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Halogen Replacement on the Lysine Side Chain of Lys-Urea-Glu-Based PSMA Inhibitors Leads to Significant Changes in Targeting Properties

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Abstract

Purpose

Investigate the impact of various halogens on pharmacokinetics, biodistribution, and micro positron emission tomography/computed tomography (PET/CT) imaging of Glu-urea-Lys-based prostate-specific membrane antigen (PSMA) inhibitors.

Procedures

Based on the modification of SC691, a small molecule inhibitor of PSMA previously developed by our group, we synthesized 68Ga-labeled compounds by modifying the lysine terminal amino with different halogenated phenyl substituents. After complete characterization, in vitro and in vivo properties were studied.

Results

The [68Ga]Ga-DOTA-SC691-R possesses a high radiochemical yield (98–99%). The internalization values of [68Ga]Ga-DOTA-SC691-H, [68Ga]Ga-DOTA-SC691-Cl, and [68Ga]Ga-DOTA-SC691-Br in LNCaP cells all displayed time-dependent pattern enhanced with time. The results of in vitro competitive inhibition assay showed that the affinity of natGa-DOTA-SC691-R for PSMA had a trend of H < F < Cl < Br < I. The blocking imaging and dynamic imaging on micro-PET/CT of male non-obese diabetic/severe combined immunodeficiency mice with LNCaP tumors showed the rapid tumor targeting properties of [68Ga]Ga-DOTA-SC691-R with specificity for PSMA. Static imaging of micro-PEC/CT of these compounds could rapidly localize LNCaP tumors with decent image quality (except for [68Ga]Ga-DOTA-SC691-H). Biodistribution data showed that [68Ga]Ga-DOTA-SC691-R were metabolized via the kidney and tumor accumulation followed the order of H ≈ F ≈ Cl < I < Br uptake values at 1 h. [68Ga]Ga-DOTA-SC691-Br showed the highest tumor accumulation and retention (15.21 ± 5.57%ID/g at 30 min, 20.39 ± 4.38%ID/g at 60 min, and 13.30 ± 4.39%ID/g at 120 min), which is consistent with the results of the competitive inhibition assay and cell binding assay.

Conclusions

It was demonstrated that the halogen substituent on the lysine terminal amino group on the Glu-urea-Lys backbone did positively affect the binding of [68Ga]Ga-DOTA-SC691-R to PSMA. The bulkier and less electronegative Br (or I) elements are preferred for structural modifications here.

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Funding

The authors would like to thank the National Natural Science Foundation of China for funding this work (U20A20384), the Sichuan Science and Technology Foundation (2021YJ0131), the Doctoral Research Initiation Fund of Affiliated Hospital of Southwest Medical University, Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province (HYX19001), and the Luzhou-Southwest Medical University Cooperative Application Foundation (2020LZXNYDJ50).

Author information

Authors and Affiliations

  1. Department of Nuclear Medicine, Affiliated Hospital of Southwest Medical University, Jiangyang District, Luzhou, Sichuan, China

    Li Xia, Yang Liu, Ping Cai, Yue Feng, Hongmei Yuan, Sufan Tang, Yin wen Wang, Nan Liu, Yue Chen & Zhijun Zhou

  2. Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Jiangyang District, Luzhou, Sichuan, China

    Li Xia, Yang Liu, Ping Cai, Yue Feng, Hongmei Yuan, Sufan Tang, Yin wen Wang, Yue Chen & Zhijun Zhou

  3. Institute of Nuclear Medicine, Southwest Medical University, Jiangyang District, Luzhou, Sichuan, China

    Yang Liu, Yue Feng, Yue Chen & Zhijun Zhou

  4. Department of Pharmaceutics, School of Pharmacy, Southwest Medical University, Jiangyang District, Luzhou, Sichuan, China

    Li Xia, Ping Cai, Hongmei Yuan, Sufan Tang, Yin wen Wang & Zhijun Zhou

  5. Department of Nuclear Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Sichuan, Chengdu, China

    Nan Liu

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  1. Li Xia
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Contributions

Conceptualization: Zhijun Zhou and Yue Chen; methodology: Li Xia, Nan Liu, and Zhijun Zhou; validation: Li Xia and Yang Liu; formal analysis: Zhijun Zhou and Li Xia; investigation: Li Xia, Yang Liu, Ping Cai, Yue Feng, Hongmei Yuan, Sufan Tang, and Yinwen Wang; data curation: Li Xia and Yang Liu; writing: Li Xia; funding acquisition: Yue Chen and Zhijun Zhou; resources: Yue Chen and Zhijun Zhou; review: Zhijun Zhou, Li Xia, Yang Liu, Ping Cai, Yue Feng, Hongmei Yuan, Sufan Tang, Yinwen Wang, Yue Chen, and Nan Liu.

Corresponding authors

Correspondence to Nan Liu, Yue Chen or Zhijun Zhou.

Ethics declarations

Ethics Approval

The Ethics Committee for Southwest Medical University (2021-02-29) approved the study. All methods were carried out following relevant guidelines and regulations, and all methods are reported per ARRIVE guidelines.

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The authors declare no competing interests.

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Supplementary Information

ESM 1:

Suppl. Fig. 1 1H NMR of DOTA-SC691-H. Suppl. Fig. 2 Mass Spectroscopy of DOTA-SC691-H. Suppl. Fig. 3 1H NMR of DOTA-SC691-F. Suppl. Fig. 4 Mass Spectroscopy of DOTA-SC691-F. Suppl. Fig. 5 1H NMR of DOTA-SC691-Cl. Suppl. Fig. 6 Mass Spectroscopy of DOTA-SC691-Cl. Suppl. Fig. 7 1H NMR of DOTA-SC691-Br. Suppl. Fig. 8 Mass Spectroscopy of DOTA-SC691-Br. Suppl. Fig. 9 1H NMR of DOTA-SC691-3FM. Suppl. Fig. 10 Mass Spectroscopy of DOTA-SC691-3FM. Suppl. Fig. 11 1H NMR of DOTA-SC691-6KL. Suppl. Fig. 12 Mass Spectroscopy of DOTA-SC691-6KL. Suppl. Fig. 13 1H NMR of DOTA-SC691-7KL. Suppl. Fig. 14 Mass Spectroscopy of DOTA-SC691-7KL. Suppl. Fig. 15 Stability of [68Ga]Ga-DOTA-SC691-R. Suppl. Fig. 16 Displacement curves of natGa-DOTA-SC691-R and natGa-PSMA-11 competitive inhibition of [68Ga]Ga-PSMA-11 binding to LNCaP cells. Suppl. Fig. 17 %ID/gmean curves of dynamic Micro-PET/CT scans. Suppl. Fig. 18 Micro-PET/CT images of blocking studies. Suppl. Table 1 Organ biodistribution of [68Ga]Ga-DOTA-SC691-Br and [68Ga]Ga-DOTA-SC691-I. (DOCX 21376 kb)

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Xia, L., Liu, Y., Cai, P. et al. Halogen Replacement on the Lysine Side Chain of Lys-Urea-Glu-Based PSMA Inhibitors Leads to Significant Changes in Targeting Properties. Mol Imaging Biol 25, 765–775 (2023). https://doi.org/10.1007/s11307-023-01804-x

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