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

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Abstract

Purpose

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

Methods

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.

Result

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.

Conclusion

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.

Trial registration

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

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Abbreviations

PET/CT:

Positron emission tomography/computed tomography

HPLC:

High performance liquid chromatography

MIP:

Maximum intensity projection

PBS:

Phosphate-buffered saline

p.i.:

Post-injection

2-PMPA:

2-(Phosphonomethyl) pentanedioic acid

PSMA:

Prostate-specific membrane antigen

SD:

Standard deviation

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Acknowledgements

We thank Prof. Xing Yang and Dr. Xiaojiang Duan (Department of Nuclear Medicine, Peking University First Hospital) for providing the 22Rv1 tumor-bearing mice and technical assistance.

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Authors and Affiliations

  1. Department of Nuclear Medicine, Chinese PLA General Hospital, No. 28 Fu-Xing Rd., Beijing, 100853, China

    Yitian Wu, Xiaojun Zhang, Haoxi Zhou, Baixuan Xu, Jiahe Tian, Shuwei Sun & Jinming Zhang

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  1. Yitian Wu
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  2. Xiaojun Zhang
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Contributions

J. Zhang and Y. Wu conceived and designed the experiments. Y. Wu performed the experiments. Y. Wu and H. Zhou analyzed the data. J. Zhang contributed reagents, materials, and analysis tools. Y. Wu wrote the paper.

Corresponding author

Correspondence to Jinming Zhang.

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Ethics approval

The rat studies in this research were regulated under the Animals (Scientific Procedures) Act 1986 Amendment Regulations 2012 following ethical review by the Animal Care and Use Committee of Chinese PLA General Hospital. The preliminary human study was approved by the Ethics Committee of Chinese PLA General Hospital (approval of No. S2020-324–01).

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Informed consent was obtained from all individual participants included in the study.

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The authors declare no competing interests.

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This article is part of the Topical Collection on Oncology—Genitourinary

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Wu, Y., Zhang, X., Zhou, H. et al. Synthesis, preclinical evaluation, and first-in-human study of Al18F-PSMA-Q for prostate cancer imaging. Eur J Nucl Med Mol Imaging 49, 2774–2785 (2022). https://doi.org/10.1007/s00259-022-05775-z

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