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  - 
TY  - JOUR
A1  - Bajda, Marek
A1  - Wieckowska, Anna
A1  - Hebda, Michalina
A1  - Guzior, Natalia
A1  - Sotriffer, Christoph A.
A1  - Malawska, Barbara
T1  - Structure-Based Search for New Inhibitors of Cholinesterases
JF  - International Journal of Molecular Sciences
N2  - Cholinesterases are important biological targets responsible for regulation of cholinergic transmission, and their inhibitors are used for the treatment of Alzheimer’s disease. To design new cholinesterase inhibitors, of different structure-based design strategies was followed, including the modification of compounds from a previously developed library and a fragment-based design approach. This led to the selection of heterodimeric structures as potential inhibitors. Synthesis and biological evaluation of selected candidates confirmed that the designed compounds were acetylcholinesterase inhibitors with \(IC_{50}\) values in the mid-nanomolar to low micromolar range, and some of them were also butyrylcholinesterase inhibitors.
KW  - fragment-based design
KW  - cholinesterases inhibitors
KW  - butyrylcholinesterase
KW  - acetylcholinesterase
KW  - drug design
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129423
VL  - 14
IS  - 3
ER  -