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Reducing the Kidney Uptake of High Contrast CXCR4 PET Imaging Agents via Linker Modifications Kwon, Daniel; Zhang, Zhengxing; Zeisler, Jutta; Kuo, Hsiou-Ting; Lin, Kuo-Shyan; Bénard, François
Abstract
Purpose: The C-X-C chemokine receptor 4 (CXCR4) is highly expressed in many subtypes of cancers, notably in several kidney-based malignancies. We synthesized, labeled, and assessed a series of radiotracers based on a previous high contrast PET imaging radiopharmaceutical [68Ga]Ga-BL02, with modifications to its linker and metal chelator, in order to improve its tumor-to-kidney contrast ratio. Methods: Based on the design of BL02, a piperidine-based cationic linker (BL06) and several anionic linkers (tri-Aad (BL17); tri-D-Glu (BL20); tri-Asp (BL25); and tri-cysteic acid (BL31)) were substituted for the triglutamate linker. Additionally, the DOTA chelator was swapped for a DOTAGA chelator (BL30). Each radiotracer was labeled with 68Ga and evaluated in CXCR4-expressing Daudi xenograft mice with biodistribution and/or PET imaging studies. Results: Of all the evaluated radiotracers, [68Ga]Ga-BL31 showed the most promising biodistribution profile, with a lower kidney uptake compared to [68Ga]Ga-BL02, while retaining the high imaging contrast capabilities of [68Ga]Ga-BL02. [68Ga]Ga-BL31 also compared favorably to [68Ga]Ga-Pentixafor, with superior imaging contrast in all non-target organs. The other anionic linker-based radiotracers showed either equivocal or worse contrast ratios compared to [68Ga]Ga-BL02; however, [68Ga]Ga-BL25 also showed lower kidney uptake, as compared to that of [68Ga]Ga-BL02. Meanwhile, [68Ga]Ga-BL06 had high non-target organ uptake and relatively lower tumor uptake, while [68Ga]Ga-BL30 showed significantly increased kidney uptake and similar tumor uptake values. Conclusions: [68Ga]Ga-BL31 is an optimized CXCR4-targeting radiopharmaceutical with lower kidney retention that has clinical potential for PET imaging and radioligand therapy.
Item Metadata
Title |
Reducing the Kidney Uptake of High Contrast CXCR4 PET Imaging Agents via Linker Modifications
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Creator | |
Contributor | |
Publisher |
Multidisciplinary Digital Publishing Institute
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Date Issued |
2022-07-20
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Description |
Purpose: The C-X-C chemokine receptor 4 (CXCR4) is highly expressed in many subtypes of cancers, notably in several kidney-based malignancies. We synthesized, labeled, and assessed a series of radiotracers based on a previous high contrast PET imaging radiopharmaceutical [68Ga]Ga-BL02, with modifications to its linker and metal chelator, in order to improve its tumor-to-kidney contrast ratio. Methods: Based on the design of BL02, a piperidine-based cationic linker (BL06) and several anionic linkers (tri-Aad (BL17); tri-D-Glu (BL20); tri-Asp (BL25); and tri-cysteic acid (BL31)) were substituted for the triglutamate linker. Additionally, the DOTA chelator was swapped for a DOTAGA chelator (BL30). Each radiotracer was labeled with 68Ga and evaluated in CXCR4-expressing Daudi xenograft mice with biodistribution and/or PET imaging studies. Results: Of all the evaluated radiotracers, [68Ga]Ga-BL31 showed the most promising biodistribution profile, with a lower kidney uptake compared to [68Ga]Ga-BL02, while retaining the high imaging contrast capabilities of [68Ga]Ga-BL02. [68Ga]Ga-BL31 also compared favorably to [68Ga]Ga-Pentixafor, with superior imaging contrast in all non-target organs. The other anionic linker-based radiotracers showed either equivocal or worse contrast ratios compared to [68Ga]Ga-BL02; however, [68Ga]Ga-BL25 also showed lower kidney uptake, as compared to that of [68Ga]Ga-BL02. Meanwhile, [68Ga]Ga-BL06 had high non-target organ uptake and relatively lower tumor uptake, while [68Ga]Ga-BL30 showed significantly increased kidney uptake and similar tumor uptake values. Conclusions: [68Ga]Ga-BL31 is an optimized CXCR4-targeting radiopharmaceutical with lower kidney retention that has clinical potential for PET imaging and radioligand therapy.
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Subject | |
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Type | |
Language |
eng
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Date Available |
2023-01-11
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Provider |
Vancouver : University of British Columbia Library
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Rights |
CC BY 4.0
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DOI |
10.14288/1.0423029
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URI | |
Affiliation | |
Citation |
Pharmaceutics 14 (7): 1502 (2022)
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Publisher DOI |
10.3390/pharmaceutics14071502
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Peer Review Status |
Reviewed
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Scholarly Level |
Faculty
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Rights
CC BY 4.0