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C-11-Labeling of a potent hydroxyethylamine BACE-1 inhibitor and evaluation in vitro and in vivo
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
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2014 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 41, no 6, 536-543 p.Article in journal (Refereed) Published
Abstract [en]

Introduction

The 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.

Methods

11[C]-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.

Results

The 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.

Conclusion

11[C]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.

Place, publisher, year, edition, pages
2014. Vol. 41, no 6, 536-543 p.
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-203010DOI: 10.1016/j.nucmedbio.2014.03.024ISI: 000318694100107OAI: oai:DiVA.org:uu-203010DiVA: diva2:634960
Available from: 2013-07-02 Created: 2013-07-01 Last updated: 2017-12-06Bibliographically approved

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Nordeman, PatrikEstrada, SergioOdell, LukeLarhed, MatsAntoni, Gunnar

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