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COMPOSITIONS AND METHODS FOR LEUKOCYTE-TARGETING MULTI-VALENT IMAGING PROBES
专利权人:
DONGFENG; Pan
发明人:
DONGFENG, Pan,BERR, Stuart, S.,ZHANG, Yi
申请号:
USUS2011/033430
公开号:
WO2011/133773A3
申请日:
2011.04.21
申请国别(地区):
WO
年份:
2012
代理人:
摘要:
The present application discloses a new multivalent peptide ligand specifically targeting polymorphonuclear leukocytes (PMNs) with favorable pharmacological parameters to monitor sites of inflammation for imaging. The detailed synthesis, characterization, and pharmacological evaluation of the ligands are reported here. Two separate peptide binding ligands for formyl peptide and tuftsin receptors were chosen to link together based on the high expression levels of the two receptors on activated PMNs The heterobivalency and pegylated links were incorporated in the structural design to improve the sensitivity of the detection and to improve the bioavailability along with blood clearance profile, respectively. Two chemical constructs: cFLFLF-(PEG)n-TKPPR-99mTc (n=4, 12) were evaluated in vitro with human PMNs for binding affinity and bioavailability. As a result, FLFLF-(PEG)12-TKPPR-99mTc was found to have more favorable pharmacological properties and was therefore used for further in vivo studies. Preliminary in vivo assessment of the agent was performed using Single Gamma Emission Computed Tomography (SPECT) imaging of a mouse model of ear inflammation. The results of these studies indicate cFLFLF-(PEG)12- TKPPR-99mTc may be a desirable imaging agent for binding to PMNs to identify sites of inflammation by SPECT.La présente invention concerne un nouveau ligand de peptide multivalent qui cible spécifiquement des leucocytes polymorphonucléaires (PMN) avec des paramètres pharmacologiques favorables afin de surveiller des sites dinflammation en vue dune imagerie. La synthèse, la caractérisation et lévaluation pharmacologique détaillées des ligands sont rapportées ici. Deux ligands de liaison de peptide séparés pour récepteurs de peptide formyle et de tuftsine ont été choisis pour se lier ensemble sur la base des niveaux dexpression élevés des deux récepteurs sur les PMN activés. Les liens hétérobivalents et pégylés ont été incorporés dans la conception structurelle pour am
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