title: Longitudinal PET imaging of muscular inflammation using 18F-DPA-714 and 18F-Alfatide II and differentiation with tumors.
abstract: OBJECTIVE
  (18)F-DPA-714 is a PET tracer that recognizes macrophage translocator protein (TSPO), and (18)F-Alfatide II ((18)F-AlF-NOTA-E[PEG4-c(RGDfk)]2) is specific for integrin αvβ3. This study aims to apply these two tracers for longitudinal PET imaging of muscular inflammation, and evaluate the value of (18)F-DPA-714 in differentiating inflammation from tumor.
  
  
  METHODS
  RAW264.7 mouse macrophage cells were used for cell uptake analysis of (18)F-DPA-714. A mouse hind limb muscular inflammation model was established by intramuscular injection of turpentine oil. For the inflammation model, PET imaging was performed at different days using (18)F-DPA-714 and (18)F-Alfatide II. The specificity of the imaging probes was tested by co- or pre-injection of PK11195 or unlabeled RGD (Arg-Gly-Asp) peptide. PET imaging using (18)F-DPA-714 was performed in A549, HT29, U87MG, INS-1, and 4T1 xenograft models. Immunofluorescence staining was performed to evaluate infiltrated macrophages and angiogenesis in inflammation and/or tumors.
  
  
  RESULTS
  Uptake of (18)F-DPA-714 in RAW264.7 cells was 45.5% at 1 h after incubation, and could be blocked by PK11195. PET imaging showed increased (18)F-DPA-714 and (18)F-Alfatide II uptake at inflammatory muscles. Peak uptake of (18)F-DPA-714 was seen on day 6 (4.02 ± 0.64 %ID/g), and peak uptake of (18)F-Alfatide II was shown on day 12 (1.87 ± 0.35 %ID/g) at 1 h p.i.. Tracer uptakes could be inhibited by PK11195 for (18)F-DPA-714 or cold RGD for (18)F-Alfatide II. Moreover, macrophage depletion with liposomal clodronate also reduced the local accumulation of both tracers. A549, HT29, U87MG, INS-1, and 4T1 tumor uptakes of (18)F-DPA-714 (0.46 ± 0.28, 0.91 ± 0.08, 1.69 ± 0.67, 1.13 ± 0.33, 1.22 ± 0.55 %ID/g at 1 h p.i., respectively) were significantly lower than inflammation uptake (All P < 0.05).
  
  
  CONCLUSIONS
  PET imaging using (18)F-DPA-714 as a TSPO targeting tracer could evaluate the dynamics of macrophage activation and infiltration in different stages of inflammatory diseases. The concomitant longitudinal PET imaging with both (18)F-DPA-714 and (18)F-Alfatide II matched the causal relationship between macrophage infiltration and angiogenesis. Moreover, we found (18)F-DPA-714 uptake in several types of tumors is significantly lower than that in inflammatory muscles, suggesting (18)F-DPA-714 PET has the potential for better differentiation of tumor and non-tumor inflammation.
authors.affiliation: 1. Department of Nuclear Medicine, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, China. ; 2. Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Bethesda, USA.
authors.forename: Chenxi
authors.initials: C
authors.lastname: Wu
authors.affiliation: 2. Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Bethesda, USA.
authors.forename: Xuyi
authors.initials: X
authors.lastname: Yue
authors.affiliation: 2. Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Bethesda, USA.
authors.forename: Lixin
authors.initials: L
authors.lastname: Lang
authors.affiliation: 2. Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Bethesda, USA.
authors.forename: Dale O
authors.initials: DO
authors.lastname: Kiesewetter
authors.affiliation: 1. Department of Nuclear Medicine, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.affiliation: 1. Department of Nuclear Medicine, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, China.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: 2. Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Bethesda, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Niu
authors.affiliation: 2. Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Bethesda, USA.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D002460:Cell Line; D003937:Diagnosis, Differential; D004195:Disease Models, Animal; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D019042:Muscle Neoplasms / Q000175:diagnosis* / Q000000981:diagnostic imaging; D009220:Myositis / Q000175:diagnosis* / Q000000981:diagnostic imaging; D010456:Peptides, Cyclic; D049268:Positron-Emission Tomography / Q000379:methods*; D011720:Pyrazoles; D011743:Pyrimidines; D011859:Radiography
chemical_list: D005462:Fluorine Radioisotopes; C530129:N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo(1,5-a)pyrimidin-3-yl)acetamide; D010456:Peptides, Cyclic; D011720:Pyrazoles; D011743:Pyrimidines; C586680:alfatide II
keywords: 18F-Alfatide II; 18F-DPA-714; TSPO; inflammation; positron emission tomography; tumor