title: Evaluation of [¹¹¹In]-labeled zinc-dipicolylamine tracers for SPECT imaging of bacterial infection.
abstract: OBJECTIVE
  This study prepared three structurally related zinc-dipicolylamine (ZnDPA) tracers with [(111)In] labels and conducted biodistribution and single-photon emission computed tomography/computed tomography (SPECT/CT) imaging studies of a mouse leg infection model.
  
  
  METHODS
  Two monovalent tracers, ZnDPA-[(111)In]DTPA and ZnDPA-[(111)In]DOTA, each with a single zinc-dipicolylamine targeting unit, and a divalent tracer, Bis(ZnDPA)-[(111)In]DTPA, with two zinc-dipicolylamine units were prepared. Organ biodistribution and SPECT and CT imaging studies were performed on living mice with a leg infection created by injection of clinically relevant Gram positive Streptococcus pyogenes. Fluorescent and luminescent Eu(3+)-labeled versions of these tracers were also prepared and used to measure relative affinity for the exterior membrane surface of bacterial cells and mimics of healthy mammalian cells.
  
  
  RESULTS
  All three (111)In-labeled radiotracers were prepared with a radiopurity of >90 %. The biodistribution studies showed that the two monovalent tracers were cleared from the body through the liver and kidney, with retained percentage injected dose for all organs of <8 % at 20 h and infected leg target to non-target ratio (T/NT) ratio of ≤3.0. Clearance of the divalent tracer from the bloodstream was slower and primarily through the liver, with a retained percentage injected dose for all organs <37 % at 20 h and T/NT ratio rising to 6.2 after 20 h. The SPECT/CT imaging indicated the same large difference in tracer pharmacokinetics and higher accumulation of the divalent tracer at the site of infection.
  
  
  CONCLUSIONS
  All three [(111)In]-ZnDPA tracers selectively targeted the site of a clinically relevant mouse infection model that could not be discerned by visual external inspection of the living animal. The highest target selectivity, observed with a divalent tracer equipped with two zinc-dipicolylamine targeting units, compares quite favorably with the imaging selectivities previously reported for other nuclear tracers that target bacterial cell surfaces. The tracer pharmacokinetics depended heavily on tracer molecular structure suggesting that it may be possible to rapidly fine tune the structural properties for optimized in vivo imaging performance and clinical translation.
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, 46556, USA.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Rice
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Plaunt
authors.forename: Serhan
authors.initials: S
authors.lastname: Turkyilmaz
authors.forename: Miles
authors.initials: M
authors.lastname: Smith
authors.forename: Yuzhen
authors.initials: Y
authors.lastname: Wang
authors.forename: Mary
authors.initials: M
authors.lastname: Rusckowski
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Smith
mesh_terms: D000818:Animals; D001424:Bacterial Infections / Q000000981:diagnostic imaging*; D002462:Cell Membrane / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D005063:Europium; D005121:Extremities / Q000000981:diagnostic imaging / Q000382:microbiology; D007205:Indium Radioisotopes; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009942:Organometallic Compounds / Q000097:blood; D010848:Picolinic Acids / Q000097:blood; D013297:Streptococcus pyogenes / Q000166:cytology; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed; D051598:Whole Body Imaging
chemical_list: D007205:Indium Radioisotopes; D009942:Organometallic Compounds; D010848:Picolinic Acids; C529174:bis-dipicolylamine-Zinc(II); D005063:Europium