title: Imaging microglial/macrophage activation in spinal cords of experimental autoimmune encephalomyelitis rats by positron emission tomography using the mitochondrial 18 kDa translocator protein radioligand [¹⁸F]DPA-714.
abstract: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. Activated microglia/macrophages play a key role in the immunopathogenesis of MS and its corresponding animal models, experimental autoimmune encephalomyelitis (EAE). Microglia activation begins at early stages of the disease and is associated with elevated expression of the 18 kDa mitochondrial translocator protein (TSPO). Thus, positron emission tomography (PET) imaging of microglial activation using TSPO-specific radioligands could be valuable for monitoring disease-associated neuroinflammatory processes. EAE was induced in rats using a fragment of myelin basic protein, yielding acute clinical disease that reflects extensive spinal cord inflammation. Enhanced TSPO expression in spinal cords of EAE rats versus those of controls was confirmed by Western blot and immunohistochemistry. Biodistribution studies in control and EAE rats were performed using the TSPO radioligand [¹⁸F]DPA-714 [N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide]. At 1 h after injection, almost fivefold higher levels of [¹⁸F]DPA-714 were measured in spinal cords of EAE rats versus controls. The specific binding of [¹⁸F]DPA-714 to TSPO in spinal cords was confirmed in competition studies, using unlabeled (R,S)-PK11195 [(R,S)-N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)isoquinoline-3-carboxamide)] or DPA-714 in excess. MicroPET studies affirm that this differential radioactivity uptake in spinal cords of EAE versus control rats could be detected and quantified. Using [¹⁸F]DPA-714, neuroinflammation in spinal cords of EAE-induced rats could be visualized by PET, offering a sensitive technique for monitoring neuroinflammatory lesions in the CNS and particularly in the spinal cord. In addition to current MRI protocols, this approach could provide molecular images of neuroinflammation for detection, monitoring, and research in MS.
authors.affiliation: Inserm, Unité 1023, Université Paris Sud, 91400 Orsay, France.
authors.forename: Galith
authors.initials: G
authors.lastname: Abourbeh
authors.forename: Benoit
authors.initials: B
authors.lastname: Thézé
authors.forename: Renaud
authors.initials: R
authors.lastname: Maroy
authors.forename: Albertine
authors.initials: A
authors.lastname: Dubois
authors.forename: Vincent
authors.initials: V
authors.lastname: Brulon
authors.forename: Yoann
authors.initials: Y
authors.lastname: Fontyn
authors.forename: Frédéric
authors.initials: F
authors.lastname: Dollé
authors.forename: Bertrand
authors.initials: B
authors.lastname: Tavitian
authors.forename: Raphaël
authors.initials: R
authors.lastname: Boisgard
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000276:immunology / Q000473:pathology*; D005260:Female; D005462:Fluorine Radioisotopes; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D008264:Macrophages / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D017628:Microglia / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D004676:Myelin Basic Protein / Q000009:adverse effects / Q000276:immunology; D010446:Peptide Fragments / Q000009:adverse effects / Q000276:immunology; D049268:Positron-Emission Tomography; D011720:Pyrazoles; D011743:Pyrimidines; D051381:Rats; D011917:Rats, Inbred Lew; D011963:Receptors, GABA-A / Q000378:metabolism*; D013116:Spinal Cord / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology*; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D015703:Antigens, CD; D002352:Carrier Proteins; D005462:Fluorine Radioisotopes; D005904:Glial Fibrillary Acidic Protein; D007546:Isoquinolines; D004676:Myelin Basic Protein; C530129:N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo(1,5-a)pyrimidin-3-yl)acetamide; D010446:Peptide Fragments; D011720:Pyrazoles; D011743:Pyrimidines; D011963:Receptors, GABA-A; C079716:myelin basic protein 68-88; C069997:Tspo protein, rat; C037850:PK 11195