Kwon Daniel, Zhang Zhengxing, Zeisler Jutta, Kuo Hsiou-Ting, Lin Kuo-Shyan, Benard Francois
Department of Molecular Oncology, BC Cancer, Vancouver, BC V5Z 1L3, Canada.
Department of Radiology, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
Pharmaceutics. 2022 Jul 20;14(7):1502. doi: 10.3390/pharmaceutics14071502.
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 [Ga]Ga-BL02, with modifications to its linker and metal chelator, in order to improve its tumor-to-kidney contrast ratio.
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 Ga and evaluated in CXCR4-expressing Daudi xenograft mice with biodistribution and/or PET imaging studies.
Of all the evaluated radiotracers, [Ga]Ga-BL31 showed the most promising biodistribution profile, with a lower kidney uptake compared to [Ga]Ga-BL02, while retaining the high imaging contrast capabilities of [Ga]Ga-BL02. [Ga]Ga-BL31 also compared favorably to [Ga]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 [Ga]Ga-BL02; however, [Ga]Ga-BL25 also showed lower kidney uptake, as compared to that of [Ga]Ga-BL02. Meanwhile, [Ga]Ga-BL06 had high non-target organ uptake and relatively lower tumor uptake, while [Ga]Ga-BL30 showed significantly increased kidney uptake and similar tumor uptake values.
[Ga]Ga-BL31 is an optimized CXCR4-targeting radiopharmaceutical with lower kidney retention that has clinical potential for PET imaging and radioligand therapy.
C-X-C趋化因子受体4（CXCR4）在多种癌症亚型中高表达，尤其是在几种肾脏恶性肿瘤中。我们基于先前的高对比度PET成像放射性药物[Ga]Ga-BL02，对其连接子和金属螯合剂进行修饰，合成、标记并评估了一系列放射性示踪剂，以提高其肿瘤与肾脏的对比度。
基于BL02的设计，用哌啶基阳离子连接子（BL06）和几种阴离子连接子（三丙氨酸（BL17）；三-D-谷氨酸（BL20）；三-天冬氨酸（BL25）；和三半胱氨酸（BL31））取代三谷氨酸连接子。此外，将DOTA螯合剂换成DOTAGA螯合剂（BL30）。每种放射性示踪剂都用Ga标记，并在表达CXCR4的Daudi异种移植小鼠中进行生物分布和/或PET成像研究评估。
在所有评估的放射性示踪剂中，[Ga]Ga-BL31显示出最有前景的生物分布特征，与[Ga]Ga-BL02相比，肾脏摄取较低，同时保留了[Ga]Ga-BL02的高成像对比度。[Ga]Ga-BL31与[Ga]Ga-Pentixafor相比也表现良好，在所有非靶器官中具有更高的成像对比度。与[Ga]Ga-BL02相比，其他基于阴离子连接子的放射性示踪剂显示出不确定或更差的对比度；然而，与[Ga]Ga-BL02相比，[Ga]Ga-BL25的肾脏摄取也较低。同时，[Ga]Ga-BL06的非靶器官摄取较高，肿瘤摄取相对较低，而[Ga]Ga-BL30的肾脏摄取显著增加，肿瘤摄取值相似。
[Ga]Ga-BL31是一种优化的靶向CXCR4的放射性药物，肾脏滞留较低，具有PET成像和放射性配体治疗的临床潜力。
