title: Preclinical evaluation of 68Ga-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-ubiquicidin as a radioligand for PET infection imaging.
abstract: Antimicrobial peptides such as ubiquicidin (UBI) are believed to differentiate between mammalian and bacterial or fungal cells. (99m)Tc-UBI29-41 was previously tested for detecting infection in humans using SPECT. For the present study, the UBI fragment UBI29-41 (TGRAKRRMQYNRR) was conjugated to 1,4,7-triazacyclononane-triacetic acid (NOTA), radiolabeled with (68)Ga, and investigated in a rabbit infection model.
  
  
  METHODS
  (68)Ga was obtained from a 1.85-GBq (68)Ge/(68)Ga generator. New Zealand White rabbits were anesthetized with ketamine/medetomidine before tracer administration and placed in a clinical PET/CT scanner. (68)Ga-1,4,7-triazacyclononane-1,4,7-triacetic-acid-ubiquicidin29-41 ((68)Ga-NOTA-UBI29-41) was formulated in saline solution, and 101 ± 41 MBq were administered intravenously. The tracer distribution was studied by PET/CT imaging in animals (a) that were healthy, (b) bearing muscular Staphylococcus aureus infections and turpentine oil-induced muscular inflammations, and (c) bearing ovalbumin-induced lung inflammations. Static PET/CT imaging was performed at different time intervals up to 120 min after injection. For calculation of target-to-nontarget ratios, standardized uptake values were normalized against healthy thigh muscle, representing nontargeted tissue.
  
  
  RESULTS
  PET/CT images of healthy animals showed predominant distribution in the kidneys, liver, and bladder; heart and spleen showed moderate, declining uptake, only. The biologic half-life in blood was 29 min. Urinary accumulation of (68)Ga-NOTA-UBI29-41 peaked at 3.8 ± 0.91 percentage injected dose per gram (%ID) at 120 min, and 88 ± 5.2 %ID was recovered in total urine. (68)Ga-NOTA-UBI29-41 imaging in (b) selectively visualized the muscular infection site and was differentiated from sterile inflammatory processes. Standardized uptake value ratios for muscles (infected/inflamed) were 2.9 ± 0.93, 2.9 ± 0.50, 3.5 ± 0.86, and 3.8 ± 0.90 at 5, 30, 60, and 90 min after injection, respectively. Rabbit lungs with asthma showed insignificant uptake.
  
  
  CONCLUSIONS
  (68)Ga-NOTA-UBI29-41 was strongly localized in bacteria-infected areas and minimally detected in a sterile inflammation area in rabbit muscles. The findings propose this compound to be an excellent first-line PET/CT tracer to allow the distinguishing of infection from inflammation.
authors.affiliation: Department of Nuclear Medicine, University of Pretoria and Steve Biko Academic Hospital, Pretoria, South Africa.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ebenhan
authors.forename: Jan Rijn
authors.initials: JR
authors.lastname: Zeevaart
authors.forename: Jacobus D
authors.initials: JD
authors.lastname: Venter
authors.forename: Thavendran
authors.initials: T
authors.lastname: Govender
authors.forename: Gert H
authors.initials: GH
authors.lastname: Kruger
authors.forename: Neil V
authors.initials: NV
authors.lastname: Jarvis
authors.forename: Mike M
authors.initials: MM
authors.lastname: Sathekge
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry; D005710:Gallium Radioisotopes; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006573:Heterocyclic Compounds, 1-Ring; D007239:Infections / Q000175:diagnosis* / Q000000981:diagnostic imaging*; D007249:Inflammation; D008168:Lung / Q000187:drug effects; D049268:Positron-Emission Tomography / Q000379:methods; D011817:Rabbits; D019275:Radiopharmaceuticals; D012269:Ribosomal Proteins / Q000737:chemistry*; D013203:Staphylococcal Infections / Q000378:metabolism; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*; D014057:Tomography, X-Ray Computed / Q000379:methods; D014425:Turpentine / Q000737:chemistry
chemical_list: D023181:Antimicrobial Cationic Peptides; D005710:Gallium Radioisotopes; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D019275:Radiopharmaceuticals; D012269:Ribosomal Proteins; C040469:ribosomal protein S30; C048993:1,4,7-triazacyclononane-N,N',N''-triacetic acid; D014425:Turpentine
keywords: 68Ga labeling; PET/CT Imaging; UBI29-41; infection; ubiquicidin