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Kuo-shyan Lin - One of the best experts on this subject based on the ideXlab platform.
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Radiolabeled R954 Derivatives for Imaging Bradykinin B1 Receptor Expression with Positron Emission Tomography.
Molecular pharmaceutics, 2017Co-Authors: Hsiou-ting Kuo, Jinhe Pan, Joseph Lau, Chengcheng Zhang, Jutta Zeisler, Nadine Colpo, Francois Benard, Kuo-shyan LinAbstract: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 developed 68Ga- and 18F-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 and 18F-HTK01146) for B1R PET imaging. Peptides were synthesized via solid phase strategy. Nonradioactive standards were obtain by reacting GaCl3 with DOTA-dPEG2-R954 and by clicking N-propargyl-N,N-dimethylammoniomethyl-trifluoroborate with ...
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Radiolabeled R954 Derivatives for Imaging Bradykinin B1 Receptor Expression with Positron Emission Tomography
2017Co-Authors: Hsiou-ting Kuo, Jinhe Pan, Joseph Lau, Chengcheng Zhang, Jutta Zeisler, Nadine Colpo, François Bénard, Kuo-shyan LinAbstract: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 developed 68Ga- and 18F-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 and 18F-HTK01146) for B1R PET imaging. Peptides were synthesized via solid phase strategy. Nonradioactive standards were obtain by reacting GaCl3 with 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 with 68GaCl3 under acidic conditions, while 18F-HTK01146 was prepared via an 18F–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 between 68Ga-HTK01083 (8.46 ± 1.44%ID/g) and 18F-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 for 68Ga-HTK01083, and 7.24 ± 2.56 and 19.5 ± 4.29 for 18F-HTK01146. Our results indicate R954 is a good lead sequence for optimization of B1R tracers for cancer imaging
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Synthesis and evaluation of a 68Ga-labeled Bradykinin B1 Receptor agonist for imaging with positron emission tomography.
Bioorganic & medicinal chemistry, 2016Co-Authors: Guillaume Amouroux, Jinhe Pan, Chengcheng Zhang, Jutta Zeisler, Nadine Colpo, Kuo-shyan Lin, Zhengxing Zhang, Silvia Jenni, Navjit Hundal-jabal, Francois BenardAbstract:Abstract A novel 68Ga-labeled Bradykinin B1 Receptor (B1R) agonist, 68Ga-Z01115, was synthesized and evaluated for imaging with positron emission tomography (PET). Z01115 exhibited good binding affinity (Ki = 25.4 ± 5.1 nM) to hB1R. 68Ga-Z01115 was prepared in 74 ± 5 decay-corrected radiochemical yield with >99% radiochemical purity and 155 ± 89 GBq/µmol (4.2 ± 2.4 Ci/μmol) specific activity. 68Ga-Z01115 was stable in vitro in mouse plasma (93% remaining intact after 60 min incubation), and relatively stable in vivo (51 ± 5% remaining intact at 5 min post-injection). PET imaging and biodistribution studies in mice showed that 68Ga-Z01115 cleared rapidly from nontarget tissues/organs, and generated high target-to-nontarget contrast images. The uptake of 68Ga-Z01115 in B1R-positive (B1R+) tumor was 5.65 ± 0.59%ID/g at 1 h post-injection. Average contrast ratios of B1R+ tumor-to-B1R− tumor, -to-blood and -to-muscle were 24.3, 24.4 and 82.9, respectively. Uptake of 68Ga-Z01115 in B1R+ tumors was reduced by ∼90% with co-injection of cold standard, confirming it was mediated by B1R. Our data suggest that 68Ga-Z01115 is a promising tracer for imaging the expression of B1R that is overexpressed in a variety of cancers.
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Radiolabeled B9958 Derivatives for Imaging Bradykinin B1 Receptor Expression with Positron Emission Tomography: Effect of the Radiolabel–Chelator Complex on Biodistribution and Tumor Uptake
Molecular pharmaceutics, 2016Co-Authors: Zhengxing Zhang, Jinhe Pan, Chengcheng Zhang, Jutta Zeisler, Francois Benard, Guillaume Amouroux, David M Perrin, Silvia Jenni, Zhibo Liu, Kuo-shyan LinAbstract: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. 68Ga and 18F 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-...
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Design, synthesis and evaluation of (18)F-labeled Bradykinin B1 Receptor-targeting small molecules for PET imaging
Bioorganic & medicinal chemistry letters, 2016Co-Authors: Zhengxing Zhang, Hsiou-ting Kuo, Joseph Lau, Chengcheng Zhang, Jutta Zeisler, Francois Benard, Silvia Jenni, Kuo-shyan LinAbstract: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.
Niels Olsen Saraiva Câmara - One of the best experts on this subject based on the ideXlab platform.
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deletion of Bradykinin B1 Receptor reduces renal fibrosis
International Immunopharmacology, 2009Co-Authors: Pamella Huey Mei Wang, Joao Bosco Pesquero, Gabriela Campanholle, Marcos Antonio Cenedeze, Niels Olsen Saraiva Câmara, Denise Maria Avancini Costa Malheiros, Hugo A. M. Torres, Alvaro PachecosilvaAbstract:The Kallikrein-kinin system works through activation of two Receptors. One constitutive, named B2 Receptor (B2R) and another inducible, denominated B1 Receptor (B1R). In renal fibrosis, B2R Receptor activation appears to be protective, however B1R participation is unveiled. The aim of this study was to analyze how the deletion of the B1R would modify tissue responses after unilateral ureteral obstruction (UUO). For that, B1R knockout (B1KO) and wild-type mice (B1B2WT) were subjected to UUO and sacrificed at days 1, 5 and 14. Renal dysfunction was assayed by urine proteinuria/creatinine ratio and percentage of tubulointerstitial fibrosis. Kidneys were harvested at day 5 to analyze anti and pro-inflammatory molecules expression by real-time PCR. We demonstrated that at all time points, B1KO mice presented lower proteinuria/creatinine ratio from bladder urine. B1KO protection was reinforced by its lower tubular interstitial fibrosis percentage at day 14 (B1B2WT: 12.16 ± 1.53% vs. B1KO: 6.73 ± 1.07%, p<0.02). UUO was able to induce B1R expression and its highest transcription was achieved at day 5. At this day, B1KO had significant lower expression of pro-inflammatory molecules such as TGF-β, MCP-1, OPN and IL-6 and higher anti-inflammatory components, as IL-10 and HO-1. Herein, we observed that B1R deletion may be an important component in renal fibrosis prevention.
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Deletion of Bradykinin B1 Receptor reduces renal fibrosis
International immunopharmacology, 2008Co-Authors: Pamella Huey Mei Wang, Joao Bosco Pesquero, Gabriela Campanholle, Marcos Antonio Cenedeze, Alvaro Pacheco-silva, Denise Maria Avancini Costa Malheiros, Hugo A. M. Torres, Niels Olsen Saraiva CâmaraAbstract:The Kallikrein-kinin system works through activation of two Receptors. One constitutive, named B2 Receptor (B2R) and another inducible, denominated B1 Receptor (B1R). In renal fibrosis, B2R Receptor activation appears to be protective, however B1R participation is unveiled. The aim of this study was to analyze how the deletion of the B1R would modify tissue responses after unilateral ureteral obstruction (UUO). For that, B1R knockout (B1KO) and wild-type mice (B1B2WT) were subjected to UUO and sacrificed at days 1, 5 and 14. Renal dysfunction was assayed by urine proteinuria/creatinine ratio and percentage of tubulointerstitial fibrosis. Kidneys were harvested at day 5 to analyze anti and pro-inflammatory molecules expression by real-time PCR. We demonstrated that at all time points, B1KO mice presented lower proteinuria/creatinine ratio from bladder urine. B1KO protection was reinforced by its lower tubular interstitial fibrosis percentage at day 14 (B1B2WT: 12.16 ± 1.53% vs. B1KO: 6.73 ± 1.07%, p
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Correction: Bradykinin B1 Receptor Antagonism Is Beneficial in Renal Ischemia-Reperfusion Injury
PLoS ONE, 2008Co-Authors: Pamella Huey Mei Wang, Joao Bosco Pesquero, Gabriela Campanholle, Marcos Antonio Cenedeze, Carla Q. Feitoza, Giselle Martins Gonçalves, Richardt G. Landgraf, Sonia Jancar, Alvaro Pacheco-silva, Niels Olsen Saraiva CâmaraAbstract:The first word of the title is misspelled. This also affect the article's citation. The correct title should be: Bradykinin B1 Receptor Antagonism Is Beneficial in Renal Ischemia-Reperfusion Injury. The corrected citation is: Wang PHM, Campanholle G, Cenedeze MA, Feitoza CQ, Goncalves GM, et al. (2008) Bradykinin B1 Receptor Antagonism Is Beneficial in Renal Ischemia-Reperfusion Injury. PLoS ONE 3(8): e3050. doi:10.1371/journal.pone.0003050.
Rodolfo Pedro Rothlin - One of the best experts on this subject based on the ideXlab platform.
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Retinoids inhibit Bradykinin B1 Receptor-sensitized responses in human umbilical vein
European journal of pharmacology, 2000Co-Authors: Sergio Pablo Sardi, Verónica Rey-ares, Virginia Andrea Pujol-lereis, Rodolfo Pedro RothlinAbstract:Abstract Bradykinin B1 Receptors are not expressed under physiological conditions but are induced under inflammatory conditions. In isolated human umbilical vein, a spontaneous Bradykinin B1 Receptor sensitization process has been demonstrated. On the other hand, retinoids have been shown to exert anti-inflammatory and immunomodulatory actions. We have now examined the effects of all-trans-retinoic acid and 9-cis-retinoic acid on the Bradykinin B1 Receptor-sensitized responses in human umbilical vein. Both retinoids produced a concentration-dependent rightward shift of the concentration–response curves for the Bradykinin B1 Receptor agonist, des-Arg9-Bradykinin. Retinoid treatment did not modify the responses to Bradykinin B1 Receptor-unrelated agonists, Bradykinin or serotonin. In conclusion, retinoids inhibit Bradykinin B1 Receptor-sensitized responses and this action could participate in their anti-inflammatory and immunomodulatory effects.
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Bradykinin B1 Receptors in human umbilical vein: pharmacological evidence of up-regulation, and induction by interleukin-1β
European journal of pharmacology, 1998Co-Authors: Sergio Pablo Sardi, Verónica Rey Ares, Andrea Emilse Errasti, Rodolfo Pedro RothlinAbstract:Bradykinin B1 Receptor-mediated responses increase as a function of in vitro incubation in the human umbilical vein. When tissues were continuously treated with the protein synthesis inhibitor, cycloheximide, or with the protein trafficking inhibitor, brefeldin A, pEC50 and maximal response to the selective Bradykinin B1 Receptor agonist, des-Arg9-Bradykinin, were significantly diminished. The anti-inflammatory steroid, dexamethasone, produced a rightward shift of the concentration-response curve to des-Arg9-Bradykinin, without affecting the maximal response. Furthermore, lipopolysaccharide or recombinant human interleukin-1 beta potentiate the Bradykinin B1-sensitized responses, showing a leftward shift of the concentration-response curve to des-Arg9-Bradykinin, without modifying the maximal response. On the other hand, Bradykinin B2 Receptor-mediated responses were unaffected by continuous exposure to cycloheximide, dexamethasone or lipopolysaccharide. These results provide pharmacological evidence to support the view that the de novo synthesis of Bradykinin B1 Receptors is involved in the induction of vascular responses in the human umbilical vein. This up-regulation process seems to be selective for Bradykinin B1 Receptors. The inhibitory effect of dexamethasone and the potentiating actions of lipopolysaccharide and exogenous human recombinant interleukin-1 beta on des-Arg9-Bradykinin-mediated responses, suggest the possible role of interleukin-1 beta in the Bradykinin B1 Receptor up-regulation phenomenon in human umbilical vein.
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Bradykinin B1 Receptors in human umbilical vein
European Journal of Pharmacology, 1997Co-Authors: Sergio Pablo Sardi, Haydée Pérez, Paula Antúnez, Rodolfo Pedro RothlinAbstract:Abstract The present study was undertaken to demonstrate the presence of Bradykinin B1 Receptors mediating contraction of human umbilical vein. The Bradykinin B1 Receptor selective agonist, des-Arg9-Bradykinin, produced a dose-dependent contractile response of human umbilical vein rings. Furthermore, des-Arg9-Bradykinin-mediated response increased in a time-dependent manner in vitro. The maximal response to des-Arg9-Bradykinin, expressed as percentage of the maximum elicited by serotonin, was: 10 ± 2 at 15 min, 55 ± 5 at 120 min and 80 ± 3 at 300 min. Des-Arg9-Bradykinin-mediated contractions were inhibited by the specific Bradykinin B1 Receptor antagonist des-Arg9-[Leu8]Bradykinin which produced parallel shifts in the dose-response curve to the selective Bradykinin B1 Receptor agonist. Schild regression analysis of data established a pA2 value of 6.16 ± 0.06. Kinin-induced contraction was not modified by pre-treatment with indomethacin (10 μM), a cyclo-oxygenase inhibitor. On the other hand, continuous exposure to the anti-inflammatory steroid dexamethasone (100 μM) or to the protein synthesis inhibitor cycloheximide (70 μM) largely prevented the sensitization to des-Arg9-Bradykinin in incubated human umbilical vein rings. These results confirm the presence of Bradykinin B1 Receptors which mediate contraction in isolated human umbilical vein. These responses are up-regulated in a time- and protein synthesis-dependent process.
Joao Bosco Pesquero - One of the best experts on this subject based on the ideXlab platform.
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Cardiac morphofunctional characteristics of transgenic rats with overexpression of the Bradykinin B1 Receptor in the endothelium.
Physiological research, 2017Co-Authors: R. F. Levy, Joao Bosco Pesquero, Andrey Jorge Serra, Edinei L. Antônio, L Dos Santos, Danilo Sales Bocalini, Michael Bader, Vanessa F. Merino, H. A. De Oliveira, E. C. De Arruda VeigaAbstract:Our aim was to evaluate whether endothelial overexpressing of the Bradykinin B1 Receptor could be associated with altered left ventricular and myocardial performance. Echocardiography and hemodynamic were employed to assess left ventricular morphology and function in Sprague Dawley transgenic rats overexpressing the endothelial Bradykinin B1 Receptor (Tie2B1 rats). The myocardial inotropism was evaluated on papillary muscles contracting in vitro. In Tie2B1 animals, an enlarged left ventricular cavity and lower fractional shortening coupled with a lower rate of pressure change values indicated depressed left ventricular performance. Papillary muscle mechanics revealed that both Tie2B1 and wild-type rat groups had the same contractile capacities under basal conditions; however, in transgenic animals, there was accentuated inotropism due to post-pause potentiation. Following treatment with the Arg(9)-BK agonist, Tie2B1 papillary muscles displayed a reduction in myocardial inotropism. Endothelial B1 Receptor overexpression has expanded the LV cavity and worsened its function. There was an exacerbated response of papillary muscle in vitro to a prolonged resting pause, and the use of a B1 Receptor agonist impairs myocardial inotropism.
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deletion of Bradykinin B1 Receptor reduces renal fibrosis
International Immunopharmacology, 2009Co-Authors: Pamella Huey Mei Wang, Joao Bosco Pesquero, Gabriela Campanholle, Marcos Antonio Cenedeze, Niels Olsen Saraiva Câmara, Denise Maria Avancini Costa Malheiros, Hugo A. M. Torres, Alvaro PachecosilvaAbstract:The Kallikrein-kinin system works through activation of two Receptors. One constitutive, named B2 Receptor (B2R) and another inducible, denominated B1 Receptor (B1R). In renal fibrosis, B2R Receptor activation appears to be protective, however B1R participation is unveiled. The aim of this study was to analyze how the deletion of the B1R would modify tissue responses after unilateral ureteral obstruction (UUO). For that, B1R knockout (B1KO) and wild-type mice (B1B2WT) were subjected to UUO and sacrificed at days 1, 5 and 14. Renal dysfunction was assayed by urine proteinuria/creatinine ratio and percentage of tubulointerstitial fibrosis. Kidneys were harvested at day 5 to analyze anti and pro-inflammatory molecules expression by real-time PCR. We demonstrated that at all time points, B1KO mice presented lower proteinuria/creatinine ratio from bladder urine. B1KO protection was reinforced by its lower tubular interstitial fibrosis percentage at day 14 (B1B2WT: 12.16 ± 1.53% vs. B1KO: 6.73 ± 1.07%, p<0.02). UUO was able to induce B1R expression and its highest transcription was achieved at day 5. At this day, B1KO had significant lower expression of pro-inflammatory molecules such as TGF-β, MCP-1, OPN and IL-6 and higher anti-inflammatory components, as IL-10 and HO-1. Herein, we observed that B1R deletion may be an important component in renal fibrosis prevention.
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Deletion of Bradykinin B1 Receptor reduces renal fibrosis
International immunopharmacology, 2008Co-Authors: Pamella Huey Mei Wang, Joao Bosco Pesquero, Gabriela Campanholle, Marcos Antonio Cenedeze, Alvaro Pacheco-silva, Denise Maria Avancini Costa Malheiros, Hugo A. M. Torres, Niels Olsen Saraiva CâmaraAbstract:The Kallikrein-kinin system works through activation of two Receptors. One constitutive, named B2 Receptor (B2R) and another inducible, denominated B1 Receptor (B1R). In renal fibrosis, B2R Receptor activation appears to be protective, however B1R participation is unveiled. The aim of this study was to analyze how the deletion of the B1R would modify tissue responses after unilateral ureteral obstruction (UUO). For that, B1R knockout (B1KO) and wild-type mice (B1B2WT) were subjected to UUO and sacrificed at days 1, 5 and 14. Renal dysfunction was assayed by urine proteinuria/creatinine ratio and percentage of tubulointerstitial fibrosis. Kidneys were harvested at day 5 to analyze anti and pro-inflammatory molecules expression by real-time PCR. We demonstrated that at all time points, B1KO mice presented lower proteinuria/creatinine ratio from bladder urine. B1KO protection was reinforced by its lower tubular interstitial fibrosis percentage at day 14 (B1B2WT: 12.16 ± 1.53% vs. B1KO: 6.73 ± 1.07%, p
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Correction: Bradykinin B1 Receptor Antagonism Is Beneficial in Renal Ischemia-Reperfusion Injury
PLoS ONE, 2008Co-Authors: Pamella Huey Mei Wang, Joao Bosco Pesquero, Gabriela Campanholle, Marcos Antonio Cenedeze, Carla Q. Feitoza, Giselle Martins Gonçalves, Richardt G. Landgraf, Sonia Jancar, Alvaro Pacheco-silva, Niels Olsen Saraiva CâmaraAbstract:The first word of the title is misspelled. This also affect the article's citation. The correct title should be: Bradykinin B1 Receptor Antagonism Is Beneficial in Renal Ischemia-Reperfusion Injury. The corrected citation is: Wang PHM, Campanholle G, Cenedeze MA, Feitoza CQ, Goncalves GM, et al. (2008) Bradykinin B1 Receptor Antagonism Is Beneficial in Renal Ischemia-Reperfusion Injury. PLoS ONE 3(8): e3050. doi:10.1371/journal.pone.0003050.
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absence of diabetic hyperalgesia in Bradykinin B1 Receptor knockout mice
Regulatory Peptides, 2005Co-Authors: Bichoy H Gabra, Joao Bosco Pesquero, Michael Bader, Vanessa F. Merino, Pierre SiroisAbstract:Experimental evidence has shown that the inducible Bradykinin (BK) B1 Receptor (BKB1-R) subtype is involved in the development of hyperalgesia associated with type 1 diabetes. Selective BKB1-R antagonists inhibited, whereas selective agonists increased the hyperalgesic activity in diabetic mice in thermal nociceptive tests. Here we evaluate the development of diabetic hyperalgesia in a BKB1-R-knockout (KO) genotype compared to wild-type (WT) mice. The BKB1-R-KO mice were backcrossed for 10 generations to C57BL/6 genetic background before use in the experiments. Diabetes was induced by streptozotocin (STZ) and thermal nociception was assessed by the hot plate and tail immersion tests. The hyperalgesia observed in wild type mice was totally absent in the BKB1-R-KO mice. Furthermore, the selective BKB1-R agonist, desArg9BK, significantly increased the hyperalgesic activity in diabetic WT mice but had no effect on nociceptive responses in diabetic BKB1-R-KO mice. Taken together, the results confirm the crucial role of the BKB1-R, upregulated alongside inflammatory diabetes, in the development of diabetes-induced hyperalgesia.
Zhengxing Zhang - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and evaluation of a 68Ga-labeled Bradykinin B1 Receptor agonist for imaging with positron emission tomography.
Bioorganic & medicinal chemistry, 2016Co-Authors: Guillaume Amouroux, Jinhe Pan, Chengcheng Zhang, Jutta Zeisler, Nadine Colpo, Kuo-shyan Lin, Zhengxing Zhang, Silvia Jenni, Navjit Hundal-jabal, Francois BenardAbstract:Abstract A novel 68Ga-labeled Bradykinin B1 Receptor (B1R) agonist, 68Ga-Z01115, was synthesized and evaluated for imaging with positron emission tomography (PET). Z01115 exhibited good binding affinity (Ki = 25.4 ± 5.1 nM) to hB1R. 68Ga-Z01115 was prepared in 74 ± 5 decay-corrected radiochemical yield with >99% radiochemical purity and 155 ± 89 GBq/µmol (4.2 ± 2.4 Ci/μmol) specific activity. 68Ga-Z01115 was stable in vitro in mouse plasma (93% remaining intact after 60 min incubation), and relatively stable in vivo (51 ± 5% remaining intact at 5 min post-injection). PET imaging and biodistribution studies in mice showed that 68Ga-Z01115 cleared rapidly from nontarget tissues/organs, and generated high target-to-nontarget contrast images. The uptake of 68Ga-Z01115 in B1R-positive (B1R+) tumor was 5.65 ± 0.59%ID/g at 1 h post-injection. Average contrast ratios of B1R+ tumor-to-B1R− tumor, -to-blood and -to-muscle were 24.3, 24.4 and 82.9, respectively. Uptake of 68Ga-Z01115 in B1R+ tumors was reduced by ∼90% with co-injection of cold standard, confirming it was mediated by B1R. Our data suggest that 68Ga-Z01115 is a promising tracer for imaging the expression of B1R that is overexpressed in a variety of cancers.
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Radiolabeled B9958 Derivatives for Imaging Bradykinin B1 Receptor Expression with Positron Emission Tomography: Effect of the Radiolabel–Chelator Complex on Biodistribution and Tumor Uptake
Molecular pharmaceutics, 2016Co-Authors: Zhengxing Zhang, Jinhe Pan, Chengcheng Zhang, Jutta Zeisler, Francois Benard, Guillaume Amouroux, David M Perrin, Silvia Jenni, Zhibo Liu, Kuo-shyan LinAbstract: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. 68Ga and 18F 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-...
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Design, synthesis and evaluation of (18)F-labeled Bradykinin B1 Receptor-targeting small molecules for PET imaging
Bioorganic & medicinal chemistry letters, 2016Co-Authors: Zhengxing Zhang, Hsiou-ting Kuo, Joseph Lau, Chengcheng Zhang, Jutta Zeisler, Francois Benard, Silvia Jenni, Kuo-shyan LinAbstract: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.
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Optimizing the Design of Bradykinin B1 Receptor-targeting PET Tracers via the Selection of Radiolabel Chelate
The Journal of Nuclear Medicine, 2016Co-Authors: Zhengxing Zhang, Jinhe Pan, Chengcheng Zhang, Jutta Zeisler, Francois Benard, Guillaume Amouroux, David M Perrin, Silvia Jenni, Zhibo Liu, Kuo-shyan LinAbstract:448 Objectives The Bradykinin B1 Receptor (B1R), a G-protein-coupled Receptor, is up-regulated in many types of cancer. Due to its low expression in normal tissues, B1R is an attractive target for cancer imaging. Previously, we identified a promising B1R-targeting tracer 18F-L08060 (18F-AmBF3-Mta-Pip-B9958). It contains a potent sequence B9958 (Lys-Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-D-Tic-Cpg) and a preferable linker Pip (4-amino-(1-carboxymethyl)piperidine). 18F labeling was achieved via 18F-19F isotope exchange on the trifluoroborate moiety of AmBF3-Mta (4-(N-trifluoroborylmethyl-N,N-dimethylammonio)methyl-1,2,3-triazole-1-acetic acid). In this study, we investigated if tumor uptake and tumor-to-background contrast could be further improved by the selection of various radiolabel chelates. Methods DOTA and NODA-Mpaa(4-methylphenylacetic acid) conjugated Pip-B9958 were synthesized using solid phase approach. Ga complexation was performed by incubating DOTA- and NODA-Mpaa-conjugated peptides with GaCl3. AlOH complexation was achieved by incubating NODA-Mpaa-conjugated peptides with AlCl3. Al-F cold standard was obtained by the reaction of AlOH-NODA-conjugated peptide with NaF. Binding affinity was measured by in vitro competition binding assays. 68Ga and 18F labeling experiments were performed in acidic buffer using 68GaCl3 and 18F-fluoride, respectively. Imaging/biodistribution studies were performed in mice bearing both HEK293T wild-type (B1R-) and HEK293T::hB1R (B1R+) tumors. Results The binding affinities (Ki) of Z02176 (Ga-DOTA-Pip-B9958), Z02137 (Ga-NODA-Mpaa-Pip-B9958) and Z04139 (AlF-NODA-Mpaa-Pip-B9958) towards hB1R were 2.5, 2.6, and 14.0 nM, respectively. 18F-Z04139, 68Ga-Z02176 and 68Ga-Z02137 were prepared with decay-corrected radiochemical yields of 46 ± 2, 47 ± 11 and 32 ± 11 %, respectively. The radiochemical purities were > 99% and the specific activities of 18F-Z04139, 68Ga-Z02176 and 68Ga-Z02137 were 210 ± 72, 261 ± 74, and 100 ± 8 GBq/μmol, respectively. Biodistribution/imaging studies (at 1-h post-injection) showed that all three tracers cleared rapidly from background 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 for 68Ga-Z02176 (28.9 ± 6.21 %ID/g) and 18F-Z04139 (22.6 ± 3.41 %ID/g) than 68Ga-Z02137 (14.0 ± 4.86 %ID/g) and previously identified 18F-L08060 (4.20 ± 0.98 %ID/g). The B1R+ tumor-to-blood and B1R+ tumor-to-muscle contrast ratios were also higher for 68Ga-Z02176 (56.1 ± 17.3 and 167 ± 57.6) and 18F-Z04139 (58.0 ± 20.9 and 173 ± 42.9) than 68Ga-Z02137 (34.3 ± 15.2 and 103 ± 30.2) and 18F-L08060 (14.7 ± 3.56 and 48.6 ± 10.7). Conclusions 68Ga-Z02176 and 18F-Z04139 outperformed 68Ga-Z02137, 18F-L08060, and previously reported 68Ga and 18F-labeled B1R-targeting tracers. With superior tumor uptake and target-to-background contrast ratios, 68Ga-Z02176 and 18F-Z04139 are promising B1R-trageting PET tracers, and warrant further investigation for cancer imaging.
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Comparison of two high affinity gallium-68-labeled Bradykinin Receptor antagonists for in vivo imaging of Bradykinin B1 Receptor expression
The Journal of Nuclear Medicine, 2016Co-Authors: Jinhe Pan, Chengcheng Zhang, Jutta Zeisler, Francois Benard, Guillaume Amouroux, Zhengxing Zhang, Silvia Jenni, Kuo-shyan LinAbstract:113 Objectives The Bradykinin B1 Receptor (B1R) is a G protein-coupled Receptor and is minimally expressed in normal tissues. Due to its overexpression in a variety of cancers, B1R is a promising cancer imaging biomarker. In this study, we synthesized and evaluated two B1R-targeting peptides, 68Ga-P05022 (68Ga-DOTA-Pip-B9858) and 68Ga-Z02176 (68Ga-DOTA-Pip-B9958), for imaging B1R expression with PET (Pip: 4-amino-(1-carboxymethyl)piperidine; B9858:Lys-Lys-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic; B9958: Lys-Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-D-Tic-Cpg). Methods The DOTA-conjugated peptides were synthesized by solid phase peptide synthesis, and reacted with GaCl3 to obtain cold standards. B1R binding affinity was measured by in vitro competition binding assays. The peptides were labeled with 68Ga by microwave heating followed by HPLC purification. LogD7.4 values were determined via traditional shake flask method. PET/CT imaging and biodistribution studies were performed in NODSCID/IL2RKO mice bearing both B1R-negative (B1R-) HEK293T wild-type tumor and B1R-positive (B1R+) HEK293T::hB1R tumor. Blocking studies were performed by co-injecting the tracers with their respective cold standard (100 μg). Results P05022 and Z02176 were obtained with 12 % and 18 % overall yield. The binding affinities (Ki) of P05022 and Z02176 to hB1R were 5.5 ± 0.1 and 2.5 ± 0.8 nM, respectively. 68Ga-labeled P05022 and Z02176 were prepared in 42 - 76 % decay-corrected radiochemical yield, with > 99 % radiochemical purity and 41 - 282 GBq/μmol specific activity. Both tracers were highly hydrophilic with LogD7.4 of -2.65 ± 0.15 and -4.15 ± 0.04 for P05022 and Z02176, respectively. The PET imaging and biodistribution studies at 1-h post-injection showed extremely low background (~ 1 %ID/g or less) of both tracers. Only kidneys, bladder, and B1R+ tumor were clearly visualized in PET images. The biodistribution data showed that both tracers were excreted mainly via the renal pathway. At 1-h post-injection, B1R+ tumor uptake for 68Ga-Z02176 (28.9 ± 6.21 %ID/g) was higher than 68Ga-P05022 (11.6 ± 3.30 %ID/g). The B1R+ tumor-to-blood and B1R+ tumor-to-muscle ratios were also higher with 68Ga-Z02176 (56.1 ± 17.3 and 167 ± 57.6) compared to 68Ga-P05022 (34.3 ± 15.2 and 103 ± 30.2). Negligible uptake in B1R- tumors indicated that the uptake in B1R+ tumors was Receptor mediated. In addition, co-injecting with the cold standard reduced B1R+ tumor uptake by more than 85 % for both radiotracers. Conclusions 68Ga-P05022, 68Ga-Z02176, and their cold compounds were successfully synthesized and characterized. Both tracers had high binding affinities for B1R. PET imaging and biodistribution studies revealed that 68Ga-Z02176 was superior to 68Ga-P05022 and other previously reported tracers for B1R-targeting imaging. Our results indicate that 68Ga-Z02176 warrants further studies for potential clinical translation.