Thursday, April 3, 2025
4/3/2025
Investigate neuroinflammation in the brain of PD using S1P1 radioligands - A. Project Summary This goal of this project is to investigate neuroinflammation in Parkinson disease (PD) using positron emission tomography (PET) with a sphingosine 1-phosphate receptor 1 (S1PR1) specific radiotracer [11C]CS1P1. Neuroinflammation is a key element in the pathogenesis and progression of PD, thus quantitative measures of neuroinflammation provide key evidence for pathogenesis, identification of therapeutic targets and quantification of target engagement in PD. S1PR1 is the most abundant receptor in the S1P receptor 5 member family. In the central nervous system (CNS), S1PR1 is expressed in neurons and glial cells, including astrocytes, microglia, and oligodendrocytes. Dysregulation of S1PR1 signaling plays a critical pathophysiological role in inflammatory diseases in the CNS. We reported that [11C]CS1P1, previously called [11C]TZ3321, specifically targets S1PR1 receptors with increased uptake at sites of inflammation in three animal models of inflammatory disease. We had received FDA approval of [11C]CS1P1 for human use (IND#:146548) and completed whole body dosimetry PET scans for 5 male and 5 female normal healthy participants, and brain PET scans in 10 MS patients; our results demonstrated that [11C]CS1P1 PET is able to detect neuroinflammation in MS. Macaques with a unilateral nigrostriatal brain injury, caused by intracarotid (ic) infusion of the neurotoxin MPTP, were used to directly compare brain uptake of [11C]CS1P1 with the widely used neuroinflammation tracer [11C]PBR28. Four macaques were scanned with each tracer under baseline conditions and following unilateral injury. Surprisingly, 6-8 weeks after MPTP-induced injury, both radiotracers had increased cortical brain uptake demonstrating a robust neuroinflammatory response that highly correlated with each other (r2 = 0.7-0.8). However, when compared with baseline imaging, the post-MPTP increase in ipsilateral frontal cortex compared to contralateral cortex for [11C]CS1P1 (89%) significantly exceeded that for [11C]PBR28 (12%). Therefore, we propose to validate the PET measures and systematically evaluate the ability of [11C]CS1P1 to quantitatively measure neuroinflammation after MPTP-induced injury in macaques. We hypothesize that PET with the S1PR1 radiotracer [11C]CS1P1 can quantify neuroinflammation in humans with PD. To test our hypothesis, we propose two specific aims. Aim-1# is to investigate regional S1PR1 expression in the brain of MPTP-treated NHPs by longitudinal PET imaging and terminal post-PET autoradiography, immunohistochemical (IHC) staining, immunofluorescence (IF) analysis, and ELISA studies of the brain tissues. Aim-2# is to investigate S1PR1 expression in the brains of PD patients and healthy controls through PET imaging as well as in vitro studies of banked postmortem tissue from PD cases and controls, including autoradiography, IHC staining, IF analysis and ELISA studies. We expect to demonstrate that PET with [11C]S1P1 radiotracer can quantify neuroinflammation in PD and other neurodegenerative diseases.
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