Dataset Information

Evaluating infusion methods and simplified quantification of synaptic density in vivo with [¹¹C]UCB-J and [¹⁸F]SynVesT-1 PET.

ABSTRACT: For some positron emission tomography studies, radiotracer is administered as bolus plus continuous infusion (B/I) to achieve a state of equilibrium. This approach can reduce scanning time and simplify data analysis; however, the method must be validated and optimized for each tracer. This study aimed to validate a B/I method for in vivo quantification of synaptic density using radiotracers which target the synaptic vesicle glycoprotein 2 A: [¹¹C]UCB-J and [¹⁸F]SynVesT-1. Observed mean standardized uptake values (SUV) in target tissue relative to that in plasma (C_T/C_P) or a reference tissue (SUVR-1) were calculated for 30-minute intervals across 120 or 150-minute dynamic scans and compared against one-tissue compartment (1TC) model estimates of volume of distribution (V_T) and binding potential (BP_ND), respectively. We were unable to reliably achieve a state of equilibrium with [¹¹C]UCB-J, and all 30-minute windows yielded overly large bias and/or variability for C_T/C_P and SUVR-1. With [¹⁸F]SynVesT-1, a 30-minute scan 90-120 minutes post-injection yielded C_T/C_P and SUVR-1 values that estimated their respective kinetic parameter with sufficient accuracy and precision (within 7±6%) . This B/I approach allows a clinically feasible scan at equilibrium with potentially better accuracy than a static scan SUVR following a bolus injection.

SUBMITTER: Asch RH

PROVIDER: S-EPMC10925870 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Evaluating infusion methods and simplified quantification of synaptic density in vivo with [11C]UCB-J and [18F]SynVesT-1 PET.

Asch Ruth H RH Naganawa Mika M Nabulsi Nabeel N Huan Yiyun Y Esterlis Irina I Carson Richard E RE

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20230905 12

For some positron emission tomography studies, radiotracer is administered as bolus plus continuous infusion (B/I) to achieve a state of equilibrium. This approach can reduce scanning time and simplify data analysis; however, the method must be validated and optimized for each tracer. This study aimed to validate a B/I method for in vivo quantification of synaptic density using radiotracers which target the synaptic vesicle glycoprotein 2 A: [11C]UCB-J and [18F]SynVe ...[more]

PMID: 37669455

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Project description:PurposeSynapse 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.ProceduresWe 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.ResultsUsing 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.ConclusionsThis 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.

Project description:The use of synaptic vesicle glycoprotein 2A radiotracers with PET imaging could provide a way to measure synaptic density quantitatively in living humans. 11C-UCB-J ((R)-1-((3-(11C-methyl-11C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one), previously developed and assessed in nonhuman primates and humans, showed excellent kinetic properties as a PET radioligand. However, it is labeled with the short half-life isotope 11C. We developed a new tracer, an 18F-labeled difluoro-analog of UCB-J (18F-SynVesT-1, also known as 18F-SDM-8), which displayed favorable properties in monkeys. The purpose of this first-in-human study was to assess the kinetic and binding properties of 18F-SynVesT-1 and compare with 11C-UCB-J. Methods: Eight healthy volunteers participated in a baseline study of 18F-SynVesT-1. Four of these subjects were also scanned after a blocking dose of the antiepileptic drug levetiracetam (20 mg/kg). Metabolite-corrected arterial input functions were measured. Regional time-activity curves were analyzed using 1-tissue-compartment (1TC) and 2-tissue-compartment (2TC) models and multilinear analysis 1 to compute total distribution volume (V T) and binding potential (BP ND). The centrum semiovale was used as a reference region. The Lassen plot was applied to compute levetiracetam occupancy and nondisplaceable distribution volume. SUV ratio-1 (SUVR-1) over several time windows was compared with BP ND Results: Regional time-activity curves were fitted better with the 2TC model than the 1TC model, but 2TC V T estimates were unstable. The 1TC V T values matched well with those from the 2TC model (excluding the unstable values). Thus, 1TC was judged as the most useful model for quantitative analysis of 18F-SynVesT-1 imaging data. The minimum scan time for stable V T measurement was 60 min. The rank order of V T and BP ND was similar between 18F-SynVesT-1 and 11C-UCB-J. Regional V T was slightly higher for 11C-UCB-J, but BP ND was higher for 18F-SynVesT-1, though these differences were not significant. Levetiracetam reduced the uptake of 18F-SynVesT-1 in all regions and produced occupancy of 85.7%. The SUVR-1 of 18F-SynVesT-1 from 60 to 90 min matched best with 1TC BP ND Conclusion: The novel synaptic vesicle glycoprotein 2A tracer, 18F-SynVesT-1, displays excellent kinetic and in vivo binding properties in humans and holds great potential for the imaging and quantification of synaptic density in neuropsychiatric disorders.

Dataset Information

Evaluating infusion methods and simplified quantification of synaptic density in vivo with [¹¹C]UCB-J and [¹⁸F]SynVesT-1 PET.

Publications

Evaluating infusion methods and simplified quantification of synaptic density <i>in vivo</i> with [<sup>11</sup>C]UCB-J and [<sup>18</sup>F]SynVesT-1 PET.

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Dataset Information

Evaluating infusion methods and simplified quantification of synaptic density in vivo with [11C]UCB-J and [18F]SynVesT-1 PET.

Publications

Evaluating infusion methods and simplified quantification of synaptic density &lt;i&gt;in vivo&lt;/i&gt; with [&lt;sup&gt;11&lt;/sup&gt;C]UCB-J and [&lt;sup&gt;18&lt;/sup&gt;F]SynVesT-1 PET.

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OmicsDI is part of the ELIXIR infrastructure

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Evaluating infusion methods and simplified quantification of synaptic density in vivo with [¹¹C]UCB-J and [¹⁸F]SynVesT-1 PET.

Evaluating infusion methods and simplified quantification of synaptic density <i>in vivo</i> with [<sup>11</sup>C]UCB-J and [<sup>18</sup>F]SynVesT-1 PET.