title: Prokineticin receptor 1 antagonist PC-10 as a biomarker for imaging inflammatory pain.
abstract: Prokineticin receptor 1 (PKR1) and its ligand Bv8 were shown to be expressed in inflammation-induced pain and by tumor-supporting fibroblasts. Blocking this receptor might prove useful for reducing pain and for cancer therapy. However, there is no method to quantify the levels of these receptors in vivo.
  
  
  METHODS
  A nonpeptidic PKR1 antagonist, N-{2-[5-(4-fluoro-benzyl)-1-(4-methoxy-benzyl)-4,6-dioxo-1,4,5,6-tetrahydro-[1,3,5]triazin-2-ylamino]-ethyl}-guanidine, which contains a free guanidine group, was labeled with (18)F by reacting the guanidine function with N-succinimidyl-4-(18)F-fluorobenzoate to give the guanidinyl amide N-(4-(18)F-fluoro-benzoyl)-N'-{2-[5-(4-fluoro-benzyl)-1-(4-methoxy-benzyl)-4,6-dioxo-1,4,5,6-tetrahydro-[1,3,5]triazin-2-ylamino]-ethyl}-guanidine ((18)F-PC-10). Inflammation was induced in C57BL/6 mice by subcutaneous injection of complete Freund adjuvant in the paw. The mice were imaged with (18)F-PC-10, (18)F-FDG, and (64)Cu-pyruvaldehyde bis(4-methyl-3-thiosemicarbazone) ((64)Cu-PTSM) at 24 h after complete Freund adjuvant injection using a small-animal PET device.
  
  
  RESULTS
  (18)F-PC-10 was synthesized with a radiochemical yield of 16% ± 3% (decay-corrected). (18)F-PC-10 accumulated specifically in the inflamed paw 4- to 5-fold more than in the control paw. Compared with (18)F-PC-10, (18)F-FDG and (64)Cu-PTSM displayed higher accumulation in the inflamed paw but also had higher accumulation in the control paw, demonstrating a reduced signal-to-background ratio. (18)F-PC-10 also accumulated in PKR1-expressing organs, such as the salivary gland and gastrointestinal tract.
  
  
  CONCLUSIONS
  (18)F-PC-10 can be used to image PKR1, a biomarker of the inflammation process. However, the high uptake of (18)F-PC-10 in the gastrointestinal tract, due to specific uptake and the metabolic processing of this highly lipophilic molecule, would restrict its utility.
authors.affiliation: Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Orit
authors.initials: O
authors.lastname: Jacobson
authors.forename: Ido D
authors.initials: ID
authors.lastname: Weiss
authors.forename: Gang
authors.initials: G
authors.lastname: Niu
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Balboni
authors.forename: Cenzo
authors.initials: C
authors.lastname: Congiu
authors.forename: Valentina
authors.initials: V
authors.lastname: Onnis
authors.forename: Dale O
authors.initials: DO
authors.lastname: Kiesewetter
authors.forename: Roberta
authors.initials: R
authors.lastname: Lattanzi
authors.forename: Severo
authors.initials: S
authors.lastname: Salvadori
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D015415:Biomarkers; D016466:CHO Cells; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D003412:Cricetulus; D005462:Fluorine Radioisotopes; D005528:Foot / Q000000981:diagnostic imaging / Q000473:pathology; D006146:Guanidines / Q000138:chemical synthesis; D007202:Indicators and Reagents; D007249:Inflammation / Q000000981:diagnostic imaging*; D007553:Isotope Labeling / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D010146:Pain / Q000000981:diagnostic imaging*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D014018:Tissue Distribution; D014227:Triazines / Q000138:chemical synthesis
chemical_list: D015415:Biomarkers; D005462:Fluorine Radioisotopes; D006146:Guanidines; D007202:Indicators and Reagents; C558460:N-(4-fluorobenzoyl)-N'-(2-(5-(4-fluorobenzyl)-1-(4-methoxybenzyl)-4,6-dioxo-1,4,5,6-tetrahydro(1,3,5)triazin-2-ylamino)ethyl)guanidine; C525015:PKR1 protein, mouse; D019275:Radiopharmaceuticals; D043562:Receptors, G-Protein-Coupled; D014227:Triazines