In vivo Characterization of Four 18 F-Labeled S1PR1 Tracers for Neuroinflammation
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RESEARCH ARTICLE
In vivo Characterization of Four 18F-Labeled S1PR1 Tracers for Neuroinflammation Hui Liu, Zonghua Luo, Jiwei Gu, Hao Jiang, Sumit Joshi, Kooresh I. Shoghi, Yun Zhou, Robert J. Gropler, Tammie L. S. Benzinger, Zhude Tu Department of Radiology, Washington University School of Medicine, 510 S. Kingshighway Blvd., St. Louis, MO, 63110, USA
Abstract Purpose: The sphingosine-1-phosphate receptor 1 (S1PR1) is an important biomarker for imaging inflammation in the central nervous system (CNS). Herein, we report our recent evaluation of four 18F-labeled S1PR1 tracers (18F-TZ43113, 18F-TZ35104, 18F-TZ4877, and 18FTZ4881) in a rat model of multiple sclerosis (MS). Procedures: MicroPET studies of each tracer’s uptake and kinetics were performed in an experimental autoimmune encephalomyelitis (EAE) rat model of MS to quantify upregulated S1PR1 expression in the lumbar spinal cord of EAE rats. Western blot analysis was conducted to confirm the differences in the expression of S1PR1 protein level between EAE and sham rats. Radiometabolite analysis was performed for the most promising candidate in rats. Results: All four S1PR1 tracers detected increased S1PR1 levels in response to neuroinflammation in the lumbar spinal cord of EAE rats, which was supported by western blot results. The ranked order of tracer uptake in rat spinal cord was 18F-TZ4877 9 18F-TZ4881 9 18FTZ35104 9 18F-TZ43113. 18F-TZ4877 had the highest uptake of the four tracers and showed good kinetic modeling fits in rat spinal cord using an image-based method of arterial blood input function. Radiometabolite analysis of 18F-TZ4877 showed good in vivo stability with no major radiometabolite accumulation in the rat brain. Conclusion: Among these four new PET tracers, 18F-TZ4877 showed the most favorable profile for assessing S1PR1 expression in the EAE rat model of MS. Further characterization of these radiotracers in other models of neuroinflammation is warranted to identify a promising 18Flabeled tracer for imaging S1PR1 in vivo. Key words: Sphingosine-1-phosphate receptor 1, PET radioligands, Neuroinflammation, Fluorine-18
Introduction Sphingosine 1-phosphate (S1P) is a membrane-derived bioactive lysophospholipid which plays critical regulatory roles in inflammatory diseases through binding to its five
Electronic supplementary material The online version of this article (https:// doi.org/10.1007/s11307-020-01514-8) contains supplementary material, which is available to authorized users. Correspondence to: Zhude Tu; e-mail: [email protected]
S1P receptor subtypes 1–5 (S1PR1-5) [1, 2]. Among the five S1PR subtypes, S1PR1 is the most abundant one; it is highly expressed in inflammatory cells and activated glial cells [3, 4]. Dysregulation of S1PR1 signaling plays a key pathophysiological role in inflammatory diseases of the central nervous system (CNS) [5–7]. The nonselective S1P modulator, fingolimod, is the first approved oral therapeutic drug for treating relapsing MS. It is phosphorylated in vivo where it binds all S1P receptor subtypes excep
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