Purpose <p>The prostate-specific membrane antigen (PSMA) inhibitor [²¹¹At]YF2 was investigated in a Phase 0 microdose study in patients with metastatic castration resistant prostate cancer (mCRPC). The x-rays from ²¹¹At decay were used to assess biodistribution and dosimetry.</p> Methods <p>The biodistribution of [²¹¹At]YF2 initially was evaluated in CD-1 mice and human-equivalent estimated radiation doses were calculated using Rapid 3D-RD software. Three patients with PSMA-positive metastases confirmed by [⁶⁸Ga]Ga-PSMA-11 PET/CT received [²¹¹At]YF2 (29.6–44.4 MBq) intravenously. Whole-body planar imaging was performed at 1, 4, and 24&#xa0;h while SPECT/CT was conducted at 4 and 24&#xa0;h. Safety assessment was performed for 7 d. Volumes of interest were manually delineated to generate time-activity curves for radiation dosimetry calculation with Rapid 3D-RD software.</p> Results <p>Preliminary human dosimetry estimates based on murine data indicated that the kidneys received the highest dose (35.14 mGy/MBq). [²¹¹At]YF2 was well tolerated with all adverse events being ≤ Grade 2. High uptake of [²¹¹At]YF2 was observed initially in kidneys, bladder, salivary glands, and thyroid, followed by rapid clearance. Even at 24&#xa0;h, pronounced uptake of [²¹¹At]YF2 in metastases identified by PSMA-PET was observed in all patients with the most prominent metastasis receiving an average dose of 31.4 mGy/MBq. A kidney dose of 15.3 mGy/MBq was calculated from patient images, considerably lower than predicted from murine biodistribution-derived human dosimetry.</p> Conclusions <p>[²¹¹At]YF2 was safely administered to mCRPC patients and metastatic lesions were clearly delineated by ²¹¹At imaging. Normal organ accumulation resulted in favorable dosimetry. Based on these results, [²¹¹At]YF2 warrants further clinical development.</p> Graphical Abstract <p></p>