[11C]DAC-PET for Noninvasively Monitoring Neuroinflammation and Immunosuppressive Therapy Efficacy in Rat Experimental Autoimmune Encephalomyelitis Model

Abstract

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.

PET Imaging of Disease Progression and Treatment Effects in the Experimental Autoimmune Encephalomyelitis Rat Model

“…A noninvasive imaging technique such as PET could differentiate and quantify MS hallmarks and thus could be an important tool to monitor therapeutic response and help to better understand drug mechanisms. The potential of PET for imaging several hallmarks of MS was shown in animal models (4)(5)(6)(7)(8)(9)(10)(11)(12)(13) and in patients (14)(15)(16)(17)(18)(19)(20)(21)(22), but different hallmarks were not longitudinally measured at the same time in these studies. Despite the fact that MS comprises multiple aspects that are important for therapy monitoring and drug development, PET is not yet regularly applied in a clinical setting.…”

Translocator protein (18 kDa), a potential molecular imaging biomarker for non-invasively distinguishing non-alcoholic fatty liver disease

“…PET with radiolabeled TSPO probes has allowed non-invasive and reliable investigation of TSPO in neuropathological damages of experimental animals and humans [7][8][9][10][11][12]. Mitochondrial dysfunction plays a key role in the physiopathology of NASH irrespective of the initial cause.…”

“…is a specific PET probe for TSPO imaging, developed by our research group [7,9]. Here, TSPO expression and NAFLD progression were evaluated and quantified using [ 18 F]FEDAC-PET, computerized tomography (CT), histology, and gene analysis in methionine and choline-deficient (MCD) diet-fed mice, one of the most commonly used NASH animal models with severe oxidative stress and hepatocellular injury [17,18].…”

Imaging Microglial Activation with TSPO PET: Lighting Up Neurologic Diseases?

“…In the experimental autoimmune encephalomyelitis animal model, spinal TSPO expression has been imaged using numerous different PET radiotracers. When the radiotracers 11 C-DAC and 18 F-GE180 were used with PET, increased TSPO expression was observed in the brains of these mice, compared with controls, and this expression was shown to correlate with expression on ex vivo autoradiography and immunohistochemistry studies (13). Importantly, after treatment with immunosuppressant drugs, radiotracer uptake was greatly reduced, indicating the future use of TSPO PET as a noninvasive biomarker for evaluating and monitoring the effect of multiple sclerosis therapies on disease activity (13,14).…”

“…When the radiotracers 11 C-DAC and 18 F-GE180 were used with PET, increased TSPO expression was observed in the brains of these mice, compared with controls, and this expression was shown to correlate with expression on ex vivo autoradiography and immunohistochemistry studies (13). Importantly, after treatment with immunosuppressant drugs, radiotracer uptake was greatly reduced, indicating the future use of TSPO PET as a noninvasive biomarker for evaluating and monitoring the effect of multiple sclerosis therapies on disease activity (13,14). Clinical studies on patients with multiple sclerosis have shown increased radiotracer uptake in lesional and perilesional white matter compared with nonlesional white matter using 18 F-PBR111 and 11 C-PBR28 but not 18 F-FEDAA1106 (15)(16)(17), with radiotracer uptake shown to correlate positively with disease duration or severity, indicating potential utility for TSPO PET in monitoring disease activity.…”