TSPO imaging in animal models of brain diseases

Abstract

Over the last 30 years, the 18-kDa TSPO protein has been considered as the PET imaging biomarker of reference to measure increased neuroinflammation. Generally assumed to image activated microglia, TSPO has also been detected in endothelial cells and activated astrocytes. Here, we provide an exhaustive overview of the recent literature on the TSPO-PET imaging (i) in the search and development of new TSPO tracers and (ii) in the understanding of acute and chronic neuroinflammation in animal models of neurological disorders. Generally, studies testing new TSPO radiotracers against the prototypic [11C]-R-PK11195 or more recent competitors use models of acute focal neuroinflammation (e.g. stroke or lipopolysaccharide injection). These studies have led to the development of over 60 new tracers during the last 15 years. These studies highlighted that interpretation of TSPO-PET is easier in acute models of focal lesions, whereas in chronic models with lower or diffuse microglial activation, such as models of Alzheimer’s disease or Parkinson’s disease, TSPO quantification for detection of neuroinflammation is more challenging, mirroring what is observed in clinic. Moreover, technical limitations of preclinical scanners provide a drawback when studying modest neuroinflammation in small brains (e.g. in mice). Overall, this review underlines the value of TSPO imaging to study the time course or response to treatment of neuroinflammation in acute or chronic models of diseases. As such, TSPO remains the gold standard biomarker reference for neuroinflammation, waiting for new radioligands for other, more specific targets for neuroinflammatory processes and/or immune cells to emerge.

Neuroinflammation, Stroke, Blood-Brain Barrier Dysfunction, and Imaging Modalities

“…87 This is partly due to human TSPO polymorphisms causing differential affinity for TSPO ligands, although this does not appear to be an issue in preclinical animal studies. 87,88…”

“…87 This is partly due to human TSPO polymorphisms causing differential affinity for TSPO ligands, although this does not appear to be an issue in preclinical animal studies. 87,88 PET studies in animal models and patients have shown that TSPO expression is low in the first days after stroke, increases in the following weeks (Figure 2, middle), and normalizes again after several months. 88,89 Nevertheless, activation of microglia, colocalized with secondary tissue degeneration, has been detected in noninfarcted areas of chronic patients beyond 6 to 12 months after stroke.…”

Positron Emission Tomography in Animal Models of Tauopathies

“…The most widely used neuroinflammation probes are those targeting at 18 kDa Translocator Protein (TSPO), locates on the outer mitochondrial membrane, and overexpressed by microglia during activation ( Van Camp et al, 2021 ; Zhou R. et al, 2021 ). TSPO PET tracers that have been applied in tau animal models include first generation (R)-[ 11 C]PK11195, second generation [ 18 F]FEBMP, [ 18 F]DPA-714, [ 11 C]AC-5216, ( 125 I) CLINDE, [ 11 C]PBR28, [ 18 F]FEDAA1106, and [ 11 C]DAA1106 ( Ji et al, 2008 , 2021 ; Maeda et al, 2011 ; Jacobs and Tavitian, 2012 ; Mirzaei et al, 2016 ; Ishikawa et al, 2018 ; Tournier et al, 2019 , 2020 ; Barron et al, 2020 ; Takuwa et al, 2020 ; Chaney et al, 2021 ; Fairley et al, 2021 ; Leng and Edison, 2021 ; Zhou X. et al, 2021 ), and third generation [ 18 F]GE-180, etc.…”

Positron Emission Tomography in Animal Models of Alzheimer’s Disease Amyloidosis

“…Several recent articles have provided thorough reviews on neuroinflammation PET imaging in AD patients and AD animal models [16,[176][177][178][179][180]. Thus here we discuss briefly the recent development in neuroinflammation imaging in AD amyloidosis animal models.…”