Imaging Bradykinin B1 Receptor with 68Ga-Labeled [des-Arg10]Kallidin Derivatives: Effect of the Linker on Biodistribution and Tumor Uptake
| Autor: | Zhibo Liu, Chengcheng Zhang, Jinhe Pan, Francois Benard, Kuo-Shyan Lin, Navjit Hundal-Jabal, Nadine Colpo, Guillaume Amouroux, Zhengxing Zhang, Silvia Jenni |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Biodistribution Contrast Media Pharmaceutical Science Bradykinin Gallium Radioisotopes Mice SCID Receptor Bradykinin B1 Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Pharmacokinetics Mice Inbred NOD Neoplasms Drug Discovery Image Processing Computer-Assisted Animals Humans Tissue Distribution Receptor 030304 developmental biology Mice Knockout Mice Inbred BALB C 0303 health sciences Kallidin Receptors Interleukin-2 Molecular biology Peptide Fragments In vitro 3. Good health HEK293 Cells chemistry Biochemistry Positron-Emission Tomography 030220 oncology & carcinogenesis Renal physiology Molecular Medicine Radiopharmaceuticals Tomography X-Ray Computed Linker |
| Zdroj: | Molecular Pharmaceutics. 12:2879-2888 |
| ISSN: | 1543-8392 1543-8384 |
| DOI: | 10.1021/acs.molpharmaceut.5b00070 |
| Popis: | 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 Ki values of SH01078, P03034, P04115, and P04168 were 27.8±4.9, 16.0±1.9, 11.4±2.5, and 3.6±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 (1.96-2.17%ID/g) at 1 h postinjection. 68Ga-P04168 generated higher HEK293T::hB1R tumor uptake (4.15±1.13%ID/g) and lower background activity, leading to a2-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. |
| Databáze: | OpenAIRE |
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