PSMA-617. Long-term toxicity studies in healthy, immunocompetent CD-1 mice revealed kidney as the dose-limiting organ. Conclusion: 203 Pb-L1-203 Pb-L5 demonstrated favorable pharmacokinetics for 212 Pb-based TRT. The antitumor efficacy of 212 Pb-L2 supports the corresponding 203 Pb/ 212 Pb theranostic pair for PSMA-based α-particle TRT in advanced PC.

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These observations suggest that CDAD originated predominantly in patients from LTCFs (46.1%) and community (33.3%) rather than from hospitalized patients (20.6%). Diarrhea was the presenting complaint in LTCF patients in only 15.2% of cases. Hence, CDAD should be suspected if LTCF patients present with symptoms such as abdominal pain, fever, or altered mental status along with loose stools. Majority of the LTCF patients were found to be on PPIs, a risk factor for CDAD, with as many as 24% of these patients with no valid indication for their use.