Assessment of neuroinflammation in transferred EAE via a translocator protein ligand

Neuroinflammation is involved in the pathogenesis and progression of neurological disorders such as Alzheimer's disease and multiple sclerosis (MS) (Doorduin et al., 2008). MS has been considered a T cell-mediated autoimmune disorder of the central nervous system (CNS), characterized by inflammatory cell infiltration and myelin destruction (Hauser et al., 1986) and focal demyelinated lesions in the white matter are the traditional hallmarks of MS. However more recent evidence suggests more widespread damage to the brain and spinal cord, to areas of white matter distant from the inflammatory lesions and demyelination of deep and cortical grey matter (McFarland & Martin, 2007). Experimental autoimmune encephalomyelitis (EAE) is an extensively used model of T-cell mediated CNS inflammation; modelling disease processes involved in MS. EAE can be induced in several species by immunization with myelin antigens or via adoptive transfer of myelin-reactive T cells. The models of EAE in rodents [actively induced and transferred] provide information about different phases [inflammation, demyelination and remyelination] and types [monophasic, chronic-relapsing and chronic-progressive] of the human disease multiple sclerosis and a vast amount of clinical and histopathologic data has been accumulated through the decades. A key aim of current investigations is developing the ability to recognise the early symptoms of the disease and to follow its course and response to treatment. Molecular imaging is a rapidly evolving field of research that involves the evaluation of biochemical and physiological processes utilising specific, radioactive, fluorescent and magnetic resonance imaging probes. However, it is positron emission tomography (PET) and single photon emission computer tomography (SPECT) which, due to their exquisite sensitivity involving specifically designed radiolabelled molecules, that is leading the way in molecular imaging and has greatly enabled the non-invasive “visualisation” of many diseases in both animal models and humans. Furthermore, PET and SPECT molecular imaging are providing invaluable imaging data based on a biochemical-molecular biology interaction rather than from the traditional anatomical view. Increasingly, PET and SPECT radiotracers have been exploited to study or identify molecular biomarkers of disease, monitor disease progression, determining the effects of a drug on a particular pathology and assess the pharmacokinetic behaviour of pharmaceuticals in vivo. Significantly, these new imaging systems provide investigators with an unprecedented ability to examine and measure in vivo biological and pharmacological processes over time in the same animals thus reducing experimental variability, time and costs. Molecular imaging based on the radiotracer principle allows chemical processes ranging from cellular events, to cellular communication and interaction in their environment, to the organisation and function of complete tissue and organs to be studied in real time without perturbation. One of the key benefits of molecular imaging is a technique that allows longitudinal studies vital for monitoring intra-individual progression in disease, or regression with supplementary pharmacotherapies. This is key in animal models of diseases such as MS, where there is significant intra-individual variability in the disease course and severity. Recent investigations have proposed the translocator protein (TSPO; 18 kDa), also known as the peripheral benzodiazepine receptor (PBR), as a molecular target for imaging neuroinflammation (Chen & Guilarte, 2008; Doorduin et al., 2008; Papadopoulos et al., 2006). TSPO (18 kDa) is a multimeric protein consisting of five transmembrane helices, which, in association with a 32 kDa subunit that functions as a voltage dependent anion channel and a 30 kDa subunit that functions as an adenine nucleotide carrier forms part of a hetero-oligomeric complex (McEnery et al., 1992) responsible for cholesterol, heme and calcium transport in specific tissue. TSPO is primarily located on the outer mitochondrial membrane and is predominantly expressed in visceral organs (kidney, heart) and the steroid hormone producing cells of the adrenal cortex, testis and ovaries. In the central nervous system (CNS), TSPO is sparsely expressed under normal physiological conditions, however its expression is significantly upregulated following CNS injury (Chen et al., 2004; Papadopoulos et al., 1997; Venneti et al., 2006; Venneti, et al., 2008). Several studies have identified activated glial cells as the cells responsible for TSPO upregulation in inflamed brain tissue, both in humans and in experimental models (Mattner et al., 2011; Myers et al., 1991a; Stephenson et al., 1995; Vowinckel et al., 1997) and the TSPO ligand [11C]-PK11195 was one of the first PET ligands used for imaging activated microglia in various neurodegenerative diseases (Venneti et al., 2006). Although [11C]-(R)-PK11195 is widely used for imaging of microglia, its considerable high plasma protein binding, high levels of nonspecific binding, relatively poor blood–brain barrier permeability and short half-life, limits its use in brain imaging (Chauveau et al., 2008). Recently, alternative PET radioligands for TSPO including the phenoxyarylacetamide derivative [11C]-DAA1106 and its analogues (Gulyas et al., 2009; Takano et al., 2010; Venneti et al., 2008), the imidazopyridines (PBR111) and its analogues (Boutin et al., 2007a; Fookes et al., 2008) and the pyrazolo[1,5-a]pyrimidine derivatives [18F]-DPA-714 and [11C]-DPA-713 (Boutin et al., 2007b; James et al., 2008) have been investigated. In addition to imaging with PET, recent advances in new generation of hybrid SPECT imaging systems enabling increased resolution and morphological documentation with associated computed tomography have been made for use clinically and preclinically. These advances have created a need and an opportunity for SPECT tracers; particularly those incorporating the longer lived radiotracer iodine-123 (t ½ = 13.2 h), to facilitate extended longitudinal imaging studies. In this study the recently developed high-affinity TSPO, SPECT ligand, 6-chloro-2-(4′-iodophenyl)-3-(N,N-diethyl)-imidazo[1,2-a]pyridine-3-acetamide or CLINDE , was used to explore the expression of activated glia in a model of transferred EAE (tEAE). [123I]-CLINDE has demonstrated its potency and specificity for TSPO binding, its ability to penetrate the blood-brain barrier and suitable pharmacokinetics for SPECT imaging studies (Mattner et al., 2008). It has also been shown that [123I]-CLINDE was able to detect in vivo inflammatory processes characterized by increased density of TSPO in several animal models (Arlicot et al., 2008; Arlicot et al., 2010; Mattner et al., 2005; Mattner et al., 2011; Song et al., 2010), thus representing a promising SPECT radiotracer for imaging neuroinflammation. The present study aimed to investigate the effectiveness of [123I]-CLINDE to detect and quantify the activated glia and consequently correlate the intensity of TSPO upregulation with the severity of disease in a model of tEAE. © 2022 IntechOpen (Open Access).
Inflammation, Proteins, Ligands, Pathogenesis, Immune systems diseases, Single photon emission computed tomography, Diseases, Labelled compounds
Mattner, F., Staykova, M., Callaghan, P., Berghofer, P., Ballantyne, P., Gregoire, M. C., Fordham, S., Pham, T., Rahardjo, G., Jackson, T., Linares, D., & Katsifis. (2012). Assessment of neuroinflammation in transferred EAE via a translocator protein ligand. In Weissert, R. , (Ed.). (2012). Experimental Autoimmune Encephalomyelitis - Models, Disease Biology and Experimental Therapy. (Chapter 3., pp. 47, 64) IntechOpen. doi:10.5772/31310