11C-Labeling of a potent hydroxyethylamine BACE-1 inhibitor and evaluation in vitro and in vivo |
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| Institution: | 1. Preclinical PET Platform, Department of Medicinal Chemistry, Uppsala University, SE-751 23 Uppsala, Sweden;2. Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, SE-751 23 Uppsala, Sweden;1. Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea 137-701;2. Department of General Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea 137-701;1. Department of Nuclear Medicine, University of Leipzig, Liebigstrasse 18, D-04103 Leipzig, Germany;2. Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Permoserstrasse 15, D-04318 Leipzig, Germany;3. ABX advanced biochemical compounds GmbH, Heinrich-Glaeser-Strasse 10-14, D-01454 Radeberg, Germany;4. Multimodal Image Processing, Central Institute ZEA-2-Electronic Systems, Forschungszentrum Jülich GmbH, D-52425 Jülich, Germany;5. Department of Psychiatry, University of Leipzig, Semmelweisstrasse 10, D-04103 Leipzig, Germany;6. Integrated Research and Treatment Centre (IFB) Adiposity Diseases, Leipzig University Medical Centre, Leipzig, Germany;1. Department of Nuclear Medicine, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China;2. Department of Nuclear Medicine, The Second People’s Hospital of Wuhu, Wuhu, 241000, China;3. Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China |
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| Abstract: | IntroductionThe enzyme β-secretase 1 (BACE-1) is associated with the catalytic cleavage of amyloid precursor protein (APP) which leads to the production of amyloid-β, an amyloidogenic peptide that forms insoluble fibrils and is linked to neurodegeneration and Alzheimer's disease (AD). A PET-radioligand for the quantification of BACE-1 would be useful for the understanding of AD. In this report, we describe the synthesis and carbon-11 radiolabeling of a potent hydroxyethylamine BACE-1 enzyme inhibitor (BSI-IV) and its evaluation in vitro and in vivo.Methods11C]-N1-((2S,3R)-4-(cyclopropylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-(N-methylmethyl-sulfonamido)-N3-((R)-1-phenylethyl)isophthalamide, a β-secretase inhibitor, denoted here as 11C]BSI-IV was synthesized through a palladium-mediated aminocarbonylation with an aryl halide precursor (I or Br) and 11C]CO. The effect of different palladium/ligand-complexes on radiochemical yield in the carbonylative reaction was investigated. The binding of the labeled compound to BACE-1 enzyme was studied in vitro by frozen section autoradiography from brains of healthy rats. Dynamic small animal PET-CT studies and ex vivo biodistribution were performed in male rats.ResultsThe halide precursors were synthesized in six steps starting from methyl-3-nitrobenzoate with an overall yield of 21–26%. 11C]BSI-IV was obtained in 29 ± 12% decay corrected radiochemical yield (n = 12) with a specific activity of 790 ± 155 GBq/μmol at the end of synthesis with a radiochemical purity of > 99%. The preclinical studies showed that 11C]BSI-IV has a rapid metabolism in rat with excretion to the small intestines.Conclusion11C]BSI-IV was obtained in sufficient amount and purity to enable preclinical investigation. The preclinical studies showed low specific binding in vitro and fast clearance in vivo and a low uptake in the brain. These findings suggests that 11C]BSI-IV has limited use as a PET-ligand for the study of BACE-1 or AD. |
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