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Development of [¹⁸F]Maleimide-Based Glycogen Synthase Kinase-3β Ligands for Positron Emission Tomography Imaging.

ABSTRACT: Dysregulation of glycogen synthase kinase-3β (GSK-3β) is implicated in the pathogenesis of neurodegenerative and psychiatric disorders. Thus, development of GSK-3β radiotracers for positron emission tomography (PET) imaging is of paramount importance, because such a noninvasive imaging technique would allow better understanding of the link between the activity of GSK-3β and central nervous system disorders in living organisms, and it would enable early detection of the enzyme's aberrant activity. Herein, we report the synthesis and biological evaluation of a series of fluorine-substituted maleimide derivatives that are high-affinity GSK-3β inhibitors. Radiosynthesis of a potential GSK-3β tracer [¹⁸F]10a is achieved. Preliminary in vivo PET imaging studies in rodents show moderate brain uptake, although no saturable binding was observed in the brain. Further refinement of the lead scaffold to develop potent [¹⁸F]-labeled GSK-3 radiotracers for PET imaging of the central nervous system is warranted.

SUBMITTER: Hu K

PROVIDER: S-EPMC5346984 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Development of [<sup>18</sup>F]Maleimide-Based Glycogen Synthase Kinase-3β Ligands for Positron Emission Tomography Imaging.

Hu Kongzhen K Patnaik Debasis D Collier Thomas Lee TL Lee Katarzyna N KN Gao Han H Swoyer Matthew R MR Rotstein Benjamin H BH Krishnan Hema S HS Liang Steven H SH Wang Jin J Yan Zhiqiang Z Hooker Jacob M JM Vasdev Neil N Haggarty Stephen J SJ Ngai Ming-Yu MY

ACS medicinal chemistry letters 20170202 3

Dysregulation of glycogen synthase kinase-3β (GSK-3β) is implicated in the pathogenesis of neurodegenerative and psychiatric disorders. Thus, development of GSK-3β radiotracers for positron emission tomography (PET) imaging is of paramount importance, because such a noninvasive imaging technique would allow better understanding of the link between the activity of GSK-3β and central nervous system disorders in living organisms, and it would enable early detection of the enzyme's aberrant activity ...[more]

PMID: 28337318

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Project description:IntroductionConventional methods of imaging brain tumors fail to assess metabolically active tumor regions, which limits their capabilities for tumor detection, localization, and response assessment. Positron emission tomography (PET) with 18F-fluciclovine (fluciclovine) provides regional assessment of amino acid uptake in tumors that could overcome some of the limitations of conventional imaging. However, the biological basis of enhanced fluciclovine uptake is insufficiently characterized in brain tumors, which confounds clinical interpretation and application. This study sought to address this gap by correlating multiple biologic quantities with fluciclovine PET uptake across a range of human glioblastoma xenograft models.MethodsThirty-one rats underwent orthotopic implantations with one of five different human glioblastoma cell lines. After tumors were established, fluciclovine PET and magnetic resonance imaging (MRI) scans were performed. The fluciclovine tumor-to-normal-brain (TN) uptake ratio was used to quantify fluciclovine uptake. MRI scans were used to assess tumor volume and gadolinium enhancement status. Histologic assessments quantified tumor cell proliferation, tumor cell density, and tumor cell amino acid transporters (LAT1 and ASCT2). Multivariate linear regression models related fluciclovine uptake with the other measured quantities.ResultsWithin the multivariate regression, the fluciclovine TN uptake ratio (measured 15 to 35 minutes after fluciclovine injection) was most strongly associated with tumor ASCT2 levels (β=0.64; P=0.001). The fluciclovine TN uptake ratio was also significantly associated with tumor volume (β=0.45; P=0.001) and tumor enhancement status (β=0.40; P=0.01). Tumor cell proliferation, tumor cell density, and LAT1 levels were not significantly associated with fluciclovine uptake in any of the multivariate models. In general, both enhancing and non-enhancing tumors could be visualized on fluciclovine PET images, with the median TN uptake ratio across the five tumor lines being 2.4 (range 1.1 to 8.9).ConclusionsIncreased fluciclovine PET uptake was associated with increased levels of the amino acid transporter ASCT2, suggesting fluciclovine PET may be useful for assessing brain tumor amino acid metabolism. Fluciclovine PET uptake was elevated in both enhancing and non-enhancing tumors but the degree of uptake was greater in larger tumors and tumors with enhancement, indicating these variables could confound fluciclovine metabolic measurements if not accounted for.

Project description:BackgroundTo investigate the current knowledge and attitudes towards [18F]fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) among non-radiologist medical staff in China.MethodsThis cross-sectional study was conducted between November 18, 2022, and December 6, 2022, at the First Affiliated Hospital (Southwest Hospital) of the Army Medical University (Third Military Medical University) among non-radiologist staff (medical, nursing, and others). The questionnaire survey (Cronbach's α = 0.887) included 28 items: 10 on demographics, 11 on knowledge (maximum score of 22), and seven on attitudes (maximum score of 35). The factors influencing knowledge and attitudes were identified using multivariable logistic regression analysis.ResultsThis study analyzed 631 valid questionnaires. The mean knowledge score was 7.16 ± 6.48 (32.55%), indicating poor knowledge. The mean attitude score was 22.859 ± 2.36 (65.29%), indicating positive attitudes. Nursing (OR = 0.301, 95%CI: 0.159-0.571), other occupations (OR = 0.426, 95%CI: 0.200-0.905), departments with high volumes of PET/CT prescriptions (OR = 0.419, 95%CI: 0.269-0.652), radioprotection training (OR = 2.520, 95%CI: 1.576-4.030), underwent (or a relative) a PET/CT (OR = 1.713, 95%CI: 1.063-2.761), and contact with 1-10 (OR = 2.429, 95%CI: 1.627-3.627) or > 10 (OR = 3.575, 95%CI: 1.762-7.252) patients per month were independently associated with higher knowledge scores. Only the knowledge scores (OR = 1.063, 95%CI: 1.032-1.094) were independently associated with higher attitude scores.ConclusionNon-radiologist medical staff members in China have poor knowledge but positive attitudes toward PET/CT. This study identified knowledge areas worth improving in future training interventions. Radioprotection training appears particularly useful in improving the knowledge of PET/CT, which should translate into more favorable attitudes.Trial registrationNot applicable.

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Development of [¹⁸F]Maleimide-Based Glycogen Synthase Kinase-3β Ligands for Positron Emission Tomography Imaging.

Publications

Development of [<sup>18</sup>F]Maleimide-Based Glycogen Synthase Kinase-3β Ligands for Positron Emission Tomography Imaging.

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Development of [18F]Maleimide-Based Glycogen Synthase Kinase-3β Ligands for Positron Emission Tomography Imaging.

Publications

Development of [<sup>18</sup>F]Maleimide-Based Glycogen Synthase Kinase-3β Ligands for Positron Emission Tomography Imaging.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Development of [¹⁸F]Maleimide-Based Glycogen Synthase Kinase-3β Ligands for Positron Emission Tomography Imaging.