In vivo Characterization of Four 18F-Labeled S1PR1 Tracers for Neuroinflammation

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 18 F-labeled S1PR1 tracers ( 18 F-TZ43113, 18 F-TZ35104, 18 F-TZ4877, and 18 F-TZ4881) in a rat model of multiple sclerosis (MS).Procedures: MicroPET studies of each tracer's uptake and kinetics were performed in the 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 in 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 18 F-TZ4877> 18 F-TZ4881> 18 F-TZ35104> 18 F-TZ43113. 18 F-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 18 F-TZ4877 showed good in vivo stability with no major radiometabolite accumulation in the brain. Conclusion:Among these four new PET tracers, 18 F-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 18 F-labeled tracer for imaging S1PR1 in vivo.

Does Siponimod Exert Direct Effects in the Central Nervous System?

“…Beyond, it has been shown that S1Pr expression levels dynamically change during the formation of inflammatory lesion in MS, such as increased S1Pr1 and S1Pr3 expression levels on reactive astrocytes in active and chronic inactive MS lesions [104], indicating that astrocytes may act as target of fingolimod and siponimod within the CNS. Induced S1Pr expression levels have as well been reported in the EAE model [105][106][107]. Interestingly, it has been suggested that overexpression of the S1Pr1 on reactive astrocytes drives the neuropathology of the MS rebound after fingolimod discontinuation [108].…”

“…Cells 2020, 9, x FOR PEER REVIEW 7 of 17 siponimod within the CNS. Induced S1Pr expression levels have as well been reported in the EAE model [105][106][107]. Interestingly, it has been suggested that overexpression of the S1Pr1 on reactive astrocytes drives the neuropathology of the MS rebound after fingolimod discontinuation [108].…”

Differential sphingosine-1-phosphate receptor-1 protein expression in the dorsolateral prefrontal cortex between schizophrenia Type 1 and Type 2

“…These results have important implications for the future schizophrenia subtype-based studies with in vivo PET S1PR1. The S1PR1 has recently emerged as a promising radiotracer for in vivo PET imaging (Liu et al, 2017; Liu et al, 2016; Liu et al, 2020; Luo et al, 2019). The S1PR1 protein upregulation only in Type 2 demonstrated in this study was in line with previous reports on the S1PR1 mRNA upregulation only in Type 2 schizophrenia patients (Bowen et al, 2019).…”

“…A serious limitation of mRNA expression studies like that of Bowen et al (Bowen et al, 2019) is that they require brain tissue which is generally not available except at autopsy. Fortunately PET ligands for one of the genes differentially expressed in the Type 2 schizophrenic brains, sphingosine-1-phosphate receptor-1 (S1PR1) have been developed in the Mallinckrodt Institute of Radiology, Washington University in St. Louis (Jin et al, 2017; Liu et al, 2017; Liu et al, 2016; Liu et al, 2020; Luo et al, 2019). The present study examines the differential expression of S1PR1 in the DLPFC of Type 1 and Type 2 schizophrenic patients at the protein level as a preliminary step towards the use of PET to distinguish Type 1 from Type 2 schizophrenia during life.…”

“…S1PR1 radioligand has gained significant interest for in vivo targeted imaging of inflammation in brain diseases, with the recent FDA approval of the first orally administered S1PR1 receptor-targeted drug, FTY720 (Fingolimod) for multiple sclerosis (Marciniak et al, 2020). PET S1PR1 has recently gone into living humans successfully at Washington University in St. Louis (Liu et al, 2017; Liu et al, 2016; Liu et al, 2020; Luo et al, 2019). We have completed more than 7 PET S1PR1 studies in normal humans safely (unpublished data).…”