Imaging Bradykinin B1 Receptor with 68Ga-Labeled [des-Arg10]Kallidin Derivatives: Effect of the Linker on Biodistribution and Tumor Uptake

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• 作者：Guillaume Amouroux ; Jinhe Pan ; Silvia Jenni ; Chengcheng Zhang ; Zhengxing Zhang ; Navjit Hundal-Jabal ; Nadine Colpo ; Zhibo Liu ; Fran莽ois B茅nard ; Kuo-Shyan Lin
• 刊名：Molecular Pharmaceutics
• 出版年：2015
• 出版时间：August 3, 2015
• 年：2015
• 卷：12
• 期：8
• 页码：2879-2888
• 全文大小：429K
• ISSN：1543-8392

文摘

Bradykinin B1 receptor (B1R) that is overexpressed in cancers but minimally expressed in normal healthy tissues represents an attractive biomarker for the development of cancer imaging agents. The goal of this study was to evaluate the effect of different linkers on the pharmacokinetics and tumor uptake of a B1R-targeting radio-peptide sequence, ⁶⁸Ga-DOTA-linker-Lys-Arg-Pro-Hyp-Gly-Cha-Ser-Pro-Leu. Four peptides, SH01078, P03034, P04115, and P04168, with 6-aminohexanoic acid, 9-amino-4,7-dioxanonanoic acid, Gly-Gly, and 4-amino-(1-carboxymethyl)piperidine, respectively, as the linker were synthesized and evaluated. In vitro competition binding assays showed that the K_i values of SH01078, P03034, P04115, and P04168 were 27.8 卤 4.9, 16.0 卤 1.9, 11.4 卤 2.5, and 3.6 卤 0.2 nM, respectively. Imaging and biodistribution studies were performed in mice bearing both B1R-positive HEK293T::hB1R and B1R-negative HEK293T tumors. All tracers showed mainly renal excretion with excellent tumor visualization and minimal background activity except for kidneys and bladder. The average uptake of ⁶⁸Ga-labeled SH01078, P03034, and P04115 in HEK293T::hB1R tumor was similar (1.96鈥?.17%ID/g) at 1 h postinjection. ⁶⁸Ga-P04168 generated higher HEK293T::hB1R tumor uptake (4.15 卤 1.13%ID/g) and lower background activity, leading to a >2-fold improvement in HEK293T::hB1R tumor-to-background (HEK293T tumor, blood, muscle, and liver) contrasts over those of ⁶⁸Ga-labeled SH01078, P03034, and P04115. Our results indicate that the choice of linker affects binding affinity, pharmacokinetics, and tumor targeting. The use of the cationic 4-amino-(1-carboxymethyl)piperidine linker improved tumor visualization, and the resulting ⁶⁸Ga-P04168 might be promising for clinical application for imaging B1R-expressing tumors with positron emission tomography.