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Development of triazole-based positron emission tomography ligands targeting glutaminyl cyclases (QCs) in the brain.

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Názov: Development of triazole-based positron emission tomography ligands targeting glutaminyl cyclases (QCs) in the brain.
Autori: Li W; Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, China., Zhang X; Department of Nuclear Medicine, Chinese PLA General Hospital, Beijing, 100853, China., Yu L; Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200092, China., Huang D; Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, China., Di X; Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, China., Du X; Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, China., Zhou K; Center for Advanced Materials Research & Faculty of Arts and Sciences, Beijing Normal University at Zhuhai, Zhuhai, 519087, China., Wang P; Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200092, China., Xu S; Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: slxu@simm.ac.cn., Zhang J; Department of Nuclear Medicine, Chinese PLA General Hospital, Beijing, 100853, China. Electronic address: zhangjm301@163.com., Cui M; Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, China; Center for Advanced Materials Research & Faculty of Arts and Sciences, Beijing Normal University at Zhuhai, Zhuhai, 519087, China., Fu H; Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, China. Electronic address: fuhualong@bnu.edu.cn.
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2025 Dec 05; Vol. 299, pp. 118060. Date of Electronic Publication: 2025 Aug 13.
Spôsob vydávania: Journal Article
Jazyk: English
Informácie o časopise: Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 0420510 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1768-3254 (Electronic) Linking ISSN: 02235234 NLM ISO Abbreviation: Eur J Med Chem Subsets: MEDLINE
Imprint Name(s): Publication: Paris : Editions Scientifiques Elsevier
Original Publication: Paris, S.E.C.T. [etc.]
Výrazy zo slovníka MeSH: Aminoacyltransferases*/metabolism , Aminoacyltransferases*/antagonists & inhibitors , Brain*/diagnostic imaging , Brain*/metabolism , Positron-Emission Tomography* , Radiopharmaceuticals*/chemistry , Radiopharmaceuticals*/chemical synthesis , Triazoles*/chemistry , Triazoles*/pharmacology , Triazoles*/chemical synthesis , Triazoles*/metabolism, Animals ; Humans ; Male ; Mice ; Rats ; Alzheimer Disease/diagnostic imaging ; Alzheimer Disease/metabolism ; Dose-Response Relationship, Drug ; Fluorine Radioisotopes ; Ligands ; Mice, Transgenic ; Molecular Structure ; Structure-Activity Relationship ; Tissue Distribution ; Pharmacokinetics
Abstrakt: Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Glutaminyl cyclases (QCs), including secreted sQC and Golgi-resident gQC, catalyze pyroglutamate formation and play a crucial role in Alzheimer's disease (AD). Here, we present the development of two triazole-cored QC-targeting PET ligands, [ 18 F]SEN177 ([ 18 F]8) and [ 18 F]QP5020 ([ 18 F]9). Compound 9 displayed superior binding potency toward both sQC and gQC with IC 50 values of 30.6 and 9.2 nM, respectively, outperforming 8 (sQC IC 50  = 231.6 nM, gQC IC 50  = 67.1 nM). In vitro autoradiography studies in rat brain sections revealed specific binding of both radioligands to QCs with different regional distributions. Notably, [ 18 F]9 demonstrated increased binding in cortical regions of a transgenic AD mouse, which correlated with Aβ plaque density, suggesting its utility in detecting QCs alteration in vitro. However, both ligands showed limited brain uptake (<0.2 % ID/g at 2 min post-injection) in murine biodistribution studies. PET imaging with [ 18 F]8 in transgenic mice demonstrated low brain uptake, but pretreatment with unlabeled 9 reduced brain radioactivity by 26.2 %, indicating specific binding to QCs in vivo. These findings provide a foundation for refining triazole-cored QCs inhibitors to develop new PET ligands with enhanced brain pharmacokinetics and isoform selectivity.
(Copyright © 2025 Elsevier Masson SAS. All rights reserved.)
Contributed Indexing: Keywords: Alzheimer's disease; Brain kinetics; Glutaminyl cyclases; In vitro autoradiography; Triazole-cored inhibitors
Substance Nomenclature: EC 2.3.2.- (Aminoacyltransferases)
0 (Fluorine Radioisotopes)
EC 2.3.2.5 (glutaminyl-peptide cyclotransferase)
0 (Ligands)
0 (Radiopharmaceuticals)
0 (Triazoles)
Entry Date(s): Date Created: 20250827 Date Completed: 20250908 Latest Revision: 20250909
Update Code: 20250910
DOI: 10.1016/j.ejmech.2025.118060
PMID: 40865141
Databáza: MEDLINE
Popis
Abstrakt:Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br />Glutaminyl cyclases (QCs), including secreted sQC and Golgi-resident gQC, catalyze pyroglutamate formation and play a crucial role in Alzheimer's disease (AD). Here, we present the development of two triazole-cored QC-targeting PET ligands, [ <sup>18</sup> F]SEN177 ([ <sup>18</sup> F]8) and [ <sup>18</sup> F]QP5020 ([ <sup>18</sup> F]9). Compound 9 displayed superior binding potency toward both sQC and gQC with IC <subscript>50</subscript> values of 30.6 and 9.2 nM, respectively, outperforming 8 (sQC IC <subscript>50</subscript>  = 231.6 nM, gQC IC <subscript>50</subscript>  = 67.1 nM). In vitro autoradiography studies in rat brain sections revealed specific binding of both radioligands to QCs with different regional distributions. Notably, [ <sup>18</sup> F]9 demonstrated increased binding in cortical regions of a transgenic AD mouse, which correlated with Aβ plaque density, suggesting its utility in detecting QCs alteration in vitro. However, both ligands showed limited brain uptake (&lt;0.2 % ID/g at 2 min post-injection) in murine biodistribution studies. PET imaging with [ <sup>18</sup> F]8 in transgenic mice demonstrated low brain uptake, but pretreatment with unlabeled 9 reduced brain radioactivity by 26.2 %, indicating specific binding to QCs in vivo. These findings provide a foundation for refining triazole-cored QCs inhibitors to develop new PET ligands with enhanced brain pharmacokinetics and isoform selectivity.<br /> (Copyright © 2025 Elsevier Masson SAS. All rights reserved.)
ISSN:1768-3254
DOI:10.1016/j.ejmech.2025.118060