دورية أكاديمية
Development of a PET Tracer for OGA with Improved Kinetics in the Living Brain.
| العنوان: | Development of a PET Tracer for OGA with Improved Kinetics in the Living Brain. |
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| المؤلفون: | Cook BE; Biogen, Cambridge, Massachusetts., Nag S; Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.; Stockholm County Council, Stockholm, Sweden; and., Arakawa R; Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.; Stockholm County Council, Stockholm, Sweden; and., Lin EY; Biogen, Cambridge, Massachusetts., Stratman N; Biogen, Cambridge, Massachusetts., Guckian K; Biogen, Cambridge, Massachusetts., Hering H; Biogen, Cambridge, Massachusetts., Lulla M; Biogen, Cambridge, Massachusetts., Choi J; Biogen, Cambridge, Massachusetts., Salinas C; Biogen, Cambridge, Massachusetts., Genung NE; Biogen, Cambridge, Massachusetts., Morén AF; Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.; Stockholm County Council, Stockholm, Sweden; and., Bolin M; Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.; Stockholm County Council, Stockholm, Sweden; and., Boscutti G; Invicro, London, United Kingdom., Plisson C; Invicro, London, United Kingdom., Martarello L; Biogen, Cambridge, Massachusetts., Halldin C; Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.; Stockholm County Council, Stockholm, Sweden; and., Kaliszczak MA; Biogen, Cambridge, Massachusetts; maciej.kaliszczak@biogen.com. |
| المصدر: | Journal of nuclear medicine : official publication, Society of Nuclear Medicine [J Nucl Med] 2023 Oct; Vol. 64 (10), pp. 1588-1593. Date of Electronic Publication: 2023 Jul 06. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Society of Nuclear Medicine Country of Publication: United States NLM ID: 0217410 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1535-5667 (Electronic) Linking ISSN: 01615505 NLM ISO Abbreviation: J Nucl Med Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Reston, VA : Society of Nuclear Medicine Original Publication: [Chicago, Ill.] : S.N. Turiel & Assoc. |
| مواضيع طبية MeSH: | beta-N-Acetylhexosaminidases* , Brain*, Humans ; Rats ; Animals ; Pyrans |
| مستخلص: | O -GlcNAcylation is thought to play a role in the development of tau pathology in Alzheimer's disease because of its ability to modulate tau's aggregation propensity. O -GlcNAcylation is regulated by 2 enzymes: O -GlcNAc transferase and O -GlcNAcase (OGA). Development of a PET tracer would therefore be an essential tool for developing therapeutic small-molecule inhibitors of OGA, enabling clinical testing of target engagement and dose selection. Methods: A collection of small-molecule compounds was screened for inhibitory activity and high-affinity binding to OGA, as well as favorable PET tracer attributes (multidrug resistance protein 1 efflux, central nervous system PET multiparameter optimization, etc.). Two lead compounds with high affinity and selectivity for OGA were selected for further profiling, including OGA binding to tissue homogenate using a radioligand competition binding assay. In vivo pharmacokinetics were established using a microdosing approach with unlabeled compounds in rats. In vivo imaging studies were performed in rodents and nonhuman primates (NHPs) with 11 C-labeled compounds. Results: Two selected candidates, BIO-735 and BIO-578, displayed promising attributes in vitro. After radiolabeling with tritium, [ 3 H]BIO-735 and [ 3 H]BIO-578 binding in rodent brain homogenates demonstrated dissociation constants of 0.6 and 2.3 nM, respectively. Binding was inhibited, concentration-dependently, by homologous compounds and thiamet G, a well-characterized and structurally diverse OGA inhibitor. Imaging studies in rats and NHPs showed both tracers had high uptake in the brain and inhibition of binding to OGA in the presence of a nonradioactive compound. However, only BIO-578 demonstrated reversible binding kinetics within the time frame of a PET study with a 11 C-labeled molecule to enable quantification using kinetic modeling. Specificity of tracer uptake was confirmed with a 10 mg/kg blocking dose of thiamet G. Conclusion: We describe the development and testing of 2 11 C PET tracers targeting the protein OGA. The lead compound BIO-578 demonstrated high affinity and selectivity for OGA in rodent and human postmortem brain tissue, leading to its further testing in NHPs. NHP PET imaging studies showed that the tracer had excellent brain kinetics, with full inhibition of specific binding by thiamet G. These results suggest that the tracer [ 11 C]BIO-578 is well suited for further characterization in humans. (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.) |
| فهرسة مساهمة: | Keywords: Alzheimer; O-GlcNAcase; OGA; PET |
| المشرفين على المادة: | EC 3.2.1.50 (hexosaminidase C) 0 (thiamet G) EC 3.2.1.52 (beta-N-Acetylhexosaminidases) 0 (Pyrans) |
| تواريخ الأحداث: | Date Created: 20231107 Date Completed: 20231108 Latest Revision: 20240228 |
| رمز التحديث: | 20240228 |
| DOI: | 10.2967/jnumed.122.265225 |
| PMID: | 37934021 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1535-5667 |
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| DOI: | 10.2967/jnumed.122.265225 |