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In vivo evaluation of [¹¹C]preladenant positron emission tomography for quantification of adenosine A_2A receptors in the rat brain.

ABSTRACT: [¹¹C]Preladenant was developed as a novel adenosine A_2A receptor positron emission tomography radioligand. The present study aims to evaluate the suitability of [¹¹C]preladenant positron emission tomography for the quantification of striatal A_2A receptor density and the assessment of striatal A_2A receptor occupancy by KW-6002. Sixty- or ninety-minute dynamic positron emission tomography imaging was performed on rats. Tracer kinetics was quantified by the two-tissue compartment model, Logan graphical analysis and several reference tissue-based models. Test-retest reproducibility was assessed by repeated imaging on two consecutive days. Two-tissue compartment model and Logan plot estimated comparable distribution volume ( V_T) values of ?10 in the A_2A receptor-rich striatum and substantially lower values in all extra-striatal regions (?1.5-2.5). The simplified reference tissue model with midbrain or occipital cortex as the reference region proved to be the best non-invasive model for quantification of A_2A receptor, showing a striatal binding potential ( BP_ND) value of ?5.5, and a test-retest variability of ?5.5%. The brain metabolite analysis showed that at 60-min post injection, 17% of the radioactivity in the brain was due to radioactive metabolites. The ED₅₀ of KW-6002 in rat striatum for i.p. injection was 0.044-0.062?mg/kg. The study demonstrates that [¹¹C]preladenant is a suitable tracer to quantify striatal A_2A receptor density and assess A_2A receptor occupancy by A_2A receptor-targeting molecules.

SUBMITTER: Zhou X

PROVIDER: S-EPMC5381452 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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In vivo evaluation of [11C]preladenant positron emission tomography for quantification of adenosine A2A receptors in the rat brain.

Zhou Xiaoyun X Khanapur Shivashankar S de Jong Johan R JR Willemsen Antoon Tm AT Dierckx Rudi Ajo RA Elsinga Philip H PH de Vries Erik Fj EF

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20160720 2

[11C]Preladenant was developed as a novel adenosine A2A receptor positron emission tomography radioligand. The present study aims to evaluate the suitability of [11C]preladenant positron emission tomography for the quantification of striatal A2A receptor density and the assessment of striatal A2A receptor occupancy by KW-6002. Sixty- or ninety-minute dynamic positron emission tomography imaging was performed on rats. Tracer kinetics was quan ...[more]

PMID: 26917190

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Project description:ObjectiveSynaptic loss is an early feature of neurodegenerative disease models, and is severe in post mortem clinical studies, including frontotemporal dementia. Positron emission tomography (PET) with radiotracers that bind to synaptic vesicle glycoprotein 2A enables quantification of synaptic density in vivo. This study used [11 C]UCB-J PET in participants with behavioral variant frontotemporal dementia (bvFTD), testing the hypothesis that synaptic loss is severe and related to clinical severity.MethodsEleven participants with clinically probable bvFTD and 25 age- and sex-matched healthy controls were included. Participants underwent dynamic [11 C]UCB-J PET, structural magnetic resonance imaging, and a neuropsychological battery, including the revised Addenbrooke Cognitive Examination, and INECO frontal screening. General linear models compared [11 C]UCB-J binding potential maps and gray matter volume between groups, and assessed associations between synaptic density and clinical severity in patients. Analyses were also performed using partial volume corrected [11 C]UCB-J binding potential from regions of interest (ROIs).ResultsPatients with bvFTD showed severe synaptic loss compared to controls. [11 C]UCB-J binding was reduced bilaterally in medial and dorsolateral frontal regions, inferior frontal gyri, anterior and posterior cingulate gyrus, insular cortex, and medial temporal lobe. Synaptic loss in the frontal and cingulate regions correlated significantly with cognitive impairments. Synaptic loss was more severe than atrophy. Results from ROI-based analyses mirrored the voxelwise results.InterpretationIn accordance with preclinical models, and human postmortem evidence, there is widespread frontotemporal loss of synapses in symptomatic bvFTD, in proportion to severity. [11 C]UCB-J PET could support translational studies and experimental medicine strategies for new disease-modifying treatments for neurodegeneration. ANN NEUROL 2023;93:142-154.

Dataset Information

In vivo evaluation of [¹¹C]preladenant positron emission tomography for quantification of adenosine A_2A receptors in the rat brain.

Publications

In vivo evaluation of [<sup>11</sup>C]preladenant positron emission tomography for quantification of adenosine A<sub>2A</sub> receptors in the rat brain.

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