[(11)C]DAC-PET for noninvasively monitoring neuroinflammation and immunosuppressive therapy efficacy in rat experimental autoimmune encephalomyelitis model.
Neuroimaging measures have potential for monitoring neuroinflammation to guide treatment before the occurrence of significant functional impairment or irreversible neuronal damage in multiple sclerosis (MS). N-Benzyl-N-methyl-2-(7-[(11)C]methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl) acetamide ([(11)C]DAC), a new developed positron emission tomography (PET) probe for translocator protein 18 kDa (TSPO), has been adopted to evaluate the neuroinflammation and treatment effects of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. [(11)C]DAC-PET enabled visualization of neuroinflammation lesion of EAE by tracing TSPO expression in the spinal cords; the maximal uptake value reached in day 11 and 20 EAE rats with profound inflammatory cell infiltration compared with control, day 0 and 60 EAE rats. Biodistribution studies and in vitro autoradiography confirmed these in vivo imaging results. Doubling immunohistochemical studies showed the infiltration and expansion of CD4+ T cells and CD11b+ microglia; CD68+ macrophages were responsible for the increased TSPO levels visualized by [(11)C]DAC-PET. Furthermore, mRNA level analysis of the cytokines by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) revealed that TSPO+/CD4 T cells, TSPO+ microglia and TSPO+ macrophages in EAE spinal cords were activated and secreted multiple proinflammation cytokines to mediate inflammation lesions of EAE. EAE rats treated with an immunosuppressive agent: 2-amino-2-[2-(4-octylphenyl)ethyl] propane-1,3-diolhydrochloride (FTY720), which exhibited an absence of inflammatory cell infiltrates, displaying a faint radioactive signal compared with the high accumulation of untreated EAE rats. These results indicated that [(11)C] DAC-PET imaging is a sensitive tool for noninvasively monitoring the neuroinflammation response and evaluating therapeutic interventions in EAE.
Division of Radiation Safety and Immune Tolerance, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan.
Lin
L
Xie
Tomoteru
T
Yamasaki
Naotsugu
N
Ichimaru
Joji
J
Yui
Kazunori
K
Kawamura
Katsushi
K
Kumata
Akiko
A
Hatori
Norio
N
Nonomura
Ming-Rong
MR
Zhang
Xiao-Kang
XK
Li
Shiro
S
Takahara
D000081:Acetamides / Q000493:pharmacokinetics; D000818:Animals; D001345:Autoradiography; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000000981:diagnostic imaging* / Q000188:drug therapy; D005260:Female; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D011917:Rats, Inbred Lew; D018079:Receptors, GABA / Q000378:metabolism*; D013116:Spinal Cord / Q000000981:diagnostic imaging*; D014018:Tissue Distribution
D000081:Acetamides; C463819:Bzrp protein, mouse; D002250:Carbon Radioisotopes; D007166:Immunosuppressive Agents; D019275:Radiopharmaceuticals; D018079:Receptors, GABA