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Theranostics 2023; 13(13):4559-4573. doi:10.7150/thno.87663 This issue Cite

Research Paper

Lys-urea-Aad, Lys-urea-Cmc and Lys-urea-Cms as potential pharmacophores for the design of PSMA-targeted radioligands to reduce off-target uptake in kidneys and salivary glands

Hsiou-Ting Kuo1, Zhengxing Zhang1, Chengcheng Zhang1, Helen Merkens1, Ruiyan Tan1, Antonio A. W. L. Wong1, Carlos F. Uribe2,3, François Bénard1,2,3✉, Kuo-Shyan Lin1,2,3✉

1. Department of Molecular Oncology, BC Cancer, Vancouver, BC V5Z1L3, Canada
2. Department of Functional Imaging, BC Cancer, Vancouver, BC V5Z4E6, Canada
3. Department of Radiology, University of British Columbia, Vancouver, BC V5Z1M9, Canada

✉ Corresponding author: François Bénard, MD. Address: 675 West 10th Avenue, Rm 14-111, Vancouver, BC V5Z1L3, Canada. Phone: 604-675-8206 Fax: 604-675-8218 E-mail: fbenardca Kuo-Shyan Lin, PhD. Address: 675 West 10th Avenue, Rm 4-123, More

Citation:
Kuo HT, Zhang Z, Zhang C, Merkens H, Tan R, Wong AAWL, Uribe CF, Bénard F, Lin KS. Lys-urea-Aad, Lys-urea-Cmc and Lys-urea-Cms as potential pharmacophores for the design of PSMA-targeted radioligands to reduce off-target uptake in kidneys and salivary glands. Theranostics 2023; 13(13):4559-4573. doi:10.7150/thno.87663. https://www.thno.org/v13p4559.htm
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Abstract

Graphic abstract

High kidney and salivary gland uptake is a common feature of prostate-specific membrane antigen (PSMA)-targeted radioligands derived from the lysine-urea-glutamic acid (Lys-urea-Glu) pharmacophore. In this study we investigated if radioligands derived from lysine-urea-2-aminoadipic acid (Lys-urea-Aad), lysine-urea-S-carboxylmethylcysteine (Lys-urea-Cmc) and lysine-urea-O-carboxylmethylserine (Lys-urea-Cms) pharmacophores with/without an albumin binder could retain good PSMA-targeting capability but with minimized kidney and salivary gland uptake.

Methods: HTK03177 and HTK03187 were obtained by replacing Aad in the previously reported

Lys-urea-Aad-derived HTK03149 with Cmc and Cms, respectively. HTK03170, HTK04048 and HTK04028 were derived from HTK03149, HTK03177 and HTK03187, respectively, with the conjugation of an albumin-binding moiety, 4-(p-methoxyphenyl)butyric acid. In vitro competition binding assays were conducted using PSMA-expressing LNCaP prostate cancer cells and [18F]DCFPyL as the radioligand. Imaging and biodistribution studies of 68Ga-labeled HTK03177 and HTK03187, and 177Lu-labeled HTK03170, HTK04048 and HTK04028 were performed in LNCaP tumor-bearing mice. Radioligand therapy study of [177Lu]Lu-HTK03170 was carried out in LNCaP tumor-bearing mice and [177Lu]Lu-PSMA-617 was used for comparison.

Results: The calculated Ki(PSMA) values of Ga-HTK03177, Ga-HTK03187, Lu-HTK03170, Lu-HTK04048 and Lu-HTK04028 were 5.0±2.4, 10.6±2.0, 1.6±0.4, 1.4±1.0 and 13.9±3.2 nM, respectively. PET Imaging and biodistribution studies at 1 h post-injection showed that both [68Ga]Ga-HTK03177 and [68Ga]Ga-HTK03187 had high uptake in LNCaP tumor xenografts (24.7±6.85 and 21.1±3.62 %ID/g, respectively) but minimal uptake in normal organs/tissues including kidneys (7.76±1.00 and 2.83±0.45 %ID/g, respectively) and salivary glands (0.22±0.02 and 0.16±0.02 %ID/g, respectively). SPECT imaging and biodistribution studies showed that the LNCaP tumor uptake of 177Lu-labeled HTK03170, HTK04048 and HTK04028 peaked at 4-24 h post-injection at ~43-65 %ID/g and was relatively sustained over time. Their peaked average uptake in kidneys (≤ 17.4 %ID/g) and salivary glands (≤ 2.92 %ID/g) was lower and continuously reduced over time. Radioligand therapy study showed that compared with [177Lu]Lu-PSMA-617 (37 MBq), a quarter dose of [177Lu]Lu-HTK03170 (9.3 MBq) led to a better median survival (63 vs 90 days).

Conclusions: Our data demonstrate that that Lys-urea-Aad, Lys-urea-Cmc and Lys-urea-Cms are promising pharmacophores for the design of PSMA-targeted radioligands especially for radiotherapeutic applications to minimize toxicity to kidneys and salivary glands.

Keywords: Prostate-specific membrane antigen, Targeted radioligand therapy, Salivary gland, Off-target uptake, Tumor-to-kidney absorbed dose ratio

Citation styles

APA
Kuo, H.T., Zhang, Z., Zhang, C., Merkens, H., Tan, R., Wong, A.A.W.L., Uribe, C.F., Bénard, F., Lin, K.S. (2023). Lys-urea-Aad, Lys-urea-Cmc and Lys-urea-Cms as potential pharmacophores for the design of PSMA-targeted radioligands to reduce off-target uptake in kidneys and salivary glands. Theranostics, 13(13), 4559-4573. https://doi.org/10.7150/thno.87663.

ACS
Kuo, H.T.; Zhang, Z.; Zhang, C.; Merkens, H.; Tan, R.; Wong, A.A.W.L.; Uribe, C.F.; Bénard, F.; Lin, K.S. Lys-urea-Aad, Lys-urea-Cmc and Lys-urea-Cms as potential pharmacophores for the design of PSMA-targeted radioligands to reduce off-target uptake in kidneys and salivary glands. Theranostics 2023, 13 (13), 4559-4573. DOI: 10.7150/thno.87663.

NLM
Kuo HT, Zhang Z, Zhang C, Merkens H, Tan R, Wong AAWL, Uribe CF, Bénard F, Lin KS. Lys-urea-Aad, Lys-urea-Cmc and Lys-urea-Cms as potential pharmacophores for the design of PSMA-targeted radioligands to reduce off-target uptake in kidneys and salivary glands. Theranostics 2023; 13(13):4559-4573. doi:10.7150/thno.87663. https://www.thno.org/v13p4559.htm

CSE
Kuo HT, Zhang Z, Zhang C, Merkens H, Tan R, Wong AAWL, Uribe CF, Bénard F, Lin KS. 2023. Lys-urea-Aad, Lys-urea-Cmc and Lys-urea-Cms as potential pharmacophores for the design of PSMA-targeted radioligands to reduce off-target uptake in kidneys and salivary glands. Theranostics. 13(13):4559-4573.

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