Cholinergic PET imaging in infections and inflammation using 11C-donepezil and 18F-FEOBV

Introduction 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 F-18-FDG, and C-11-donepezil and F-18-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 C-11-donepezil and F-18-FEOBV uptake displayed progressive increase, and at 120-144 h was nearly at the FDG level. Moderate C-11-donepezil and slightly lower F-18-FEOBV uptake were seen in pig abscesses. PCR analyses suggested that the C-11-donepezil signal in inflammatory cells is derived from both acetylcholinesterase and sigma-1 receptors. In humans, very high C-11-donepezil uptake was seen in a lobar pneumonia and in peri-tumoral inflammation surrounding a non-small cell lung carcinoma, markedly superseding the F-18-FDG uptake in the inflammation. In a renal clear cell carcinoma no C-11-donepezil uptake was seen. Discussion The time course of cholinergic tracer accumulation in murine abscesses was considerably different from (18)FFDG, demonstrating in the C-11-donepezil and F-18-FEOBV image distinct aspects of immune modulation. Preliminary data in humans strongly suggest that C-11-donepezil can exhibit more intense accumulation than F-18-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.