title: Neutrophil targeting heterobivalent SPECT imaging probe: cFLFLF-PEG-TKPPR-99mTc.
abstract: A new heterobivalent peptide ligand specifically targeting polymorphonuclear leukocytes (PMNs) with favorable pharmacological parameters to monitor sites of inflammation for imaging is designed. 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-(99m)Tc (n = 4, 12), were evaluated in vitro with human PMNs for binding affinity and bioavailability. As a result, cFLFLF-(PEG)(12)-TKPPR-(99m)Tc 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-(99m)Tc may be a desirable imaging agent for binding to PMNs to identify sites of inflammation by SPECT.
authors.affiliation: Research Division of the Department of Radiology and Department of Chemistry, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Xiao
authors.forename: Mahendra D
authors.initials: MD
authors.lastname: Chordia
authors.forename: Landon W
authors.initials: LW
authors.lastname: Locke
authors.forename: Mark B
authors.initials: MB
authors.lastname: Williams
authors.forename: Stuart S
authors.initials: SS
authors.lastname: Berr
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Pan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005260:Female; D006801:Humans; D007249:Inflammation / Q000000981:diagnostic imaging / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000378:metabolism*; D009842:Oligopeptides / Q000138:chemical synthesis / Q000378:metabolism*; D015609:Organotechnetium Compounds / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*; D014057:Tomography, X-Ray Computed
chemical_list: D009842:Oligopeptides; D015609:Organotechnetium Compounds