title: In vivo radioimaging of bradykinin receptor b1, a widely overexpressed molecule in human cancer.
abstract: The bradykinin receptor B1R is overexpressed in many human cancers where it might be used as a general target for cancer imaging. In this study, we evaluated the feasibility of using radiolabeled kallidin derivatives to visualize B1R expression in a preclinical model of B1R-positive tumors. Three synthetic derivatives were evaluated in vitro and in vivo for receptor binding and their ability to visualize tumors by PET. Enalaprilat and phosphoramidon were used to evaluate the impact of peptidases on tumor visualization. While we found that radiolabeled peptides based on the native kallidin sequence were ineffective at visualizing B1R-positive tumors, peptidase inhibition with phosphoramidon greatly enhanced B1R visualization in vivo. Two stabilized derivatives incorporating unnatural amino acids ((68)Ga-SH01078 and (68)Ga-P03034) maintained receptor-binding affinities that were effective, allowing excellent tumor visualization, minimal accumulation in normal tissues, and rapid renal clearance. Tumor uptake was blocked in the presence of excess competitor, confirming that the specificity of tumor accumulation was receptor mediated. Our results offer a preclinical proof of concept for noninvasive B1R detection by PET imaging as a general tool to visualize many human cancers.
authors.affiliation: BC Cancer Agency, Vancouver, BC, Canada. Department of Radiology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Kuo-Shyan
authors.initials: KS
authors.lastname: Lin
authors.affiliation: BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Jinhe
authors.initials: J
authors.lastname: Pan
authors.affiliation: BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Amouroux
authors.affiliation: BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Gulisa
authors.initials: G
authors.lastname: Turashvili
authors.affiliation: BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Felix
authors.initials: F
authors.lastname: Mesak
authors.affiliation: BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Navjit
authors.initials: N
authors.lastname: Hundal-Jabal
authors.affiliation: BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Maral
authors.initials: M
authors.lastname: Pourghiasian
authors.affiliation: BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Joseph
authors.initials: J
authors.lastname: Lau
authors.affiliation: BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Silvia
authors.initials: S
authors.lastname: Jenni
authors.affiliation: BC Cancer Agency, Vancouver, BC, Canada. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Samuel
authors.initials: S
authors.lastname: Aparicio
authors.affiliation: BC Cancer Agency, Vancouver, BC, Canada. Department of Radiology, University of British Columbia, Vancouver, BC, Canada. fbenard@bccrc.ca.
authors.forename: François
authors.initials: F
authors.lastname: Bénard
mesh_terms: D000818:Animals; D005710:Gallium Radioisotopes / Q000097:blood / Q000737:chemistry*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism; D009942:Organometallic Compounds / Q000097:blood / Q000737:chemistry; D010455:Peptides / Q000097:blood / Q000737:chemistry / Q000187:drug effects*; D049268:Positron-Emission Tomography / Q000379:methods*; D043783:Receptor, Bradykinin B1 / Q000032:analysis* / Q000096:biosynthesis / Q000737:chemistry
chemical_list: D005710:Gallium Radioisotopes; D009942:Organometallic Compounds; D010455:Peptides; D043783:Receptor, Bradykinin B1