@article{GentzschChenSpatzetal.2021,
  author    = {Gentzsch, Christian and Chen, Xinyu and Spatz, Philipp and Košak, Urban and Knez, Damijan and Nose, Naoko and Gobec, Stanislav and Higuchi, Takahiro and Decker, Michael},
  title     = {Synthesis and Initial Characterization of a Reversible, Selective \(^{18}\)F-Labeled Radiotracer for Human Butyrylcholinesterase},
  series = {Molecular Imaging and Biology},
  volume    = {23},
  journal   = {Molecular Imaging and Biology},
  number    = {4},
  issn      = {1860-2002},
  doi       = {10.1007/s11307-021-01584-2},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-269870},
  pages     = {505-515},
  year      = {2021},
  abstract  = {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.},
  language  = {en}
}
@article{ScheinerSinkSpatzetal.2021,
  author    = {Scheiner, Matthias and Sink, Alexandra and Spatz, Philipp and Endres, Erik and Decker, Michael},
  title     = {Photopharmacology on Acetylcholinesterase: Novel Photoswitchable Inhibitors with Improved Pharmacological Profiles},
  series = {ChemPhotoChem},
  volume    = {5},
  journal   = {ChemPhotoChem},
  number    = {2},
  doi       = {10.1002/cptc.202000119},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-218445},
  pages     = {149 -- 159},
  year      = {2021},
  abstract  = {Considerable effort has previously been invested in a light-controlled inhibition of the enzyme acetylcholinesterase (AChE). We found that a novel azobenzene-based bistacrine AChE inhibitor switched faster than the known dithienylethene based bistacrine and inverted the photo-controlled interactions of the photoisomers compared to its dithienylethene congener. Furthermore, we have optimized a previously described light-controlled tacrine-based AChE inhibitor. Isomerization upon irradiation with UV light of the novel inhibitor was observed in aqueous medium and showed no fatigue over several cycles. The cis-enriched form showed an 8.4-fold higher inhibition of hAChE compared with its trans-enriched form and was about 30-fold more active than the reference compound tacrine with a single-digit nanomolar inhibition. We went beyond proof-of-concept to discover photoswitchable AChE inhibitors with pharmacologically desirable nanomolar inhibition, "cis-on" effect, and pronounces differences between the photoisomers.},
  language  = {en}
}