title: Design, synthesis and evaluation of (18)F-labeled bradykinin B1 receptor-targeting small molecules for PET imaging.
abstract: Two fluorine-18 ((18)F) labeled bradykinin B1 receptor (B1R)-targeting small molecules, (18)F-Z02035 and (18)F-Z02165, were synthesized and evaluated for imaging with positron emission tomography (PET). Z02035 and Z02165 were derived from potent antagonists, and showed high binding affinity (0.93±0.44 and 2.80±0.50nM, respectively) to B1R. (18)F-Z02035 and (18)F-Z02165 were prepared by coupling 2-[(18)F]fluoroethyl tosylate with their respective precursors, and were obtained in 10±5 (n=4) and 22±14% (n=3), respectively, decay-corrected radiochemical yield with >99% radiochemical purity. (18)F-Z02035 and (18)F-Z02165 exhibited moderate lipophilicity (LogD7.4=1.10 and 0.59, respectively), and were stable in mouse plasma. PET imaging and biodistribution studies in mice showed that both tracers enabled visualization of the B1R-positive HEK293T::hB1R tumor xenografts with better contrast than control B1R-negative HEK293T tumors. Our data indicate that small molecule antagonists can be used as pharmacophores for the design of B1R-targeting PET tracers.
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Zhengxing
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Hsiou-Ting
authors.initials: HT
authors.lastname: Kuo
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Joseph
authors.initials: J
authors.lastname: Lau
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Silvia
authors.initials: S
authors.lastname: Jenni
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Jutta
authors.initials: J
authors.lastname: Zeisler
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada; Department of Radiology, University of British Columbia, 950 West 10th Avenue, Vancouver, BC V5Z 4E3, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Bénard
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada; Department of Radiology, University of British Columbia, 950 West 10th Avenue, Vancouver, BC V5Z 4E3, Canada. Electronic address: klin@bccrc.ca.
authors.forename: Kuo-Shyan
authors.initials: KS
authors.lastname: Lin
mesh_terms: D000818:Animals; D065169:Bradykinin B1 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D005462:Fluorine Radioisotopes / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D008744:Methylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000000981:diagnostic imaging; D049268:Positron-Emission Tomography; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D043783:Receptor, Bradykinin B1 / Q000737:chemistry / Q000378:metabolism*; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
chemical_list: C000621410:2-(2-(((4-methoxy-2,6-dimethylphenyl)sulfonyl)methylamino)ethoxy)acetyl chloride; D065169:Bradykinin B1 Receptor Antagonists; D005462:Fluorine Radioisotopes; D008744:Methylamines; D019275:Radiopharmaceuticals; D043783:Receptor, Bradykinin B1
keywords: Antagonist; Bradykinin B1 receptor; Fluorine-18; Molecular imaging; Positron emission tomography