title: (18)F-trifluoroborate derivatives of [des-arg(10)]kallidin for imaging bradykinin b1 receptor expression with positron emission tomography.
abstract: Bradykinin B1 receptor (B1R) is involved in pain and inflammation pathways and is upregulated in inflamed tissues and cancer. Due to its minimal expression in healthy tissues, B1R is an attractive target for the development of therapeutic agents to treat inflammation, chronic pain, and cancer. The goal of this study is to synthesize and compare two (18)F-labeled peptides derived from potent B1R antagonists B9858 and B9958 for imaging B1R expression with positron emission tomography (PET). Azidoacetyl-B9858 2 and azidoacetyl-B9958 3 were synthesized by a solid-phase approach and subsequently clicked to ammoniomethyl-trifluoroborate (AmBF3)-conjugated alkyne 1 to obtain AmBF3-B9858 and AmBF3-B9958, respectively. AmBF3-B9858 and AmBF3-B9958 bound B1R with high affinity, with Ki values at 0.09 ± 0.08 and 0.46 ± 0.03 nM, respectively, as measured by in vitro competition binding assays. (18)F labeling was performed via an (18)F-(19)F isotope exchange reaction. The radiofluorinated tracers were obtained within a synthesis time of 30 min and with 23-32% non-decay-corrected radiochemical yield, >99% radiochemical purity, and 43-87 GBq/μmol specific activity at the end of the synthesis. PET imaging and biodistribution studies were carried out in mice bearing both B1R-positive (B1R(+)) HEK293T::hB1R and B1R-negative (B1R(-)) HEK293T tumors. Both tracers cleared rapidly from most organs/tissues, mainly through the renal pathway. High uptake in B1R(+) tumors ((18)F-AmBF3-B9858: 3.94 ± 1.24% ID/g, tumor-to-muscle ratio 21.3 ± 4.33; (18)F-AmBF3-B9958: 4.20 ± 0.98% ID/g, tumor-to-muscle ratio 48.6 ± 10.7) was observed at 1 h postinjection. These results indicate that (18)F-AmBF3-B9858 and (18)F-AmBF3-B9958 are promising agents for the in vivo imaging of B1R expression with PET.
authors: Chemistry Department, University of British Columbia , Vancouver, BC V6T 1Z1, Canada.
authors: Zhibo
authors: Z
authors: Liu
authors: Guillaume
authors: G
authors: Amouroux
authors: Zhengxing
authors: Z
authors: Zhang
authors: Jinhe
authors: J
authors: Pan
authors: Navjit
authors: N
authors: Hundal-Jabal
authors: Nadine
authors: N
authors: Colpo
authors: Joseph
authors: J
authors: Lau
authors: David M
authors: DM
authors: Perrin
authors: François
authors: F
authors: Bénard
authors: Kuo-Shyan
authors: KS
authors: Lin
mesh_terms: D000818:Animals; D001702:Biopharmaceutics; D001881:Borates; D001920:Bradykinin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D065169:Bradykinin B1 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry; D004355:Drug Stability; D005462:Fluorine Radioisotopes; D057809:HEK293 Cells; D006801:Humans; D007609:Kallidin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D043783:Receptor, Bradykinin B1 / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: C121350:B 9858; D001881:Borates; D065169:Bradykinin B1 Receptor Antagonists; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D043783:Receptor, Bradykinin B1; D007609:Kallidin; D001920:Bradykinin
keywords: B9858; B9958; bradykinin B1 receptor; fluorine-18; positron emission tomography; trifluoroborate