Synthesis, preclinical evaluation, and first-in-human study of Al¹⁸F-PSMA-Q for prostate cancer imaging

To investigate the potential of a novel Al¹⁸F-labeled PSMA-targeted radiotracer for PCa diagnosis through both preclinical and pilot clinical studies.

Al¹⁸F-PSMA-Q was prepared automatically. The binding affinity to PSMA was evaluated in vitro using the 22Rv1 (PSMA +) and PC-3 (PSMA -) cell lines. Pharmacokinetics evaluation, biodistribution study, Micro-PET imaging of Al¹⁸F-PSMA-Q in normal mice and tumor-bearing mice, and a comparison with ¹⁸F-DCFPyL were performed. PET/CT imaging was performed on 8 healthy volunteers and 20 newly diagnosed PCa patients at 1 h post-injection (p.i.). The biodistribution in human and preliminary diagnostic efficacy of Al¹⁸F-PSMA-Q were evaluated, and the radiation dosimetry was estimated using OLINDA/EXM 2.0 software.

Qualified Al¹⁸F-PSMA-Q was efficiently prepared with a non-decay-corrected radiochemical yield (RCY) of 22.0-28.3%, a specific activity (SA) of > 50 GBq/μmol. The hydrophilicity was comparably high with a log P value of - 3.69 ± 0.39. Al¹⁸F-PSMA-Q was found to bind to PSMA specifically with a Ki value of 17.05 ± 1.14 nM. The distribution and elimination half-lives of Al¹⁸F-PSMA-Q were 3.93 min and 14.22 min, respectively, which were shorter than those of ¹⁸F-DCFPyL. Micro-PET imaging of Al¹⁸F-PSMA-Q can clearly differentiate 22Rv1 tumors from PC-3 tumors and background with a high SUVmax of 2.17 ± 0.42 and a tumor-to-muscle ratio of 84.37 ± 31.62, which were higher than those of ¹⁸F-DCFPyL (1.79 ± 0.39 and 13.25 ± 1.65). The uptake of Al¹⁸F-PSMA-Q in 22Rv1 cells and tumors can be substantially blocked by 2-PMPA. High level accumulation of Al¹⁸F-PSMA-Q was observed in organs physiologically expressing PSMA. Twenty-six tumor lesions were detected in 20 PCa patients, and the mean SUVmax values of primary tumors, lymph node metastasis, bone metastases, and tumor-muscle ratios were 19.71 ± 16.52, 5.11, 31.30 ± 29.85, and 44.77 ± 22.29, respectively. The mean SUVmax of tumors in patients with PSA > 10 ng/mL was significantly higher than that in patients with PSA ≤ 10 ng/mL (25.97 ± 18.64 vs. 10.33 ± 3.74). Meanwhile, the mean SUVmax of tumors in patients with a Gleason score ≥ 8 was significantly higher than that in patients with a Gleason score < 8 (31.85 ± 22.09 vs. 13.18 ± 11.58). The kidneys received the highest estimated dose of 0.098 ± 0.006 mGy/MBq, and the effective dose was calculated as 0.0128 ± 0.007 mGy/MBq.

The novel qualified PSMA-targeted radiotracer Al¹⁸F-PSMA-Q was conveniently prepared with favorable yield and SA. The results of preclinical and pilot clinical studies exhibited a high specific uptake in PCa lesions and an excellent tumor-to-background ratio with a reasonable radiation exposure, which indicated the great potential of Al¹⁸F-PSMA-Q for PCa imaging.

Chinese Clinical trial registry ChiCTR2100053507, Registered 23 November 2021, retrospectively registered.