TY  - JOUR
A1  - Volpato, Daniela
A1  - Holzgrabe, Ulrike
T1  - Designing Hybrids Targeting the Cholinergic System by Modulating the Muscarinic and Nicotinic Receptors: A Concept to Treat Alzheimer’s Disease
JF  - Molecules
N2  - The cholinergic hypothesis has been reported first being the cause of memory dysfunction in the Alzheimer’s disease. Researchers around the globe have focused their attention on understanding the mechanisms of how this complicated system contributes to processes such as learning, memory, disorientation, linguistic problems, and behavioral issues in the indicated chronic neurodegenerative disease. The present review reports recent updates in hybrid molecule design as a strategy for selectively addressing multiple target proteins involved in Alzheimer’s disease (AD) and the study of their therapeutic relevance. The rationale and the design of the bifunctional compounds will be discussed in order to understand their potential as tools to investigate the role of the cholinergic system in AD.
KW  - AChE inhibitor
KW  - Alzheimer’s disease
KW  - bitopic ligand
KW  - cholinergic system
KW  - hybrid molecules
KW  - muscarinic receptors
KW  - nicotinic receptors
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197555
SN  - 1420-3049
VL  - 23
IS  - 12
ER  - 
TY  - JOUR
A1  - Gentzsch, Christian
A1  - Chen, Xinyu
A1  - Spatz, Philipp
A1  - Košak, Urban
A1  - Knez, Damijan
A1  - Nose, Naoko
A1  - Gobec, Stanislav
A1  - Higuchi, Takahiro
A1  - Decker, Michael
T1  - Synthesis and Initial Characterization of a Reversible, Selective \(^{18}\)F-Labeled Radiotracer for Human Butyrylcholinesterase
JF  - Molecular Imaging and Biology
N2  - Purpose
A neuropathological hallmark of Alzheimer's disease (AD) is the presence of amyloid-β (Aβ) plaques in the brain, which are observed in a significant number of cognitively normal, older adults as well. In AD, butyrylcholinesterase (BChE) becomes associated with A\(_{β}\) aggregates, making it a promising target for imaging probes to support diagnosis of AD. In this study, we present the synthesis, radiochemistry, in vitro and preliminary ex and in vivo investigations of a selective, reversible BChE inhibitor as PET-tracer for evaluation as an AD diagnostic.
Procedures
Radiolabeling of the inhibitor was achieved by fluorination of a respective tosylated precursor using K[\(^{18}\)F]. IC\(_{50}\) values of the fluorinated compound were obtained in a colorimetric assay using recombinant, human (h) BChE. Dissociation constants were determined by measuring hBChE activity in the presence of different concentrations of inhibitor.
Results
Radiofluorination of the tosylate precursor gave the desired radiotracer in an average radiochemical yield of 20 ± 3 %. Identity and > 95.5 % radiochemical purity were confirmed by HPLC and TLC autoradiography. The inhibitory potency determined in Ellman's assay gave an IC\(_{50}\) value of 118.3 ± 19.6 nM. Dissociation constants measured in kinetic experiments revealed lower affinity of the inhibitor for binding to the acylated enzyme (K2 = 68.0 nM) in comparison to the free enzyme (K\(_{1}\) = 32.9 nM).
Conclusions
The reversibly acting, selective radiotracer is synthetically easily accessible and retains promising activity and binding potential on hBChE. Radiosynthesis with \(^{18}\)F labeling of tosylates was feasible in a reasonable time frame and good radiochemical yield.
KW  - Alzheimer’s disease
KW  - amyloid-β (Aβ)
KW  - butyrylcholinesterase
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-269870
SN  - 1860-2002
VL  - 23
IS  - 4
ER  -