title: Radiolabeled R954 Derivatives for Imaging Bradykinin B1 Receptor Expression with Positron Emission Tomography.
abstract: Peptide receptors have emerged as promising targets for diagnosis and therapy. The aberrant overexpression of these receptors in different cancer subtypes allows for the adoption of new treatment strategies that complement conventional chemotherapies. Bradykinin B1 receptor (B1R) is a G protein-coupled receptor that is overexpressed in many cancers, with limited expression in healthy tissues. Previously, we developed68Ga- and18F-labeled derivatives of B1R antagonist peptides B9858 and B9958, and successfully targeted B1R-expressing tumor xenografts in vivo. R954 (Ac-Orn-Arg-Oic-Pro-Gly-αMePhe-Ser-d-2-Nal-Ile), a potent B1R antagonist, is reportedly more stable than B9858 against peptidase degradation. We evaluated two radiolabeled derivatives of R954 (68Ga-HTK01083 and18F-HTK01146) for B1R PET imaging. Peptides were synthesized via solid phase strategy. Nonradioactive standards were obtain by reacting GaCl3with DOTA-dPEG2-R954 and by clicking N-propargyl-N,N-dimethylammoniomethyl-trifluoroborate with azidoacetyl-dPEG2-R954. Binding affinity for B1R was determined by an in vitro competition binding assay.68Ga-HTK01083 was obtained by incubating DOTA-dPEG2-R954 with68GaCl3under acidic conditions, while18F-HTK01146 was prepared via an18F-19F isotope exchange reaction. Biodistribution and imaging studies were conducted at 1 h postinjection (p.i.) in mice inoculated with B1R-expressing (B1R+) and B1R-nonexpressing (B1R-) cells. HTK01083 and HTK01146 bound B1R with good affinity (Ki= 30.5 and 24.8 nM, respectively).68Ga/18F-labeled R954 were obtained on average in ≥10% decay-corrected radiochemical yield with >99% radiochemical purity and ≥52 GBq/μmol specific activity. For both tracers, clearance was predominantly renal with minimal involvement of the hepatobiliary system. For PET images, B1R+ tumors, kidneys, and bladder were visible. At 1 h p.i., uptake in B1R+ tumor was comparable between68Ga-HTK01083 (8.46 ± 1.44%ID/g) and18F-HTK01146 (9.25 ± 0.69%ID/g). B1R+ tumor-to-blood and B1R+ tumor-to-muscle ratios were 6.32 ± 1.44 and 20.7 ± 3.58 for68Ga-HTK01083, and 7.24 ± 2.56 and 19.5 ± 4.29 for18F-HTK01146. Our results indicate R954 is a good lead sequence for optimization of B1R tracers for cancer imaging.
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency , Vancouver, BC V5Z 1L3, Canada.
authors.forename: Hsiou-Ting
authors.initials: HT
authors.lastname: Kuo
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: Joseph
authors.initials: J
authors.lastname: Lau
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: Jutta
authors.initials: J
authors.lastname: Zeisler
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency , Vancouver, BC V5Z 1L3, Canada.
authors.forename: Nadine
authors.identifier: 0000-0001-9253-6539
authors.initials: N
authors.lastname: Colpo
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency , Vancouver, BC V5Z 1L3, Canada.|Department of Functional Imaging, BC Cancer Agency , Vancouver, BC V5Z 4E6, 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 Functional Imaging, BC Cancer Agency , Vancouver, BC V5Z 4E6, Canada.|Department of Radiology, University of British Columbia , Vancouver, BC V5Z 4E3, Canada.
authors.forename: Kuo-Shyan
authors.identifier: 0000-0002-0739-0780
authors.initials: KS
authors.lastname: Lin
mesh_terms: D000818:Animals; D065169:Bradykinin B1 Receptor Antagonists / Q000378:metabolism*; D002460:Cell Line; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism*; D005710:Gallium Radioisotopes / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000175:diagnosis / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000378:metabolism*; D043783:Receptor, Bradykinin B1 / Q000378:metabolism*; D014018:Tissue Distribution / Q000187:drug effects*
chemical_list: D065169:Bradykinin B1 Receptor Antagonists; D005710:Gallium Radioisotopes; D010455:Peptides; D019275:Radiopharmaceuticals; D043783:Receptor, Bradykinin B1; D019788:Fluorodeoxyglucose F18
keywords: R954; bradykinin B1 receptor; fluorine-18; gallium-68; positron emission tomography