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Cellina et al. Neuroimmunol Neuroinflammation 2018;5:22 I http://dx.doi.org/10.20517/2347-8659.2018.15 Page 3 of 6

TSPO is an 18 kDa translocator protein located on the outer mitochondrial membrane. It is only minimally
expressed in the healthy human brain, but highly expressed in macrophages, neutrophils, lymphocytes,
astrocytes and microglia . TSPO expression is highly up-regulated during the microglia activation process
[32]
in several acute and degenerative disorders, including AD, PD, ALS, MS, and HD; therefore, TSPO is
considered a promising target for PET imaging of neuroinflammation and has already undergone clinical
application . TSPO PET imaging, using various PET tracers binding to TPSO , has been used for both
[33]
[30]
improving the knowledge regarding the role of neuroinflammation in CNS diseases and to assess the efficacy
of novel anti-inflammatory therapeutic strategies. In a rat brain AD model elevated TSPO levels were found
in tau-rich hippocampus and entorhinal cortex region of the brain and there was a constant increase of
tracer uptake in the brain region with the progression of AD . In PD patients, microglia activation could be
[34]
detected via TPSO PET at the early phase of the disease, and its activity is correlated with the development
of dementia in PD .
[35]
Cannabinoid receptors are a family of G-protein-coupled receptors composed at least by two subtypes: type 1
and 2. While type 1 is abundantly expressed in the brain, type 2, which is the inducible isoform, is detectable
just in microglial cells, in human fetal astrocytes, and in human cerebral microvascular endothelial cells .
[36]
Several studies reported an up-regulation of CB2R on activated microglial cells in pathological conditions,
including MS, ALS, PD, or AD . The activation of CB2R by CB2 agonists is found to be effective in
[37]
reducing neurodegeneration in HD and ALS transgenic mouse model, thanks to the decrease of microglial
activation, mediated by the release inhibition of neurotoxic factors and by the decrease of neuronal cell
damage . Therapeutic modulation of CB2R could be a promising treatment for neuropathogenic disorders
[38]
characterized by a neuroinflammatory component. Over the past years, several CB2R selective ligands have
been developed and labeled with radioisotopes for PET, including pyrazole derivatives, indole derivatives,
and quinoline derivatives . The first in vivo PET of brain CB2R showed a significant increase in tracer
[30]
uptake in all brain regions in mice with lipopolysaccharide induced neuroinflammation; in this study,
tracer uptake could be blocked by a CB2R selective ligand, thus indicating the specificity of the tracer
accumulation . New synthesized radiotracers are under investigations in the preclinical settings and offer
[39]
promising opportunities for imaging CB2R expression in the future .
[31]

Cyclooxygenase (COX) is an enzyme producing important biological mediators mainly expressed in
neuroinflammation in connection with neurodegenerative diseases. Three COX subtypes (COX-1, 2, and 3)
have been identified. COX-2 is the inflammatory inducible enzyme form of this family and its expression in
brain has been associated with neurodegenerative processes of several acute and chronic diseases .
[40]
COX-2 has been identified as a molecular target of interest for pharmacological design of selective ligands
for both therapy and molecular imaging. Celecoxib is an important and widely used anti-inflammatory drug
that inhibits selectively COX-2 to treat various inflammatory diseases. In order to image neuroinflammation,
Celecoxib and other COX inhibitors were manipulated using imaging tracers (18F and 11C): these attempts have
not yet shown significant results due to the absence of specific bindings, sensitive enough to inflammatory foci .
[30]
On the other hand, a study of a rat skin model of inflammation showed significant uptake in COX-2 targeted
micro PET/ computed tomography (CT) imaging of a mouse paw inflammation induced by carrageenan .
[41]

Despite the fact that the administration of selective COX-2 inhibitors has been shown to attenuate brain
inflammatory reactions, protecting neurons against neurodegeneration in AD patients , the evidence of a direct
[42]
role of COX-2 in neurodegenerative events is still controversial: recent data demonstrates that COX-1, classically
viewed as the homeostatic isoform, is involved in brain injury induced by pro-inflammatory stimuli .
[43]

Moreover, thanks to the recent discover of high specificity of cellular expression of COX-1 within microglia
during acute neuroinflammatory process, the development of a selective COX-1 imaging probe has regained