First-in-Human Evaluation of [ ⁶⁸ Ga]Ga-HTK03149, a PSMA-Targeted Tracer for PET Imaging in Prostate Cancer

Prostate-specific membrane antigen (PSMA) is a validated target for prostate cancer imaging and therapy. [⁶⁸Ga]Ga-HTK03149 is a PSMA inhibitor designed to improve biodistribution by incorporating a 2-aminoadipic acid moiety as an alternative PSMA binding group. We report the first-in-human safety, biodistribution, and dosimetry evaluation of [⁶⁸Ga]Ga-HTK03149 and explore organ uptake relevant to future theranostic use. <b>Methods:</b> Men with biochemical recurrence of prostate cancer (prostate-specific antigen, >0.4 ng/mL) after definitive local therapy were enrolled. Each participant underwent a 60-min dynamic PET/CT scan (heart-focused for the first 6 min and then serial whole-body passes), followed by static whole-body acquisitions at 1 and 2 h after injection. In 5 participants, intravenous furosemide (40 mg) was given after the 1-h scan. Volumes of interest were drawn manually, and organ absorbed doses were calculated using OLINDA/EXM version 2.2. <b>Results:</b> Ten men (median age, 68 y; range, 61-74 y; median prostate-specific antigen, 3.3 ng/mL; range, 0.42-9.6 ng/mL) completed imaging without adverse events. Vital signs and laboratory parameters showed no clinically relevant changes. [⁶⁸Ga]Ga-HTK03149 cleared rapidly from blood and soft tissue, with prominent uptake in the lacrimal and salivary glands, liver, spleen, kidneys, and small intestine, as well as urinary excretion. The kidneys received the highest absorbed dose (0.107 ± 0.020 mGy/MBq), followed by the salivary glands (0.067 ± 0.019 mGy/MBq) and lacrimal glands (0.063 ± 0.026 mGy/MBq). The mean effective dose was 0.012 ± 0.005 mSv/MBq. Forced diuresis significantly reduced the urinary bladder wall dose (0.029 ± 0.0097 vs. 0.056 ± 0.0268 mGy/MBq, <i>P</i> = 0.04) but did not affect the kidney dose (<i>P</i> = 0.99). Lesions (<i>n</i> = 16 in 9/10 patients) showed high uptake and improved contrast at 2 h, with an SUV_max of 7.13 (range, 5.44-10.99) at 1 h versus 9.52 (range, 7.07-13.67) at 2 h (<i>P</i> < 0.001) and a tumor-to-background ratio of 15.74 (range, 10.85-21.09) at 1 h versus 20.42 (range, 12.50-27.51) at 2 h (<i>P</i> < 0.001). <b>Conclusion:</b> [⁶⁸Ga]Ga-HTK03149 is a safe PSMA-targeted PET radiopharmaceutical with biodistribution and radiation dosimetry comparable to those of existing tracers. Its high tumor uptake and improved delayed lesion contrast support further clinical evaluation for prostate cancer imaging and theranostic applications.