title: Cholinergic PET imaging in infections and inflammation using11C-donepezil and18F-FEOBV.
abstract: BACKGROUND
  Immune cells utilize acetylcholine as a paracrine-signaling molecule. Many white blood cells express components of the cholinergic signaling pathway, and these are up-regulated when immune cells are activated. However, in vivo molecular imaging of cholinergic signaling in the context of inflammation has not previously been investigated.
  
  
  METHODS
  We performed positron emission tomography (PET) using the glucose analogue 18F-FDG, and 11C-donepezil and 18F-FEOBV, markers of acetylcholinesterase and the vesicular acetylcholine transporter, respectively. Mice were inoculated subcutaneously with Staphylococcus aureus, and PET scanned at 24, 72, 120, and 144 h post-inoculation. Four pigs with post-operative abscesses were also imaged. Finally, we present initial data from human patients with infections, inflammation, and renal and lung cancer.
  
  
  RESULTS
  In mice, the FDG uptake in abscesses peaked at 24 h and remained stable. The 11C-donepezil and 18F-FEOBV uptake displayed progressive increase, and at 120-144 h was nearly at the FDG level. Moderate 11C-donepezil and slightly lower 18F-FEOBV uptake were seen in pig abscesses. PCR analyses suggested that the 11C-donepezil signal in inflammatory cells is derived from both acetylcholinesterase and sigma-1 receptors. In humans, very high 11C-donepezil uptake was seen in a lobar pneumonia and in peri-tumoral inflammation surrounding a non-small cell lung carcinoma, markedly superseding the 18F-FDG uptake in the inflammation. In a renal clear cell carcinoma no 11C-donepezil uptake was seen.
  
  
  CONCLUSIONS
  The time course of cholinergic tracer accumulation in murine abscesses was considerably different from 18F-FDG, demonstrating in the 11C-donepezil and 18F-FEOBV image distinct aspects of immune modulation. Preliminary data in humans strongly suggest that 11C-donepezil can exhibit more intense accumulation than 18F-FDG at sites of chronic inflammation. Cholinergic PET imaging may therefore have potential applications for basic research into cholinergic mechanisms of immune modulation, but also clinical applications for diagnosing infections, inflammatory disorders, and cancer inflammation.
authors: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
authors: Nis Pedersen
authors: NP
authors: Jørgensen
authors: Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Noerrebrogade 44, bygn. 10G, kaelderen, DK-8000, Aarhus C, Denmark.
authors: Aage K O
authors: AK
authors: Alstrup
authors: Department of Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
authors: Frank V
authors: FV
authors: Mortensen
authors: Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Noerrebrogade 44, bygn. 10G, kaelderen, DK-8000, Aarhus C, Denmark.
authors: Karoline
authors: K
authors: Knudsen
authors: Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Noerrebrogade 44, bygn. 10G, kaelderen, DK-8000, Aarhus C, Denmark.
authors: Steen
authors: S
authors: Jakobsen
authors: Department of Histopathology, Aarhus University Hospital, Aarhus, Denmark.
authors: Line Bille
authors: LB
authors: Madsen
authors: Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Noerrebrogade 44, bygn. 10G, kaelderen, DK-8000, Aarhus C, Denmark.
authors: Dirk
authors: D
authors: Bender
authors: Department of Endocrinology and Metabolism, Aarhus University Hospital, Aarhus, Denmark.
authors: Peter
authors: P
authors: Breining
authors: Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.
authors: Mikkel Steen
authors: MS
authors: Petersen
authors: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
authors: Mariane Høgsberg
authors: MH
authors: Schleimann
authors: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors: Frederik
authors: F
authors: Dagnæs-Hansen
authors: Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Noerrebrogade 44, bygn. 10G, kaelderen, DK-8000, Aarhus C, Denmark.
authors: Lars C
authors: LC
authors: Gormsen
authors: Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Noerrebrogade 44, bygn. 10G, kaelderen, DK-8000, Aarhus C, Denmark. perborgh@rm.dk.
authors: Per
authors: http://orcid.org/0000-0001-6391-8052
authors: P
authors: Borghammer
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000328:Adult; D000368:Aged; D000818:Animals; D002250:Carbon Radioisotopes; D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging; D002292:Carcinoma, Renal Cell / Q000000981:diagnostic imaging; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics*; D000077265:Donepezil; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D007189:Indans / Q000493:pharmacokinetics*; D007680:Kidney Neoplasms / Q000000981:diagnostic imaging; D008175:Lung Neoplasms / Q000000981:diagnostic imaging; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010880:Piperidines / Q000493:pharmacokinetics*; D000072078:Positron Emission Tomography Computed Tomography; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D013203:Staphylococcal Infections / Q000000981:diagnostic imaging*; D013552:Swine; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism
chemical_list: D002250:Carbon Radioisotopes; D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D019275:Radiopharmaceuticals; D050494:Vesicular Acetylcholine Transport Proteins; C116169:fluoroethoxy-benzovesamicol; D019788:Fluorodeoxyglucose F18; D000077265:Donepezil; D000110:Acetylcholinesterase
keywords: Acetylcholinesterase; Bacterial infection; Cholinergic; Infection; Inflammation; Positron emission tomography; Vesicular acetylcholine transporter