Figure 2 – CSF1R expression and [11C]CPPC binding in healthy and disease. A – CSF1R expression and [11C]CPPC binding are increased in LPS-induced or disease-related  neuroinflammatory conditions. B - Physicochemical properties and specific binding in animal models suggest great potential for [11C]CPPC clinical translation.
Biodistribution of [11C]CPPC in LPS-induced murine models of neuroinflammation
A previous work published by Illig, C. R. et al. 3, describes the pharmacological properties of CPPC and other CSF1R specific inhibitors. The best molecules were tested in arthritis mouse model, showing efficacy by reducing bone erosion, cartilage damage and inflammation. These data indicate that the CSF1R inhibitors may interact throughout the body before reaching the brain. Indeed, this may explain the need for blood correction to obtain significant results in blocking studies involving a systemic inflammation mouse model (i.p. LPS).
A Murine model of Alzheimer’s Disease:
Herein, aged APP-mice (16 months) were used to test [11C]CPPC uptake. At this age, these animals present high insoluble amyloid-beta (Aβ)  content widely distributed in the brain 5. In fact, recent evidence suggests microglial activation as an early stage in AD pathology, which occurs even before the formation of mature insoluble Aβ plaques 6,7. In keeping with this, [11C]CPPC could be differentially taken up in different stages of amyloidosis. A PET longitudinal study with APP-mice and [11C]CPPC, would be a very important step to elucidate initial inflammatory changes in AD8. 
A nonhuman primate LPS model of neuroinflammation:
  1. Conclusions:
It is well known that most PET radiotracers aiming the CNS fail due to its inability to cross the blood-brain barrier. The innovative PET radiotracer [11C]CPPC for imaging CSF1R discussed in this commentary, presented good brain penetrance, a moderate heterogenous distribution and good clearance. [11C]CPPC is obtained with sufficient radiochemical yield, purity and specific activity, essential features for clinical translation. Of note, [11C]CPPC has high specificity in mouse and baboon models of neuroinflammation. Additionally, in murine models of AD, there was significant increase on [11C]CPPC binding compared to controls. Together these results indicate [11C]CPPC as a potential tool to help on the diagnosis of brain diseases involving neuroinflammation, such as AD and MS. However, an important question remains: would [11C]CPPC be useful for detecting microglia activation and neuroinflammation in the early stages of AD, before the symptomatic phase?
Take home message:
What would I like to see on the follow up of this paper?
The application of [11C]CPPC targeting CSF1R in neuroinflammation-linked diseases has great potential for clinical translation. Currently, the inaccuracy of diagnosis and treatment for neurodegenerative diseases is a great matter of discussion. In AD, it seems that neuroinflammatory changes may emerge even earlier than detectable canonical Aβ and tau pathology. If [11C]CPPC could detect this initial neuroinflammatory alterations with topographical resolution could help to detect the earliest AD-related changes, opening a new window for therapeutic intervention.