Summary: Researchers report preclinical PET imaging can provide a visual map of inflammatory disease and may be used to investigate novel therapies.
Source: Society of Nuclear Medicine.
Preclinical PET imaging provides a visual map of inflammatory disease and could be used to investigate novel therapies.
The triggers of autoimmune inflammation in multiple sclerosis (MS) have eluded scientists for many years, but molecular imaging is bringing researchers closer to identifying them, while providing a means of evaluating next-generation therapies for MS, say researchers introducing a study at the 2016 Annual Meeting of the Society of Nuclear Medicine and Molecular Imaging (SNMMI).
More than 2.3 million people are affected by MS worldwide, according to estimates from the National Multiple Sclerosis Society. MS is marked by inflammation and the systematic destruction of neuronal fibers, specifically myelin, in the nervous system. Myelin is the fatty layer that both protects the fibers and increases the speed of signaling along the axon of nerve cells. Similar inflammatory processes are typical in the pathology of other neurodegenerative diseases such as Parkinson’s and Alzheimer’s, gastrointestinal diseases like Crohn’s and ulcerative colitis, and the vascular inflammation that leads to atherosclerosis.
“Inflammation is the body’s physiological defense to harmful stimuli and it plays a critical role in the immune response to injury and infection,” said senior investigator, Zhude Tu, PhD, professor of PET radiochemistry at Washington University School of Medicine in St. Louis, Mo. “However, despite the benefits of acute inflammation in promoting healing, these same processes are associated with numerous pathological conditions when chronic inflammation is left unchecked.”
This study furthers a growing body of research pointing to a process called sphingolipid signaling as a primary mechanism in inflammatory disease processes. The FDA approval in 2010 of fingolimod for relapsing MS further supports the hypotheses that the sphingosine-1-phosphate receptor 1 (S1P1) is an ideal biomarker for imaging and new therapies. Fingolimod works by turning down the autoimmune response via immune cell S1P1.
First author of the study Adam J. Rosenberg, PhD, and his colleagues produced a library of S1P1-targeted small molecules and radiolabeled them with fluorine-18. These radiotracers bind directly to S1P1 receptors and can be imaged with preclinical positron emission tomography (PET), through noninvasive methodology to investigate the physiological functions of S1P1 receptors in animal models as a precursor for human studies. In this case, researchers imaged S1P1 in rodent models of inflammatory disease and healthy controls. They found that the PET imaging agents not only were able to detect an increase in S1P1 expression in animals with an inflammatory response when compared to healthy controls, but that the compounds also crossed the blood brain barrier in healthy animals, a significant limiting factor in the development of central nervous system drugs.
“These compounds represent promising PET tracers for imaging MS and other inflammatory diseases by quantitative assessment of S1P1 expression in the body,” said Tu.
About this neuroscience research article
Source: Laurie Callahan – Society of Nuclear Medicine Image Source: This NeuroscienceNews.com image is credited to Mallinckrodt Institute of Radiology at the Washington University School of Medicine, St. Louis, Mo. Original Research:Abstract for “Development and in vivo evaluation of three F-18 labeled S1P1 ligands as PET tracers for MS” by Adam Rosenberg, Hui Liu1, Xuyi Yue, Hongjun Jin and Zhude Tu in Journal of Nuclear Medicine. Published online May 1 2016 doi:not available
The study “Development and in vivo evaluation of three F-18 labeled S1P1 ligands as PET tracers for MS,” will be presented at the SNMMI 63rd Annual Meeting in San Diego between June 11 – 15.
Cite This NeuroscienceNews.com Article
[cbtabs][cbtab title=”MLA”]Society of Nuclear Medicine. “Detecting Neuroinflammation in Multiple Sclerosis.” NeuroscienceNews. NeuroscienceNews, 13 June 2016. <https://neurosciencenews.com/neuroinflammation-ms-pet-4448/>.[/cbtab][cbtab title=”APA”]Society of Nuclear Medicine. (2016, June 13). Detecting Neuroinflammation in Multiple Sclerosis. NeuroscienceNews. Retrieved June 13, 2016 from https://neurosciencenews.com/neuroinflammation-ms-pet-4448/[/cbtab][cbtab title=”Chicago”]Society of Nuclear Medicine. “Detecting Neuroinflammation in Multiple Sclerosis.” https://neurosciencenews.com/neuroinflammation-ms-pet-4448/ (accessed June 13, 2016).[/cbtab][/cbtabs]
Development and in vivo evaluation of three F-18 labeled S1P1 ligands as PET tracers for MS
Objectives Many neurological diseases including multiple sclerosis (MS) possess a neuroinflammatory component. Sphingosine 1-phosphate receptor 1 (S1P1) is highly expressed under these neuroinflammatory conditions, and particularly in MS lesions. Currently the first-line treatment for relapse-remitting MS is FTY-720, which acts through the S1P1 receptor. Here, we explore our second-generation S1P1 specific F-18 labeled tracers for imaging in vivo in control and inflammatory animal disease models.
Methods A library of fluorine-containing S1P1 specific compounds were prepared and screened in vitro. The corresponding tosylate precursors for three ligands having high potency and selectivity for S1P1 were synthesized, and radiolabeled with F-18 by nucleophilic displacement using MeCN as the solvent and K2CO3 as a base; followed by removal of protecting groups. These radiotracers were then explored in autoradiography, biodistribution, and PET imaging studies in rodent models of MS and normal non-human primates.
Results Seventeen of the library ligands possessed a binding affinity < 50 nM for S1P1, and showed a > 1000 nM affinity for S1P2/3. Three of the most promising candidates (IC50 S1P1 < 10 nM) were labeled with F-18. [18F]TZ35110 (IC50 S1P1 = 2.6 nM), [18F]TZ43113 (IC50 S1P1 = 9.8 nM) and [18F]TZ35104 (IC50 S1P1 = 6.7 nM) were prepared in good to excellent yield and high specific activity. Rodent biodistribution showed acceptable brain uptake with peak uptake (0.7% ID/g) occurring 1h post-injection. MicroPET studies of [18F]TZ43113 utilizing the experimental autoimmune encephalomyelitis (EAE) model of MS in female Lewis rats showed a 31% increased uptake in the lumbar spinal cord of EAE vs. sham, which was confirmed by post-PET immunohistochemical staining. Non-human primate imaging of [18F]TZ35104 show excellent brain uptake and washout. Conclusions A library of fluorine-containing selective S1P1 ligands was designed and synthesized. The leading compounds were successfully radiolabeled and explored in vivo for imaging S1P1. They demonstrated the ability to cross the blood-brain barrier, as well as the ability to detect the increase of S1P1 expression in the EAE model of MS by microPET. These compounds represent promising PET tracers for imaging MS as well as other neuroinflammatory diseases, and represent a step forward for S1P1 imaging.
Research Support: #DESC0008432, NIH/NIMH #MH092797, and NIH/NINDS #NS075527, #NS061025. Research Support: #DESC0008432, NIH/NIMH #MH092797, and NIH/NINDS #NS075527, #NS061025.
“Development and in vivo evaluation of three F-18 labeled S1P1 ligands as PET tracers for MS” by Adam Rosenberg, Hui Liu1, Xuyi Yue, Hongjun Jin and Zhude Tu in Journal of Nuclear Medicine. Published online May 1 2016 doi:not available