Cold Kit for Prostate-Specific Membrane Antigen (PSMA) PET Imaging: Phase 1 Study of ⁶⁸Ga-Tris(Hydroxypyridinone)-PSMA PET/CT in Patients with Prostate Cancer

⁶⁸Ga-labeled urea-based inhibitors of the prostate-specific membrane antigen (PSMA), such as ⁶⁸Ga-labeled N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED)-PSMA-11, are promising small molecules for targeting prostate cancer. A new radiopharmaceutical, ⁶⁸Ga-labeled tris(hydroxypyridinone) (THP)-PSMA, has a simplified design for single-step kit-based radiolabeling. It features the THP ligand, which forms complexes with ⁶⁸Ga³⁺ rapidly at a low concentration, at room temperature, and over a wide pH range, enabling direct elution from a ⁶⁸Ge/⁶⁸Ga generator into a lyophilized radiopharmaceutical kit in 1 step without manipulation. The aim of this phase 1 study was to assess the safety and biodistribution of ⁶⁸Ga-THP-PSMA. Methods: Cohort A comprised 8 patients who had proven prostate cancer and were scheduled to undergo prostatectomy; they had Gleason scores of 7-10 and a mean prostate-specific antigen level of 7.8 μg/L (range, 5.4-10.6 μg/L). They underwent PET/CT after the administration of ⁶⁸Ga-THP-PSMA. All patients proceeded to prostatectomy (7 with pelvic nodal dissection). Dosimetry from multi-time-point PET imaging was performed with OLINDA/EXM. Cohort B comprised 6 patients who had positive ⁶⁸Ga-HBED-PSMA-11 PET/CT scanning results and underwent comparative ⁶⁸Ga-THP-PSMA scanning. All patients were monitored for adverse events. Results: No adverse events occurred. In cohort A, 6 of 8 patients had focal uptake in the prostate (at 2 h: average SUV_max, 5.1; range, 2.4-9.2) and correlative 3+ staining of prostatectomy specimens on PSMA immunohistochemistry. The 2 ⁶⁸Ga-THP-PSMA scans with negative results had only 1+/2+ staining. The mean effective dose was 2.07E-02 mSv/MBq. In cohort B, ⁶⁸Ga-THP-PSMA had lower physiologic background uptake than ⁶⁸Ga-HBED-PSMA-11 (in the parotid glands, the mean SUV_max for ⁶⁸Ga-THP-PSMA was 3.6 [compared with 19.2 for ⁶⁸Ga-HBED-PSMA-11]; the respective corresponding values in the liver were 2.7 and 6.3, and those in the spleen were 2.7 and 10.5; P < 0.001 for all). In 5 of 6 patients, there was concordance in the number of metastases identified with ⁶⁸Ga-HBED-PSMA-11 and ⁶⁸Ga-THP-PSMA. Thirteen of 15 nodal abnormalities were subcentimeter. In 22 malignant lesions, the tumor-to-liver contrast with ⁶⁸Ga-THP-PSMA was similar to that with ⁶⁸Ga-HBED-PSMA (4.7 and 5.4, respectively; P = 0.15), despite a higher SUV_max for ⁶⁸Ga-HBED-PSMA than for ⁶⁸Ga-THP-PSMA (30.3 and 10.7, respectively; P < 0.01). Conclusion:⁶⁸Ga-THP-PSMA is safe and has a favorable biodistribution for clinical imaging. Observed focal uptake in the prostate was localized to PSMA-expressing malignant tissue on histopathology. Metastatic PSMA-avid foci were also visualized with ⁶⁸Ga-THP-PSMA PET. Single-step production from a Good Manufacturing Practice cold kit may enable rapid adoption.