title: Radiolabeled B9958 Derivatives for Imaging Bradykinin B1 Receptor Expression with Positron Emission Tomography: Effect of the Radiolabel-Chelator Complex on Biodistribution and Tumor Uptake.
abstract: Bradykinin B1 receptor (B1R), which is upregulated in a variety of malignancies, is an attractive cancer imaging biomarker. In this study we optimized the selection of radiolabel-chelator complex to improve tumor uptake and tumor-to-background contrast of radiolabeled analogues of B9958 (Lys-Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-d-Tic-Cpg), a potent B1R antagonist. Peptide sequences were assembled on solid phase. Cold standards were prepared by incubating DOTA-/NODA-conjugated peptides with GaCl3, and by incubating AlOH-NODA-conjugated peptide with NaF. Binding affinities were measured via in vitro competition binding assays. (68)Ga and (18)F labeling experiments were performed in acidic buffer and purified by HPLC. Imaging/biodistribution studies were performed in mice bearing both B1R-positive (B1R+) HEK293T::hB1R and B1R-negative (B1R-) HEK293T tumors. Z02176 (Ga-DOTA-Pip-B9958; Pip: 4-amino-(1-carboxymethyl)piperidine), Z02137 (Ga-NODA-Mpaa-Pip-B9958; Mpaa: 4-methylphenylacetic acid), and Z04139 (AlF-NODA-Mpaa-Pip-B9958) bound hB1R with high affinity (Ki = 1.4-2.5 nM). (68)Ga-/(18)F-labeled peptides were obtained on average in ≥32% decay-corrected radiochemical yield with >99% radiochemical purity and 100-261 GBq/μmol specific activity. Biodistribution/imaging studies at 1 h postinjection showed that all tracers cleared rapidly from background tissues (except kidneys) and were excreted predominantly via the renal pathway. Only kidneys, bladders, and B1R+ tumors were clearly visualized in PET images. Uptake in B1R+ tumor was higher by using (68)Ga-Z02176 (28.9 ± 6.21 %ID/g) and (18)F-Z04139 (22.6 ± 3.41 %ID/g) than (68)Ga-Z02137 (14.0 ± 4.86 %ID/g). The B1R+ tumor-to-blood and B1R+ tumor-to-muscle contrast ratios were also higher for (68)Ga-Z02176 (56.1 ± 17.3 and 167 ± 57.6) and (18)F-Z04139 (58.0 ± 20.9 and 173 ± 42.9) than (68)Ga-Z02137 (34.3 ± 15.2 and 103 ± 30.2). With improved target-to-background contrast (68)Ga-Z02176 and (18)F-Z04139 are promising for imaging B1R expression in cancers with PET.
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency , Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Zhengxing
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency , Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Amouroux
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency , Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Jinhe
authors.initials: J
authors.lastname: Pan
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency , Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Silvia
authors.initials: S
authors.lastname: Jenni
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency , Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Jutta
authors.initials: J
authors.lastname: Zeisler
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency , Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Chemistry Department, University of British Columbia , Vancouver, British Columbia V6T 1Z1, Canada.
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Chemistry Department, University of British Columbia , Vancouver, British Columbia V6T 1Z1, Canada.
authors.forename: David M
authors.initials: DM
authors.lastname: Perrin
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency , Vancouver, British Columbia V5Z 1L3, Canada.|Department of Radiology, University of British Columbia , Vancouver, British Columbia V5Z 4E3, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Bénard
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency , Vancouver, British Columbia V5Z 1L3, Canada.|Department of Radiology, University of British Columbia , Vancouver, British Columbia V5Z 4E3, Canada.
authors.forename: Kuo-Shyan
authors.initials: KS
authors.lastname: Lin
mesh_terms: D000818:Animals; D065169:Bradykinin B1 Receptor Antagonists / Q000032:analysis*; D002851:Chromatography, High Pressure Liquid; D005462:Fluorine Radioisotopes / Q000032:analysis; D005710:Gallium Radioisotopes / Q000032:analysis; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000032:analysis*; D043783:Receptor, Bradykinin B1 / Q000378:metabolism*
chemical_list: D065169:Bradykinin B1 Receptor Antagonists; D005462:Fluorine Radioisotopes; D005710:Gallium Radioisotopes; D019275:Radiopharmaceuticals; D043783:Receptor, Bradykinin B1
keywords: B9958; bradykinin B1 receptor; fluorine-18; gallium-68; positron emission tomography; radiolabel−chelator complex