PT - JOURNAL ARTICLE AU - Hui Liu AU - Yun Zhou AU - Zonghua Luo AU - Jiwei Gu AU - Yanbo Yu AU - Hubert Flores AU - Laura Dugan AU - Joel Perlmutter AU - Zhude Tu TI - <strong>PET imaging studies of brain S1PR1 expression in Parkinson disease</strong> DP - 2019 May 01 TA - Journal of Nuclear Medicine PG - 183--183 VI - 60 IP - supplement 1 4099 - http://jnm.snmjournals.org/content/60/supplement_1/183.short 4100 - http://jnm.snmjournals.org/content/60/supplement_1/183.full SO - J Nucl Med2019 May 01; 60 AB - 183Objectives: Neuroinflammation plays a key role in the pathogenesis and/or progress of various neurodegenerative diseases including Parkinson disease (PD). Recent PET studies using TSPO radioligands provided direct in vivo measure of neuroinflammation in PD patients, and confirmed widespread microglial activation in PD brains [1], but the genotype polymorphism in human confounds TSPO PET measure. New radioligands targeting on different proteins for neuroinflammatory response are urgently needed. Sphingosine-1-phosphate receptor 1 (S1PR1) is a G protein-coupled receptor and is highly expressed in inflammatory cells during neuroinflammation. Our previous studies revealed the S1PR1 specific radiotracer 11C-TZ3321 displayed increased uptake at sites of inflammation in rodent models of multiple sclerosis, neointimal hyperplasia, and vascular inflammation [2-4]. Herein we reported 11C-TZ3321 PET imaging to quantify S1PR1 expression in an MPTP-induced PD model in nonhuman primates (NHPs) to explore the potential application of imaging S1PR1 expression for neuroinflammation in PD and other neurodegenerative diseases. Methods: A male adult macaque fasicularis underwent a series of 2-hour dynamic PET scans before and after MPTP administration using a Focus-220 microPET scanner. 11C-TZ3321, 11C-PBR28 and 11C-DTBZ were synthesized and eight scans were done for this study. Baseline scans were performed prior to the right internal carotid artery injection of MPTP (0.25 mg/kg). Post-MPTP 11C-DTBZ scan were conducted at week 4 to confirm the nigrostriatal injury, since 11C-DTBZ is a widely used marker of nigrostriatal terminal integrity [5]. Post-MPTP PET scans of 11C-TZ3321 and 11C-PBR28 were conducted at week 7-8 to detect potential inflammatory response. In addition, the animal had behavioral training to quantify parkinsonism. A simplified reference tissue model was used to analyze the PET data. The baseline cerebellar tissue activity was used as a reference tissue for analysis of all 11C-TZ3321 and 11C-PBR28 data although cerebellum reference tissue may have limitations. A spatially-constraint linear regression algorithm was used to generate distribution volume ratio (DVR) images [6]. Results: The DVR images generated from PET scans are showed in Figure 1. A marked reduction (~80%) of 11C-DTBZ uptake in the ipsilateral (right) striatum was detected at week 4, corresponding well with the stable contralateral parkinsonism. 11C-TZ3321 significantly increased throughout the whole brain by 7-8 weeks after MPTP. The global DVR values increased by 67.3%, from 1.13 to 1.89. Moreover, the tracer uptake of 11C-TZ3321 in right frontal cortex was 18.5% higher than the contralateral side post-MPTP. For striatal regions, no significant left/right side difference was observed before or after MPTP treatment. The increase of 11C-PBR28 was observed in only occipital and frontal cortex regions post-MPTP (25-30% higher than baseline). Approximately 18% higher right frontal cortical uptake of 11C-PBR28 was also found compared to the contralateral side. Conclusions: Both 11C-TZ3321 and 11C-PBR28 PET revealed increased uptake in NHP brains 7-8 weeks after MPTP treatment. The ipsilateral nigrostriatal injury and contralateral parkinsonism were confirmed by 11C-DTBZ PET measure and behavior changes at week 4 post-MPTP. The correlation of the increase uptake of 11C-TZ3321 or 11C-PBR28 with neuroinflammation induced by MPTP deserves further exploration. Larger sample size and statistical analysis are also warranted to demonstrate the ability of 11C-TZ3321 as a PET radioligand to assess neuroinflammatory response in vivo by quantifying the changes of S1PR1 expression levels. Research support: NS075527, NS103988, NS103957, EB025815. References: 1. Gerhard, Neurobiol Dis, 2006; 2. Liu, Mol Imaging Bio, 2016; 3. Jin, J Nucl Cardiol. 2017; 4. Liu, Mol Imaging, 2017; 5. Gilman, Ann Neurol, 1998; 6. Zhou, Neuroimage 2003. Figure 1 Representative DVR images at baseline and/or post-MPTP.