Pragalath Sadasivam1, Xiaotian T Fang1, Takuya Toyonaga1, Supum Lee1, Yuping Xu1, Ming-Qiang Zheng1, Joshua Spurrier2, Yiyun Huang1, Stephen M Strittmatter2, Richard E Carson1, Zhengxin Cai3. 1. Yale PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA. 2. Program in Cellular Neuroscience, Neurodegeneration, and Repair, Departments of Cell Biology, Neurology and Neuroscience, Yale University School of Medicine, New Haven, CT, USA. 3. Yale PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA. jason.cai@yale.edu.
Abstract
PURPOSE: Synapse loss is a hallmark of Alzheimer's disease (AD) and correlates with cognitive decline. The validation of a noninvasive in vivo imaging approach to quantify synapse would greatly facilitate our understanding of AD pathogenesis and assist drug developments for AD. As animal models of neurodegenerative and neuropsychiatric disorders play a critical role in the drug discovery and development process, a robust, objective, and translational method for quantifying therapeutic drug efficacy in animal models will facilitate the drug development process. In this study, we tested the quantification reliability of the SV2A PET tracer, [18F]SynVesT-1, in a mouse model of AD (APP/PS1) and wild-type controls, and developed a simplified quantification method to facilitate large cohort preclinical imaging studies. PROCEDURES: We generated nondisplaceable binding potential (BPND) and distribution volume ratio (DVR) values using the simplified reference tissue model (SRTM) on the 90-min dynamic PET imaging data, with brain stem and cerebellum as the reference region, respectively. Then, we correlated the standardized uptake value ratio (SUVR)-1 and SUVR averaged from different imaging windows with BPND and DVR, using brain stem and cerebellum as the reference region, respectively. We performed homologous competitive binding assay and autoradiographic saturation binding assay using [18F]SynVesT-1 to calculate the Bmax and Kd. RESULTS: Using brain stem as the reference region, the averaged SUVR-1 from 30 to 60 min postinjection correlated well with the BPND calculated using SRTM. Using cerebellum as the reference region, the averaged SUVR from 30 to 60 min postinjection correlated well with the SRTM DVR. From the homologous competitive binding assay and autoradiographic saturation binding assay, the calculated the Bmax and Kd were 4.5-18 pmol/mg protein and 9.8-19.6 nM, respectively, for rodent brain tissue. CONCLUSIONS: This simplified SUVR method provides reasonable SV2A measures in APP/PS1 mice and their littermate controls. Our data indicate that, in lieu of a full 90-min dynamic scan, a 30-min static PET scan (from 30 to 60 min postinjection) would be sufficient to provide quantification data on SV2A expression, equivalent to the data generated from kinetic modeling. The methods developed here are readily applicable to the evaluation of therapeutic effects of novel drugs in this rodent model using [18F]SynVesT-1 and small animal PET.
PURPOSE: Synapse loss is a hallmark of Alzheimer's disease (AD) and correlates with cognitive decline. The validation of a noninvasive in vivo imaging approach to quantify synapse would greatly facilitate our understanding of AD pathogenesis and assist drug developments for AD. As animal models of neurodegenerative and neuropsychiatric disorders play a critical role in the drug discovery and development process, a robust, objective, and translational method for quantifying therapeutic drug efficacy in animal models will facilitate the drug development process. In this study, we tested the quantification reliability of the SV2A PET tracer, [18F]SynVesT-1, in a mouse model of AD (APP/PS1) and wild-type controls, and developed a simplified quantification method to facilitate large cohort preclinical imaging studies. PROCEDURES: We generated nondisplaceable binding potential (BPND) and distribution volume ratio (DVR) values using the simplified reference tissue model (SRTM) on the 90-min dynamic PET imaging data, with brain stem and cerebellum as the reference region, respectively. Then, we correlated the standardized uptake value ratio (SUVR)-1 and SUVR averaged from different imaging windows with BPND and DVR, using brain stem and cerebellum as the reference region, respectively. We performed homologous competitive binding assay and autoradiographic saturation binding assay using [18F]SynVesT-1 to calculate the Bmax and Kd. RESULTS: Using brain stem as the reference region, the averaged SUVR-1 from 30 to 60 min postinjection correlated well with the BPND calculated using SRTM. Using cerebellum as the reference region, the averaged SUVR from 30 to 60 min postinjection correlated well with the SRTM DVR. From the homologous competitive binding assay and autoradiographic saturation binding assay, the calculated the Bmax and Kd were 4.5-18 pmol/mg protein and 9.8-19.6 nM, respectively, for rodent brain tissue. CONCLUSIONS: This simplified SUVR method provides reasonable SV2A measures in APP/PS1 mice and their littermate controls. Our data indicate that, in lieu of a full 90-min dynamic scan, a 30-min static PET scan (from 30 to 60 min postinjection) would be sufficient to provide quantification data on SV2A expression, equivalent to the data generated from kinetic modeling. The methods developed here are readily applicable to the evaluation of therapeutic effects of novel drugs in this rodent model using [18F]SynVesT-1 and small animal PET.
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