Molecular Targets for PET Imaging of Activated Microglia: The Current Situation and Future Expectations

Abstract

Microglia, as cellular mediators of neuroinflammation, are implicated in the pathogenesis of a wide range of neurodegenerative diseases. Positron emission tomography (PET) imaging of microglia has matured over the last 20 years, through the development of radiopharmaceuticals targeting several molecular biomarkers of microglial activation and, among these, mainly the translocator protein-18 kDa (TSPO). Nevertheless, current limitations of TSPO as a PET microglial biomarker exist, such as low brain density, even in a neurodegenerative setting, expression by other cells than the microglia (astrocytes, peripheral macrophages in the case of blood brain barrier breakdown), genetic polymorphism, inducing a variation for most of TSPO PET radiopharmaceuticals’ binding affinity, or similar expression in activated microglia regardless of its polarization (pro- or anti-inflammatory state), and these limitations narrow its potential interest. We overview alternative molecular targets, for which dedicated radiopharmaceuticals have been proposed, including receptors (purinergic receptors P2X7, cannabinoid receptors, α7 and α4β2 nicotinic acetylcholine receptors, adenosine 2A receptor, folate receptor β) and enzymes (cyclooxygenase, nitric oxide synthase, matrix metalloproteinase, β-glucuronidase, and enzymes of the kynurenine pathway), with a particular focus on their respective contribution for the understanding of microglial involvement in neurodegenerative diseases. We discuss opportunities for these potential molecular targets for PET imaging regarding their selectivity for microglia expression and polarization, in relation to the mechanisms by which microglia actively participate in both toxic and neuroprotective actions in brain diseases, and then take into account current clinicians’ expectations.

Pro‐inflammatory activation of microglia in the brain of patients with sepsis

“…Intravenous LPS administration to healthy humans leads to microglia activation as demonstrated by the application of the PET ligand TSPO . However, TSPO is not specific for a defined functional state of microglia and is also expressed in astrocytes . By determining the expression of functionally defined molecules, we provide evidence that increased microglia activation in the white matter is characterized by an upregulated protein expression of the phagocytosis‐associated molecule CD68.…”

[Carboxyl‐11C]Labelling of Four High‐Affinity cPLA2α Inhibitors and Their Evaluation as Radioligands in Mice by Positron Emission Tomography

“…The developmento fP ET radioligandst hat specifically target cPLA2a could helpt oe valuate and understand the role of this enzyme in the pathophysiology of human diseases and would be complementary to efforts to develop PET radioligands for other neuroinflammation targets, [8] such as translocator 18 kDa protein (TSPO), [8][9][10] COXs, [8,11,12] P2X purinoceptor 7( P2X 7 ), [8,13] and cannabinoid receptor subtype 2( CB 2 ). [8,14] So far,o nly [ 11 C]arachidonic acid has been used with PET for preclinical and clinical imaging [15,16] to explore brain cPLA2 activity. [17] However,b ecause of the involvement of arachidonic acid in neural functions other than signal transduction, such as membrane synthesis and remodelling, the incorporation rate (K*) has not been deemede ntirely specific to the cPLA2 signalling system.…”

Commentary on interactions between neurotropic pathogens, neuroinflammatory pathways, and autophagic neural cell death

“…PET imaging of COX-1, according to these preclinical studies, could be a promising approach for monitoring activated microglia in CNS diseases such as AD [31] . Neuroinflammation plays a crucial role in the development of neurodegenerative disorders.…”

“…The first in vivo PET of brain CB2R showed a significant increase in tracer 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 [39] . New synthesized radiotracers are under investigations in the preclinical settings and offer 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.…”

“…The most studied neuroinflammation related targets include translocator protein (TSPO), type 2 cannabinoid receptor (CB2R), and cyclooxygenase (COX) [31] . TSPO is an 18 kDa translocator protein located on the outer mitochondrial membrane.…”