Dataset Information

First demonstration of in vivo mapping for regional brain monoacylglycerol lipase using PET with [11C]SAR127303.

ABSTRACT: Monoacylglycerol lipase (MAGL) is a main regulator of the endocannabinoid system within the central nervous system (CNS). Recently, [11C]SAR127303 was developed as a promising radioligand for MAGL imaging. In this study, we aimed to quantify regional MAGL concentrations in the rat brain using positron emission tomography (PET) with [11C]SAR127303. An irreversible two-tissue compartment model (2-TCMi, k4?=?0) analysis was conducted to estimate quantitative parameters (k3, Ki2-TCMi, and ?k3). These parameters were successfully obtained with high identifiability (<10 %COV) for the following regions ranked in order from highest to lowest: cingulate cortex?>?striatum?>?hippocampus?>?thalamus?>?cerebellum?>?hypothalamus???pons. In vitro autoradiographs using [11C]SAR127303 showed a heterogeneous distribution of radioactivity, as seen in the PET images. The Ki2-TCMi and ?k3 values correlated relatively highly with in vitro binding (r?>?0.4, P?

SUBMITTER: Yamasaki T

PROVIDER: S-EPMC5976552 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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First demonstration of in vivo mapping for regional brain monoacylglycerol lipase using PET with [11C]SAR127303.

Yamasaki Tomoteru T Mori Wakana W Zhang Yiding Y Hatori Akiko A Fujinaga Masayuki M Wakizaka Hidekatsu H Kurihara Yusuke Y Wang Lu L Nengaki Nobuki N Ohya Tomoyuki T Liang Steven H SH Zhang Ming-Rong MR

NeuroImage 20180505

Monoacylglycerol lipase (MAGL) is a main regulator of the endocannabinoid system within the central nervous system (CNS). Recently, [11C]SAR127303 was developed as a promising radioligand for MAGL imaging. In this study, we aimed to quantify regional MAGL concentrations in the rat brain using positron emission tomography (PET) with [11C]SAR127303. An irreversible two-tissue compartment model (2-TCMi, k4 = 0) analysis was conducted to estimate quantitative paramet ...[more]

PMID: 29738910

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Project description:This was a first-in-human study of the PET radiotracer 11C-LSN3172176 for the muscarinic acetylcholine receptor subtype M1. The objectives of the study were to determine the appropriate kinetic model to quantify binding of the tracer to M1 receptors, and the reliability of the chosen quantification method. Methods: Six healthy subjects completed the test-retest protocol, and 5 healthy subjects completed the baseline-scopolamine blocking protocol. Multiple modeling methods were applied to calculate total distribution volume (V T) and nondisplaceable binding potential (BP ND) in various brain regions. The reference region was selected from the blocking study. The occupancy plot was applied to compute receptor occupancy by scopolamine and nondisplaceable distribution volume. Results: Tracer uptake was highest in the striatum, followed by neocortical regions and white matter, and lowest in the cerebellum. Regional time-activity curves were fitted well by all models. The 2-tissue-compartment (2TC) model fits were good, but the 2TC parameters often could not be reliably estimated. Because V T correlated well between the 2TC and 1-tissue-compartment (1TC) models after exclusion of unreliable estimates, the 1TC model was chosen as the most appropriate. The cerebellum showed the lowest V T, consistent with preclinical studies showing little to no specific binding in the region. Further, cerebellar V T did not change between baseline and blocking scans, indicating that the cerebellum is a suitable reference region. The simplified reference tissue model (SRTM) slightly underestimated 1TC BP ND, and the simplified reference tissue model 2 (SRTM2) improved BP ND estimation. An 80-min scan was sufficient to quantify V T and BP ND The test-retest study showed excellent absolute test-retest variability for 1TC V T (≤5%) and BP ND (≤10%). In the baseline and blocking studies, occupancy values were lower in the striatum than in nonstriatal regions, as may be attributed to differences in regional acetylcholine concentrations. Conclusion: The 1TC and SRTM2 models are appropriate for quantitative analysis of 11C-LSN3172176 imaging data. 11C-LSN3172176 displayed excellent test-retest reproducibility and is a highly promising ligand to quantify M1 receptors in the human brain.

Dataset Information

First demonstration of in vivo mapping for regional brain monoacylglycerol lipase using PET with [11C]SAR127303.

Publications

First demonstration of in vivo mapping for regional brain monoacylglycerol lipase using PET with [<sup>11</sup>C]SAR127303.

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