title: Imaging Bradykinin B1 Receptor with 68Ga-Labeled [des-Arg10]Kallidin Derivatives: Effect of the Linker on Biodistribution and Tumor Uptake.
abstract: 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 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.
authors.affiliation: †Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Amouroux
authors.affiliation: †Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Jinhe
authors.initials: J
authors.lastname: Pan
authors.affiliation: †Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Silvia
authors.initials: S
authors.lastname: Jenni
authors.affiliation: †Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: †Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Zhengxing
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: †Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Navjit
authors.initials: N
authors.lastname: Hundal-Jabal
authors.affiliation: †Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Nadine
authors.initials: N
authors.lastname: Colpo
authors.affiliation: ‡Chemistry Department, University of British Columbia, Vancouver, BC V6T 1Z1, Canada.
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Liu
authors.affiliation: †Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.|§Department of Radiology, University of British Columbia, Vancouver, BC V5Z 4E3, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Bénard
authors.affiliation: †Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.|§Department of Radiology, University of British Columbia, Vancouver, BC V5Z 4E3, Canada.
authors.forename: Kuo-Shyan
authors.initials: KS
authors.lastname: Lin
mesh_terms: D000818:Animals; D003287:Contrast Media / Q000493:pharmacokinetics; D005710:Gallium Radioisotopes / Q000493:pharmacokinetics*; D057809:HEK293 Cells; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007609:Kallidin / Q000031:analogs & derivatives* / Q000737:chemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology*; D010446:Peptide Fragments / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D043783:Receptor, Bradykinin B1 / Q000378:metabolism*; D015375:Receptors, Interleukin-2 / Q000502:physiology; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed
chemical_list: D003287:Contrast Media; D005710:Gallium Radioisotopes; D010446:Peptide Fragments; D019275:Radiopharmaceuticals; D043783:Receptor, Bradykinin B1; D015375:Receptors, Interleukin-2; D007609:Kallidin; C052787:kallidin, des-Arg(10)-
keywords: antagonist; bradykinin B1 receptor; gallium-68; kallidin; linker; positron emission tomography